Vorlesung

Accumulation of sensory cells and organs, and hence nervous cells, in the anterior region of the animal (direction of locomotion). This evolutionary trend is called „cephalization“.

• Regulation of vegetative processes (sleep/wake cycles, breathing rhythms, heart rate, hunger/motivation).

• Sensory perception, movements, orientation.

• Emotions (fear, agression, pleasure, ...).

• Cognitive functions (thinking, planning, communication through language).

• Learning and memory formation.

The nervous system determines to a large degree our identity and individuality

• Loss of memory

• Loss of faculty of speech

• Loss of ability to judge

• Changes in personality

• Strong changes in mood

1. Individual parts interact with each other („Wechselwirkung“, interdependence).

2. Emergent properties: Characteristics of the system cannot be explained by the isolated analysis of its individual components.

3. Interactions between components of the systems are local, but their effects are global.

4. Contact with the environment: Information is processed, the effects of the system are exerted onto the external world.

5. Self organization: Formation and maintenace of stabile structures (Self- stabilisation, homeostasis).

6. Information is processed, systems can learn.

Molecular level: Interaction of molecules, e.g., proteins that regulate gene transcription and translation, posttranslational processing such as phosphorylation, enzymatic transmitter synthesis, function of transmitter receptors, regulation of ion channels, ...

Cellular level: Interactions between neurons through their synaptic transactions and between neurons and glia cells.

“Systems” level: Interactions between spatially distributed sensors and effectors that integrate the body’s response to environmental challenge. Sensory systems (hearing, seeing, feeling, tasting, smelling, balancing the body, ...) affect motor systems for trunk, limb, fine motions, vescieral regulation such as body temperature, ...

Behavioral level: Interactions of animals including humans with their environment. Research links populations of neuronal circuits with the expression of learned or innate behavioral actions or responses. This also includes “higher” mental activity, such as absract reasoning, planning or speech (“cognitive neuroscience”).

Nerves were believed to be tubings through which liquids are pumped.

1. The nervous system consists, like all other tissues, of discrete cells (nervous cells, neurons). These are the elemental signal units of nervous systems.

1. Neurons are not continously connected with each other, but discretely separated from each other. They communicate via contact points (synapses).

1. Neurons communicate with each other, and information is propagated in one direction via neurites („functional polarity theory“)..

1. Neurons are not the only cell type of the nervous system! A large variety of different glia cells exist.

2. Neurons do not always communicate through chemical synapses. Sometimes, they are directly connected via “gap junctions” and are electrically coupled.

3. Information can be locally processed, and complex reciprocal synapses that signal in two directions can occur.

• Regulation of vegetative processes (sleep/wake cycles, breathing rhythms, heart rate, hunger/motivation).

• Sensory perception, movements, orientation,

• Emotions (fear, agression, pleasure, ...).

• Cognitive functions (thinking, planning, communication through language).

• Learning and memory formation.

An organized, purposeful structure that consists of interrelated and interdependent elements (components, entities, factors, members, parts etc.). These elements continually influence one another (directly or indirectly) to maintain their activity and the existence of the system, in order to achieve the goal of the system.

System (griechisch σύστημα):

1. Individual parts interact with each other („Wechselwirkung“, interdependence).

2. Emergent properties: Characteristics of the system cannot be explained by the isolated analysis of its individual components.

3. Interactions between components of the systems are local, but their effects are global.

4. Contact with the environment: Information is processed, the effects of the system are exerted onto the external world.

5. Self organization: Formation and maintenace of stabile structures (Self- stabilisation, homeostasis).

6. Information is processed, systems can learn.

The operations of nervous systems are hierarchical. Therefore, one can study nervous systems at various hierarchical levels of organization:

Molecular level: Interaction of molecules, e.g., proteins that regulate gene transcription and translation, posttranslational processing such as phosphorylation, enzymatic transmitter synthesis, function of transmitter receptors, regulation of ion channels, ...

Cellular level: Interactions between neurons through their synaptic transactions and between neurons and glia cells.

“Systems” level: Interactions between spatially distributed sensors and effectors that integrate the body’s response to environmental challenge. Sensory systems (hearing, seeing, feeling, tasting, smelling, balancing the body, ...) affect motir systems for trunk, limb, fine motions, vescieral regulation such as body temperature, ...

Behavioral level: Interactions of animals including humans with their environment. Research links populations of neuronal circuits with the expression of learned or innate behavioral actions or responses. This also includes “higher” mental activity, such as absract reasoning, planning or speech (“cognitive neuroscience”)

Camillo Golgi (1843-1926) found by coincidence a method to stain nervous cells (neurons) with silver nitrate (Golgi staining).

This showed that nervous systems, like all other tissues, also consist of cells that

a) have a cell body (soma, perikaryon)

b) have two different types of processes (neurites), i.e., arborizing dendrites

and wire-like axons.

He still was convinced of the obsolete (wrong!) reticular theory, stating that axons form a continuous network (reticulum).

Ramón y Cajal (1852-1934) used the Golgi staining technique to characterize neurons and their arrangements as circuits.

This had led to the idea that neurons are individual entities that communicate with each other. Charles Scott Sherington coined the term “synapse” in 1879 for the spots at which neurons interact.

1. The nervous system consists, like all other tissues, of discrete cells (nervous cells, neurons). These are the elemental signal units of nervous systems.

2. Neurons are not continously connected with each other, but discretely separated from each other. They communicate via contact points (synapses).

3. Neurons communicate with each other, and information is propagated in one direction via neurites („functional polarity theory“)..

• They are excitable, i.e., their membrane potential can change (depolarize), and this excitation can be propagated along the membrane. This property occurs also in many other cells, e.g., muscle cells and some gland cells.

• They can release transmitter substances (secretory function) though vesicle exocytosis. This property occurs also in many other cells, e.g., in glands.

To do so, neurons need an equipment of specific proteins, e.g. for vesicle release (synaptic proteins) and membrane conductance (ion channels, ion pumps). Many of these protein families are characteristic for neurons, but many occur also in animals without neurons, even choanoflagellates.

Not all bona fide neurons have all characteristic features of neurons (some have no processes, some do not generate action potentials, etc.), and some features are present in other cell types (e.g., epithelial cells of jellyfish generate action potentials, and even single cell animals generate membrane potential changes and communicate through “transmitter” release).

A cell that transmits information from one cell (or from a stimulus) to one or many other cells via synapses.

Useful markers for neurons include:

1. morphology: long, thin processes;

2. expression of voltage-gated ion channels;

3. synaptic molecules;

4. neuron-specific developmental molecules;

Sponges (Porifera) and Placozoa do not have neurons or nervous systems.

Neurons occurred first in Cindaria (jellyfish, sea anemones, etc.).

The molecular equipment of neurons derived from protein families that were present already much earlier, e.g., in Choanoflagellates.

The evolution of elaborate, fast-signaling nervous systems might have appeared because of predatory behavior that required fast locomotion to obtain food or avoid becoming food. Neurons derived from epithelial cells.

Hypothetical concept:

Before the evolution of neurons (A), specialized epithelial cells detect stimuli and exert effect like movements.

Specific epithelial cells evolved that are specilalized on detecting specific stimuli, e.g. mechanosensory stimuli (B). These cells transmit information onto effector cells, e.g. muscle cells. Please note: the hypothetical sensory neuron like many sensory neurons is a bipolar neuron. Also note the rule: sensory neurons do not innervate each other.

Neurons started synapses with each other (C), and motor neurons have evolved. In the example above schematicing motorneurons from Cnidaria lateral, “tangential” extension (axon collaterals) distribute the information in either direction via reciprocal synapses. This is an exception of the functional polarity rule.

This is a two-layered nervous system, consisting of sensory neurons and motor neurons. The animal can react to a stimulus with a behavioral motor response = Reflex!

The nervous systems of Cidarians are elaborate nerve nets.

The nervous system of Hydra is non-centralized (“diffuse nervous system”).

There are no specialized muscle cells, but contractible epithelial cells and various sensory neurons.

The diffuse nervous system can control several types of behavior independently.

The nervous systems of Planarians (flatworms) have interneurons, nerve cords and cephalic ganglia (brain)

Accumulation of nerve cells: ganglia.

In invertebrates somata are located peripherally, the regions of synaptic connections are called neuropil. Nerves (many axons) are arranged as longitudinal and transversal cords. Interneurons form a third layer of processing! This additional layer can

a) increase convergence and divergence, i.e., many upstream neurons converge onto one or few, or one or few neurons diverge onto many downstream neurons.

b) can switch the sign of information transfer, i.e., from excitatory to inhibitory and vice versa.

c) can integrate more complex neuronal patterns from pattern generators (pattern detector)

Articulata (arthropods like insects or crustaceans and annelids like earthworms) are segmented and have segmented nervous systems.

Articulata have a ventral nerve cord.

In each body segment (metamere) there is a ganglion. Ganglia of the two body sides are typically fused. Ganglia in the head (protocerebrum and deutocerebrum together with suboesophageal ganglion) form a brain.

Insect brains are complex, not simple.

Insect brains mediate complex behavior, e.g.

• orientation through multiple sensory signals.

• complex learning and memory formation

• communication

• sleep-wake rhythms

• aggression and courtship behavior

• selective attention

• etc.

The main body axis is the rostrocaudal axis: it extends along the animal from its beak (rostrum) to its tail (cauda). This defines the length of the embryonic neural plate and the neural tube (see slide later).

The second axis is orthogonal and called dorsoventral axis: it runs vertically from the back (dorsum) to the belly (ventrum).

The third perpendicular axis is the mediolateral axis which is horizontal and runs from the midline (medial) to the lateral margins (lateral) of the animal.

There is often bending of the axis. To determine spatial positions independent of the real body axis one can use terms like frontal/caudal, or sectioning axes like saggital and transverse sections.

Humans are particularly difficult, because our body axis is upright (superior/inferior) but in addition our brain forms a 90°C bend in the midbrain region and our face directs towards ventral. That makes comparisons between animals difficult.

When brain are sectioned for analysis, slices are typically made in one of the cardinal planes: horizontal, coronal, or sagittal.

Three main parts are directly distinguishable in all mammalian brains: cerebrum (“brain”), cerebellum (“small brain”) and brain stem that extends to the spinal cord.

The cerebrum consists of two hemispheres, divided by the Fissura longitudinalis cerebri.

In general: The right brain hemisphere processes sensory information from the left body side, the left brain hemisphere from the right body side. The same principle applies to motor control.

The cerebellum contains more neurons than both cerebrum hemispheres together. It is primarily important for movement control. The left hemisphere controls the left body side, the right hemisphere the right body side.

The brain stem is highly complex and sub-divided (see below) and controls many vital functions (breathing, body temperature, etc.). Damage of cerebrum and cerebellum are often not lethal. Damage to the brain stem often is.

The brain stem is further divided into

• Midbrain (Mesencephalon)

• Pons

• Medulla (oblongata)

Between brain stem and cerebral cortex is the Diencephalon.

The spinal cord is also part of the central nervous system

The spinal cord is surrounded by bones (vertebrae), forming a vertical column attached to the brain stem.

It conducts information between brain and body (skin, muscles, joints).

The conduction with the body happens through spinal nerves (sensory and motor functions). On each side there is a dorsal (posterior) root and a ventral (anterior) root.

Nerves 1 and 2 (olfactory tract and optic nerve) are part of the CNS, nerves 3-12 part of the PNS.

Cranial nerves often have multiple functions. They are associated with areas (nuclei) in the midbrain pons and medulla. Examples are: Nucleus cochlearis (hearing!) or nucleus vestibularis (inner ear!).

In histological sections one could differentiate grey matter from white matter.

Gray matter is simply an accumulation of cell bodies, unmyelinated axons, synapses, glia cells, capillaries. White matter is an accumulation of myelinated axon tracts.

In the brain gray matter is outside (cortex), white matter inside (tracts). In the spinal cord it is the opposite.

Properties of neurons:

• They are excitable, i.e., their membrane potential can change (depolarize), and this excitation can be propagated along the membrane. This property occurs also in many other cells, e.g., muscle cells and some gland cells.

• They can release transmitter substances (secretory function) though vesicle exocytosis. This property occurs also in many other cells, e.g., in glands.

To do so, neurons need an equipment of specific proteins, e.g. for vesicle release (synaptic proteins) and membrane conductance (ion channels, ion pumps). Many of these protein families are characteristic for neurons, but many occur also in animals without neurons, even choanoflagellates.

Not all bona fide neurons have all characteristic features of neurons (some have no processes, some do not generate action potentials, etc.), and some features are present in other cell types (e.g., epithelial cells of jellyfish generate action potentials, and even single cell animals generate membrane potential changes and communicate through “transmitter” release).

Sponges (Porifera) and Placozoa do not have neurons or nervous systems.

Neurons occurred first in Cindaria (jellyfish, sea anemones, etc.).

The nervous systems of Cidarians are elaborate nerve nets.

The nervous system of Hydra is non-centralized (“diffuse nervous system”).

There are no specialized muscle cells, but contractible epithelial cells and various sensory neurons.

The diffuse nervous system can control several types of behavior independently.

The nervous systems of Planarians (flatworms) have interneurons, nerve cords and cephalic ganglia (brain)

Accumulation of nerve cells: ganglia.

In invertebrates somata are located peripherally, the regions of synaptic connections are called neuropil. Nerves (many axons) are arranged as longitudinal and transversal cords. Interneurons form a third layer of processing! This additional layer can

a) increase convergence and divergence, i.e., many upstream neurons converge onto one or few, or one or few neurons diverge onto many downstream neurons.

b) can switch the sign of information transfer, i.e., from excitatory to inhibitory and vice versa.

c) can integrate more complex neuronal patterns from pattern generators (pattern detector), will be explained in a later lecture!

Articulata (arthropods like insects or crustaceans and annelids like earthworms) are segmented and have segmented nervous systems.

Articulata have a ventral nerve cord.

In each body segment (metamere) there is a ganglion. Ganglia of the two body sides are typically fused. Ganglia in the head (protocerebrum and deutocerebrum together with suboesophageal ganglion) form a brain.

Insect brains are complex, not simple.

In insects, ganglia are part of the insect nervous system. Unlike vertebrates, insects have a decentralized nervous system, consisting of a series of interconnected ganglia. The ganglia in insects are located in the thorax and abdomen, and they coordinate the sensory and motor functions of the insect's body.

In insects, the neuropil is found within the ganglia. It is responsible for processing and integrating information received from sensory neurons and transmitting signals to motor neurons, ultimately controlling the insect's behavior and physiological responses.

In summary, ganglia are clusters of nerve cell bodies found in the nervous system, and the neuropil refers to the dense network of nerve fibers and synapses within the ganglia that allows for information processing and communication between neurons.

Articulata (arthropods like insects or crustaceans and annelids like earthworms) are segmented and have segmented nervous systems.

Articulata have a ventral nerve cord.

In each body segment (metamere) there is a ganglion. Ganglia of the two body sides are typically fused. Ganglia in the head (protocerebrum and deutocerebrum together with suboesophageal ganglion) form a brain.

The main body axis is the rostrocaudal axis: it extends along the animal from its beak (rostrum) to its tail (cauda). This defines the length of the embryonic neural plate and the neural tube (see slide later).

The second axis is orthogonal and called dorsoventral axis: it runs vertically from the back (dorsum) to the belly (ventrum).

The third perpendicular axis is the mediolateral axis which is horizontal and runs from the midline (medial) to the lateral margins (lateral) of the animal.

There is often bending of the axis. To determine spatial positions independent of the real body axis one can use terms like frontal/caudal, or sectioning axes like saggital ansd transverse sections.

Humans are particularly difficult, because our body axis is upright (superior/inferior) but in addition our brain forms a 90°C bend in the midbrain region and our face directs towards ventral. That makes comparisons between animals difficult.

The neural tube is a hollow tube that forms during embryonic development and gives rise to the central nervous system (brain and spinal cord) in vertebrates. It emerged in the evolutionary lineage that led to vertebrates around 550 million years ago during the Cambrian period.

The basic plan of the vertebrate nervous system is already visible in lancelets (Amphioxus): a dorsal neural tube (nerve cord).

Three main parts are directly distinguishable in all mammalian brains: cerebrum (“brain”), cerebellum (“small brain”) and brain stem that extends to the spinal cord.

The cerebrum consists of two hemispheres, divided by the Fissura longitudinalis cerebri.

In general: The right brain hemisphere processes sensory information from the left body side, the left brain hemisphere from the right body side. The same principle applies to motor control.

The cerebellum contains more neurons than both cerebrum hemispheres together. It is primarily important for movement control. The left hemisphere controls the left body side, the right hemisphere the right body side.

The brain stem is highly complex and sub-divided (see below) and controls many vital functions (breathing, body temperature, etc.). Damage of cerebrum and cerebellum are often not lethal. Damage to the brain stem often is.

Three basic brain vesicles form: prosencephalon (forebrain), mesencephalon (midbrain) and rhombencephalon (hindbrain).

Specialized structures differentiate from the three primary vesicles.

The forebrain differentiates into telencephalon (two vesicles) and diencephalon. Optic vesicles will further differentiate into eyes.

The telencephalon will become to cortical hemipheres, olfactory bulb and the basal ganglia (basal telencephalon). The diencephalon will become the thalamus (“gateway to cortex”) and hypothalamus (control of visceral functions).

The midbrain further differentiates into tectum and tegmentum.

The tectum will differentiate into superior colliculus (receives input from eye) and inferior colliculus (input from ear).

The tegmentum will differentiate into substantia nigra and red nucleus (voluntary movements).

The hindbrain further differentiates into medulla and medulla pyramids.

Parts of the hindbrain (rhombencephalon) will differentiate to the cerebellum (“Kleinhirn”)

The rhombencephalon (hindbrain) will differentiate into cerebellum, medulla (e.g., cochlear nuclei) and pons (“switchboard” between cortex and cerebellum). It encompasses the fourth ventricle.

Cross Section of Spinal Cord:

• Gray matter (central) surrounded by white matter (outer).

• Gray matter contains cell bodies, white matter contains nerve fibers.

Dorsal Roots:

• Located on the back (dorsal) side of the spinal cord.

• Carry sensory information from the body to the spinal cord.

• Transmit touch, temperature, pain, and body position senses.

Ventral Roots:

• Located on the front (ventral) side of the spinal cord.

• Carry motor commands from the spinal cord to muscles and glands.

• Enable voluntary and involuntary movements.

Spinal Nerves:

• Dorsal and ventral roots merge to form spinal nerves.

• Spinal nerves exit the spinal cord and innervate specific body areas.

The spinal cord is surrounded by bones (vertebrae), forming a vertical column attached to the brain stem.

It conducts information between brain and body (skin, muscles, joints).

The conduction with the body happens through spinal nerves (sensory and motor functions). On each side there is a dorsal (posterior) root and a ventral (anterior) root.

Primary visual cortex:

• Location: Occipital lobe

• Function: Processes visual information

Primary motor cortex:

• Location: Frontal lobe (precentral gyrus)

• Function: Controls voluntary movements

Primary auditory cortex:

• Location: Temporal lobe

• Function: Processes auditory information

Food digestion

Garbage disposal &recycling

Protects DNA

Controls cell

Builds proteins

Finishes packages & ships proteins

• production of vesicles

• synthesis and modification of plasma membrane elements

• production of primary lysosomes

• post-translations modifications of proteins, e.g, cleavage;

• delivery of proteins and membranes to specific destinations („trafficking“)

Helps finish proteins

Makes membranes

Cell boundary

Controls movement of materials in & out

Recognises signals

Make ATP energy from sugar and 02

Present in axones, dendrites, synaptic structures. Cellular respiration, Krebs-Martin cycle;

Transport inside cells

Storage

Jelly-like material holding organelles in place

Nucleus

rough and smooth endoplasmatic reticulum

Ribosomes und Polyribosomes

Mitochondria

Golgi-apparatus

Cytoskeleton

3 main types:

a) microtubules

b) neurofilaments

c) microfilaments

• Microtubules consist of two different monomers

• They form a polar strand (+ and – end)

• 13 monomers per „ring“

• polymerisation requires energyx: GTP-hydrolysis

• In the mammlian brain > 20 isoformes!

• The stability is maintaines by microtubulesassociated proteins (MAPs). In Aaxons different MAPs than in dendrites!

• 3-10 x more than microtubules

• belong to the protein family of cytokeratins

• very stable, almost completely polymerized

• determine length and thickness of axons

Intermediate filaments to which neurofilaments belong are a large family of proteins.

• polar polymers of actin monomers

• GTP or GDP-binding

• several genes for actin

• dense mesh below the membrane

• fast polymerization and degradation

• small protrusions on dendrites of glutamatergic central brain neurons in mammals

• variable shape, modifiable

• provide thousands of synaptic contacts to one cell

• plastic in shape

• important for learning and memory (plasticity!)

• Deseases can affect spine morphology

• Shape determines electrical properties of synapses (resistance!) and biochemical properties.

Transports organelles, vesicles, mitohondria, elements of sER, ...

• Kinesin and Microtubuli!

• ATP-dependent

• independent from soma

There are many different forms of kinesins!

Transports organelles, vesicles, mitohondria, endosomes, etc. towards the soma

• MAP-1C (Microtubule-associated ATPase) und Microtubuli!

• MAP-1C simlar to Dynein of Ciliates! Dynein-Dynactin complex acts as motor!

• ATP-dependent

• independent of soma

only anterograde: delivery of cytoskeleton and cytoplasmic elements to periphery.

• Delivery of cytoskeletal and cytoplasmic constituents to the periphery.

• Studies suggest that cytoplasmic dynein may move microtubules with their plus ends leading.

• Neurofilaments may move on their own or may hitchhike on microtubules.

• Once cytoplasmic structures reach their destinations, they are degraded by local proteases at a rate that allows either growth (in the case of growth cones) or maintenance of steady-state levels.

• The different composition and organization of cytoplasmic elements in dendrites suggest that different pathways may be involved in delivery of cytoskeletal and cytoplasmic materials to dendrites. In addition, some mRNAs are transported into dendrites, but not into axons

The cell membranes of all cells including neurons consist of phospholipid bilayers.

Important for neurons: these bilayers are insulators (charged ions cannot pass easily).

Biological bilayers are usually composed of amphiphilic phospholipids that have a hydrophilic phosphate head and a hydrophobic tail consisting of two fatty acid chains.

The “fluid membrane mosaic model” states that membrane proteins are embedded in the phosopholipid bilayer.

These membrane proteins are important to regulate transport across the membrane.

Carbohydrates are covalently linked to proteins (glycoproteins) or lipids (glycolipids) and also an important part of cell membranes. Membrane carbohydrates perform two main functions: participate in cell recognition and adhesion, either cell- cell signaling or cell-pathogen interactions, and they have a structural role as a physical barrier.

passive (no energy consumption, driving force = concentration gradient; approaches equilibrium)

active (energy required, usually ATP, results in non-equilibrium)

There are several principal types of transport across membranes:

• simple diffusion, e.g. gases (O2, CO2, NO, CO, etc.), small non-charged molecules, also H2O.

• channel-mediated (facilitated diffusion), e.g., ions, H2O through aquaporin channels, small molecules;

• carrier-mediated (facilitated diffusion), e.g., ions, glucose, small molecules;

• active transport, e.g., ions, small molecules; against concentration gradient;

Ion channels are transmembrane proteins

1. Ion channels conduct ions

2. Recognize and select specific ions

3. Open and close upon electrical, chemical or mechanical signals.

• Ion selectivity (1:10 – 1:100)

• Mechanisms for regulation

consist of subunits

a) central, water-filled pore

b) transmembrane-domains of glyco-proteins

c) 2 oder more subunits that can be the same or different amino acid sequences

opening and closing

a) Voltage-dependent channels

b) Ligand-dependent channels

c) Mechanically gated channels

d) „resting channels“

e) Second-messenger-regulated channels

ligands, antagonists, agonists

Exogeneous factors can influece opening and closing (z.B. toxins, drugs).

Reversibel (Curare) or irreversibel (e.g., a-Bungarotoxin).

A ligand-gated ion channel is an ionotropic receptor

Ion channels can desensitize, i.e., opening decresaes their opening probability.

Modulation of channels: Examples:

a) Temporally restricted inactivation (refractory period!)

b) The conducted ion itself modulates the opening state.

c) Phosphorylation (covalent bonds) or dephosphorylation modulates the opening probability.

Binding of individual ions onto channel pore.

Ionic current is passiv (no ATP required),

Anions and cations along the elctrochemical gradient.

• Local anesthetics: lidocain, benzocain, procain (sodium channels)

• Peptide toxins (scorpion toxins, conotoxins, sea anemone toxins) (block inactivation of sodium channels)

• Alkaloid-biotoxins (Veratridin, Batrachotoxin, Aconitin) (open sodium channels, change ion selectivity)

• Tetrodotoxin (TTX), saxitoxin (block of sodium channels) 1 mg lethal, TTX in several unrelated species (buffer fish, californian newt) -> „convergent evolution“

• Ligand binding 1:1 -> Counting of sodium channels: thin axon: ~ 3/μm2, giant axon: ~ 500/μm2, node of ranvier: 3.000 – 10.000/μm2

• Measuring opening time (patch clamp): ~ 20 ms, ~100 ions pass.

• spinal reflex: the entire circuitry is restricted to the vertebrate

• monosynaptic circuit: the sensory neuron directly synapses onto the motorneuron.

• an inhibitory neuron inhibits the antagonistic muscle.

2 forces act on ions: electrochemical gradient!

1. Movement along chemical gradient (diffusion)

2. Movement along electrical fields

imbalance of ion concentrations

1. Situation: There is a concentration difference across the membrane (cations and anions)

2. Situation: If there is a selective channel, the ion can move along the concentration gradient.

3. Situation: If there is a selective channel, the ion can move along the electrical gradient

The ions move until an equilibrium is reached.

The equilibrium is reached when:

chemical potential Echem equals the electrical potential Eelect

R·T·ln [Ion]e/[Ion]i = z·F·EIon

Eion = R·T / z·F ln [Ion]e /[Ion]i

(Nernst equation)

R = Gas Constant (in J / mol * K)

T = absolute Temperature (in K)

Z = valence of the ion

F = Faraday constant (C / mol)

This can be calculated for each ion = equilibrium potential for this ion!

Only the equilibrium potential of Cl- is close (usually not exactly equal) to the membrane potential.

The equilibrium potential of K+ is more negative. If K+ channels open ions flow outside in order to reach their equilibrium potential.

The equilibrium potential of Na+ is more positive. If Na+ channels open ions flow inside in order to reach their equilibrium potential.

The equilibrium potential of Ca2+ is much more positive. If Ca2 channels open ions flow inside in order to reach their equilibrium potential.

The membrane potential is confined to a small region close to the membrane.

Voltage-dependent Na+ current:

Measurement of current at different membrane potentials. Block of potassium channels

Sodium current

Membrane potential: Depolarization from holding potential (VH) to stimulus (VS).

Recording of current (I) (sodium influx). Inactivation of channels!

Voltage-current relationship: The peak sodium current increases with increasing membrane depolarization, and decreases with further depolarization. ENa shows the equilibrium potential: the current reverts from influx to efflux (Nernst potential, see explanation below).

K+ current:

Measurement of current at different membrane potentials. Block of sodium channels.

Membrane potential: Depolarization from holding potential (VH) to stimulus (VS).

Recording of current (I) (potassium influx).

Voltage-current relationship: The peak sodium current increases with increasing membrane depolarization, and decreases with further depolarization. EK shows the equilibrium potential: the current reverts from efflux to influx (Nernst potential, see explanation below).

Ion Channel:

• Definition: An ion channel is a pore-forming protein that allows the selective passage of ions across cell membranes. It acts as a gate, regulating the flow of ions in and out of cells.

Molecular Composition:

• Ion channels are typically composed of proteins that span the cell membrane. These proteins consist of multiple subunits, with each subunit contributing to the formation of the channel pore. The subunits may be identical or different, depending on the specific type of ion channel.

Ion Selectivity Regulation:

• The ion selectivity of an ion channel refers to its ability to allow specific ions to pass while excluding others. This selectivity is primarily determined by the structure of the channel pore, including the arrangement of amino acids within the pore. The size, charge, and coordination properties of the amino acids in the pore determine which ions can pass through.

Regulation of Opening/Closing Probability:

• Ion channels can be regulated by various mechanisms to control their opening and closing probabilities. Some common mechanisms include:

  1. Voltage-gating: Ion channels can be sensitive to changes in the membrane potential. Voltage-gated channels open or close in response to specific voltage thresholds.

  2. Ligand-gating: Ion channels can be activated or inhibited by the binding of specific molecules, such as neurotransmitters or hormones. Ligand-gated channels open or close upon binding of the ligand.

  3. Phosphorylation: The addition or removal of phosphate groups can modulate the activity of ion channels. Phosphorylation by protein kinases can lead to channel opening or closing, while dephosphorylation can have the opposite effect.

  4. Temperature: Temperature changes can affect the opening and closing probabilities of some ion channels. Cold temperatures may cause channels to close, while heat can lead to channel opening.

  5. Mechanical stress: Certain ion channels are sensitive to mechanical forces. Physical pressure or stretch can influence their opening and closing.

Forces on Extracellular and Intracellular Ions:

1. Electrostatic Force: Arises from the voltage potential across the cell membrane and attracts or repels charged ions.

   • Determined by the membrane potential.

2. Diffusion Force: Drives ions from areas of higher concentration to areas of lower concentration.

   • Determined by the ion concentration gradient.

Physical Parameters:

1. Membrane Potential: Voltage difference across the cell membrane.

   • Determines the strength and direction of the electrostatic force.

2. Ion Concentration Gradient: Difference in ion concentration between the intracellular and extracellular compartments.

   • Determines the strength and direction of the diffusion force.

3. Ion Channel Permeability: Controls the ease of ion passage through channels.

   • Influences the relative contribution of electrostatic and diffusion forces.

4. Temperature: Affects the speed of ion movement through channels.

   • Higher temperatures increase ion kinetic energy, leading to faster diffusion.

Equilibrium Potential:

• Definition: Membrane potential at which electrical and concentration gradients for an ion balance, resulting in no net movement of ions across the membrane.

Calculation:

• Nernst equation: Eion = (RT/zF) * ln([ion]outside/[ion]inside)

  • Eion: Equilibrium potential for the ion.

  • R: Gas constant (8.314 J/(mol·K)).

  • T: Absolute temperature (Kelvin).

  • z: Valence of the ion (charge).

  • F: Faraday's constant (96,485 C/mol).

  • [ion]outside, [ion]inside: Concentrations of the ion outside and inside the cell, respectively.

Extracellular and Intracellular Ion Concentrations:

• Sodium (Na+):

  • Extracellular concentration: Around 135-145 millimolar (mM).

  • Intracellular concentration: Around 10-15 mM.

• Potassium (K+):

  • Extracellular concentration: Around 3.5-5 mM.

  • Intracellular concentration: Around 120-150 mM.

• Chloride (Cl-):

  • Extracellular concentration: Around 95-105 mM.

  • Intracellular concentration: Around 5-15 mM.

• Calcium (Ca2+):

  • Extracellular concentration: Around 1-2 millimolar (mM).

  • Intracellular concentration: Around 0.1-0.2 μM (micromolar).

Note: These concentrations are approximate and can vary depending on the cell type and physiological conditions.

Equilibrium Potentials:

1. Calcium (Ca2+):

- Assuming typical concentrations:

- Extracellular concentration: 1.5 mM

- Intracellular concentration: 0.1 μM (0.1 x 10^-3 mM)

- Using the Nernst equation:

E_Ca2+ = (RT/zF) * ln([Ca2+]outside/[Ca2+]inside)

- R: Gas constant (8.314 J/(mol·K))

- T: Absolute temperature (usually around 298 K)

- z: Valence of the ion (charge), which is 2 for calcium

- F: Faraday's constant (96,485 C/mol)

Plugging in the values:

E_Ca2+ = (8.314 * 298 / (2 * 96,485)) * ln(1.5 / 0.1 x 10^-3)

The equilibrium potential for calcium (Ca2+) is approximately +123 mV.

2. Sodium (Na+):

- Assuming typical concentrations:

- Extracellular concentration: 145 mM

- Intracellular concentration: 15 mM

- Using the Nernst equation:

E_Na+ = (RT/zF) * ln([Na+]outside/[Na+]inside)

- z: Valence of the ion, which is 1 for sodium

Plugging in the values:

E_Na+ = (8.314 * 298 / (1 * 96,485)) * ln(145 / 15)

The equilibrium potential for sodium (Na+) is approximately +61 mV.

3. Potassium (K+):

- Assuming typical concentrations:

- Extracellular concentration: 5 mM

- Intracellular concentration: 140 mM

- Using the Nernst equation:

E_K+ = (RT/zF) * ln([K+]outside/[K+]inside)

- z: Valence of the ion, which is 1 for potassium

Plugging in the values:

E_K+ = (8.314 * 298 / (1 * 96,485)) * ln(5 / 140)

The equilibrium potential for potassium (K+) is approximately -94 mV.

4. Chloride (Cl-):

- Assuming typical concentrations:

- Extracellular concentration: 105 mM

- Intracellular concentration: 10 mM

- Using the Nernst equation:

E_Cl- = (RT/zF) * ln([Cl-]outside/[Cl-]inside)

- z: Valence of the ion, which is -1 for chloride

Plugging in the values:

E_Cl- = (8.314 * 298 / (-1 * 96,485)) * ln(105 / 10)

The equilibrium potential for chloride (Cl-) is approximately -62 mV.

Note: These values are approximate and can vary depending on the actual concentrations used and the temperature conditions.

Electromotoric Driving Force:

• Definition:

  The electromotoric driving force, also known as the electrochemical driving force, is the net force that determines the direction and magnitude of ion movement across a cell membrane. It takes into account both the electrical potential difference (voltage) and the concentration gradient across the membrane for a specific ion.

• Calculation:

  The electromotoric driving force (EMF) for an ion can be calculated using the following equation:

  EMF = (Vm - Eion)

  • Vm represents the membrane potential (voltage).

  • Eion is the equilibrium potential for the ion (calculated using the Nernst equation).

• Significance:

  The electromotoric driving force indicates whether an ion will move into or out of the cell. If the membrane potential is more positive than the equilibrium potential (Vm > Eion), the EMF will be positive, indicating a net driving force for ion entry. Conversely, if the membrane potential is more negative than the equilibrium potential (Vm < Eion), the EMF will be negative, indicating a net driving force for ion exit.

• Importance:

  The electromotoric driving force is crucial for various cellular processes, such as the generation of electrical signals in neurons, muscle contraction, and ion transport across epithelial cells. It determines the flow of ions across the cell membrane, thereby influencing cellular excitability and the overall function of biological systems.

Effect of Ion Channel Opening at Resting Potential (-70mV) in a Neuron:

1. Sodium (Na+) Channels:

• Opening of Na+ channels at resting potential results in an influx of Na+ ions into the neuron.

• Since the equilibrium potential for Na+ is around +61 mV, which is more positive than the resting potential (-70 mV), Na+ ions move into the cell.

• This influx of positive charges depolarizes the neuron, making the membrane potential less negative or even positive.

• If the depolarization reaches the threshold potential (around -55 mV to -50 mV), it can trigger an action potential, leading to the propagation of an electrical signal along the neuron.

1. Potassium (K+) Channels:

• Opening of K+ channels at resting potential allows K+ ions to move out of the neuron.

• The equilibrium potential for K+ is around -94 mV, which is more negative than the resting potential.

• As K+ ions move out of the cell, it contributes to hyperpolarization, making the membrane potential more negative.

• This hyperpolarization makes it more difficult to reach the threshold potential, reducing the excitability of the neuron.

1. Chloride (Cl-) Channels:

• Opening of Cl- channels at resting potential allows Cl- ions to move according to their concentration gradient.

• The equilibrium potential for Cl- is around -61 mV, which is close to the resting potential.

• Opening Cl- channels does not cause significant changes in the membrane potential unless there are other ionic imbalances or active transport mechanisms involved.

1. Calcium (Ca2+) Channels:

• Opening of Ca2+ channels at resting potential allows Ca2+ ions to enter the neuron.

• The equilibrium potential for Ca2+ is around +123 mV, which is much more positive than the resting potential.

• Influx of Ca2+ ions can have various effects depending on the specific neuron and its signaling pathways.

• Ca2+ ions play a crucial role in neuronal functions, including neurotransmitter release and intracellular signaling processes.

Note: The specific effects of ion channel opening may vary depending on the neuronal context, ion channel subtype, and other factors.

Electrogenic Pump:

Definition:

An electrogenic pump is a type of ion pump that actively transports ions across the cell membrane, contributing to the generation or maintenance of the membrane potential. It creates an electrogenic effect, meaning it generates a net charge separation across the membrane.

Sodium-Potassium-ATPase:

• The sodium-potassium-ATPase, also known as the Na+/K+ pump, is an example of an electrogenic pump found in neurons.

Function in Neurons:

• The primary role of the sodium-potassium-ATPase in neurons is to maintain the resting membrane potential and regulate the ionic balance inside and outside the cell.

• It actively transports three sodium ions (Na+) out of the neuron for every two potassium ions (K+) it brings in, using energy from ATP hydrolysis.

• This process helps establish and maintain the concentration gradients of sodium and potassium ions, which are essential for generating and propagating electrical signals in neurons.

• By pumping out sodium ions and bringing in potassium ions, the sodium-potassium-ATPase contributes to the negative resting membrane potential (-70 mV) of neurons.

• Furthermore, it plays a critical role in restoring the ion concentrations after the action potential, helping to reset the neuron for subsequent signaling events.

Note: The sodium-potassium-ATPase is a fundamental component of neuronal function, ensuring the proper excitability and signaling capabilities of neurons.

1. Lidocaine:

• Lidocaine is a local anesthetic that blocks voltage-gated sodium channels.

• It inhibits the propagation of action potentials by preventing the opening of sodium channels.

• As a result, lidocaine reduces the excitability of neurons and blocks the transmission of pain signals.

1. Tetrodotoxin:

• Tetrodotoxin is a potent neurotoxin found in certain marine organisms, such as pufferfish.

• It selectively blocks voltage-gated sodium channels, specifically the pore region.

• By binding to the sodium channels, tetrodotoxin prevents the influx of sodium ions during an action potential.

• This leads to the inhibition of nerve impulse transmission, causing paralysis and potential respiratory failure.

1. Tetraethylammonium:

• Tetraethylammonium (TEA) is a potassium channel blocker.

• It inhibits voltage-gated potassium channels, specifically delaying their repolarizing effect during an action potential.

• By blocking potassium channels, TEA prolongs the duration of the action potential and increases neuronal excitability.

• It can affect the firing frequency and pattern of action potentials in neurons.

Note: These substances have specific effects on ion channels, altering the normal electrical activity of neurons. Lidocaine and tetrodotoxin target sodium channels, while tetraethylammonium affects potassium channels. Understanding the actions of these compounds is essential in studying neuronal function and developing treatments for various conditions.

If a membrane is depolarized to +50 mV, no sodium current is seen due to voltage-gated sodium channels being inactivated.

Explanation:

Voltage-gated sodium channels have three main states: closed, open, and inactivated. At resting membrane potential (-70 mV), most sodium channels are in the closed state. When the membrane is depolarized, the channels undergo a conformational change and transition from the closed state to the open state, allowing the influx of sodium ions.

However, after reaching a certain depolarization threshold (typically around -55 mV to -50 mV), a fraction of the sodium channels undergoes inactivation. Inactivation is a time-dependent process where the channel enters a non-conductive state, blocking the passage of sodium ions even when the membrane is depolarized.

At +50 mV, which is above the typical threshold for inactivation, a significant portion of the sodium channels will already be inactivated. As a result, the inactivated sodium channels are unable to conduct sodium currents, leading to the absence of sodium current at this depolarized membrane potential.

Depolarization to +20mV causes sodium influx, while depolarization to +80mV causes sodium efflux due to the voltage-gated nature of sodium channels.

Explanation:

Voltage-gated sodium channels are responsible for the flow of sodium ions across the cell membrane. These channels have different conformational states depending on the membrane potential.

1. Depolarization to +20mV:

   • At +20mV, which is above the threshold potential, voltage-gated sodium channels undergo a conformational change and transition from a closed state to an open state.

   • This conformational change occurs as a response to the depolarization of the membrane.

   • Opening of the sodium channels allows sodium ions to flow into the cell, resulting in sodium influx.

   • The influx of positive sodium ions further depolarizes the membrane, contributing to the initiation and propagation of an action potential.

1. Depolarization to +80mV:

   • At +80mV, which is a highly positive membrane potential, the voltage-gated sodium channels are inactivated.

   • Inactivation occurs as a result of sustained depolarization, causing the inactivation gate to close and block the ion pathway.

   • In the inactivated state, the sodium channels are refractory to further depolarization and cannot open.

   • As a result, depolarization to +80mV does not allow sodium influx, and instead, sodium efflux is observed.

The voltage-dependent behavior of sodium channels enables them to respond to changes in membrane potential and regulate the flow of sodium ions accordingly. Depolarization to +20mV opens the channels, allowing sodium influx, while depolarization to +80mV results in channel inactivation, preventing further sodium influx and leading to sodium efflux.

Sodium currents are transient due to rapid onset and decay caused by the gating properties of sodium channels. Opening upon depolarization, they quickly inactivate to prevent continuous ion flow, aiding in repolarization and signal coordination.

• generation of action potentials follows all-or-none signals

• refractory period ensures that signals are propagated in one direction

• only depolarizing signals

• no decay along the neurite

1. Glia cells

2. Nerve cells

1. Glia can form structures.

2. Oligodendrocytes and Schwann-Cells form myelin to isolate axons.

3. Some glia cells remove cell fragments.

4. Glia cells clear the synaptic cleft from transmitter substances.

5. Specific glia cells („radial-glia“) form trajectories along which developing axons protrude („pathfinding).

6. Glia can influence gene expression of neurons (e.g., at the nerve- muscle synapse).

7. Some glia cells (astrocytes) form a blood-brain barrier.

8. Glia cells feed neurons and release nerve growth factors (NGF).

9. Astrocytes remove excessive ions, e.g., potassium.

• high density of Na+ channels

• low membrane resistance

• slow signal propagation

• Almost no Na+ channels

• high membrane resistance

• very fast electrotonic signal propagation

(presence of substance not sufficient: ACh is also in placenta, 5HT in erythrocytes)

a) Detection: substance + synthesizing enzymes + degrading enzymes * transport system

b) Proof of release after depolarization

c) External application must mimick the effect of presynaptic stimulus

d) Pharmacological manipulation equal for externally applied transmitter and endogeneous transmitter

Graded membrane potential changes are generated through the activation of ligand-gated or mechanically-gated ion channels in response to specific stimuli. When these channels are opened, they allow the selective movement of ions across the cell membrane, resulting in a change in the membrane potential.

Ligand-gated ion channels are proteins that have binding sites for specific molecules called ligands, which can be neurotransmitters, hormones, or other signaling molecules. When a ligand binds to the channel, it induces a conformational change, leading to the opening of the channel. This allows ions to flow through the channel, either into or out of the cell, based on the specific characteristics of the channel. The movement of ions creates a local change in the membrane potential, which can be either depolarization (becoming less negative) or hyperpolarization (becoming more negative).

Mechanically-gated ion channels, on the other hand, respond to physical forces applied to the cell membrane. These forces can include pressure, stretch, or vibration. When the membrane is mechanically deformed, the ion channels embedded within it open or close, allowing ions to move across the membrane and changing the membrane potential.

The magnitude of the graded membrane potential change depends on the strength or intensity of the stimulus. A stronger stimulus leads to a larger opening of ion channels and a greater ion flow, resulting in a more significant change in membrane potential. Graded potentials allow cells to generate diverse and adaptable responses to various stimuli, playing a crucial role in sensory perception, neuronal communication, and other physiological processes.

1. Gradedmembranepotentialchanges:

   • incoming short-distance signals;

   • short-lived and localized;

   • depolarizations and hyperpolarizations are possible;

   • Graded membrane potentials spread along the neurites as local currents change adjacent regions of the membrane!

Time constant:

The time constant (τ) of a neuronal membrane refers to the time it takes for the membrane potential to reach approximately 63.2% of its final value during the charging or discharging process. It is determined by the product of the membrane resistance (Rm) and the membrane capacitance (Cm).

The formula for the time constant is τ = Rm * Cm.

Length constant:

The length constant (λ) represents the distance over which a graded potential propagates along the neuronal membrane without significant decay. It depends on the membrane resistance (Rm) and the axial resistance (Ra) of the neuronal processes (such as dendrites or axons).

The formula for the length constant is λ = √(Rm / (2 * Ra)).

The time constant and length constant are influenced by the electrical properties of the neuronal membranes.

The membrane resistance (Rm) determines how easily ions can flow through the membrane

The membrane capacitance (Cm) relates to the ability of the membrane to store electrical charge.

The axial resistance (Ra) represents the resistance to ion flow within the neuronal processes.

Overall, these parameters play crucial roles in the integration and transmission of electrical signals in neurons. The time constant affects the speed of charging or discharging of the membrane, while the length constant determines the extent of signal propagation without significant attenuation.

Both the time constant and length constant of a neurite are dependent on its diameter. A larger diameter of the neurite leads to a smaller membrane resistance (Rm) and a larger axial resistance (Ra).

For the time constant (τ), a larger neurite diameter decreases the membrane resistance and increases the capacitance (Cm), resulting in a shorter time constant. This implies faster charging or discharging of the membrane potential.

For the length constant (λ), a larger neurite diameter decreases the axial resistance and increases the membrane resistance, leading to a longer length constant. This indicates improved signal propagation with less attenuation over longer distances.

In summary, a larger neurite diameter decreases the time constant and increases the length constant. This facilitates faster signal propagation along the neurite, allowing electrical signals to travel longer distances without significant loss of amplitude.

Intracellular microelectrodes measure the intracellular membrane potential

extracellular microelectrodes measure the collective electrical activity of nearby cells.

Absolute refractory period: Brief period after an action potential when a neuron is unresponsive to stimulation due to inactivated sodium channels.

Relative refractory period: Subsequent period during which a stronger stimulus can evoke a response despite the presence of inactivated sodium channels and increased potassium conductance.

Action potentials propagate in one direction only due to the property of refractoriness. During an action potential, the region behind the depolarization wave enters an absolute refractory period, preventing backward propagation.

Graded depolarizations of neuronal membranes typically propagate in both directions because they do not involve refractory periods and can spread bidirectionally along the membrane.

1. Glia can form structures.

2. Oligodendrocytes and Schwann-Cells form myelin to isolate axons.

3. Some glia cells remove cell fragments.

4. Glia cells clear the synaptic cleft from transmitter substances.

5. Specific glia cells („radial-glia“) form trajectories along which developing axons protrude („pathfinding).

6. Glia can influence gene expression of neurons (e.g., at the nerve- muscle synapse).

7. Some glia cells (astrocytes) form a blood-brain barrier.

8. Glia cells feed neurons and release nerve growth factors (NGF).

9. Astrocytes remove excessive ions, e.g., potassium

SNARE proteins are membrane-associated proteins involved in membrane fusion events within cells. Their function is to mediate the fusion of vesicles with target membranes during processes like neurotransmitter release, hormone secretion, and intracellular trafficking. SNARE proteins form complexes between vesicle (v-SNAREs) and target (t-SNAREs) membranes, bringing them together and catalyzing their fusion. This fusion allows the release of vesicle contents into the target compartment, facilitating cellular communication and transport.

Vesicle docking:

Vesicle docking is the initial step in membrane fusion, where a vesicle approaches the target membrane and aligns in close proximity to it. Specific interactions between proteins on the vesicle membrane (v-SNAREs) and proteins on the target membrane (t-SNAREs) contribute to the docking process. This brings the vesicle into a position ready for further fusion events.

Vesicle priming:

After docking, vesicle priming occurs, which involves a series of molecular events that prepare the vesicle for fusion. During priming, the vesicle undergoes changes in protein composition and structural rearrangements, ensuring that it is in a "primed" state and ready for fusion. This process involves the recruitment of additional proteins and the buildup of calcium ions, which play a crucial role in triggering the subsequent fusion event.

Vesicle fusion:

Vesicle fusion is the final step in the process, where the vesicle and target membrane merge together, allowing the contents of the vesicle to be released into the target compartment. The SNARE proteins on the vesicle (v-SNAREs) and target (t-SNAREs) membranes interact and form a stable SNARE complex, which catalyzes the fusion process. The fusion event involves the merging of lipid bilayers, resulting in the complete integration of the vesicle membrane with the target membrane.

Together, vesicle docking, priming, and fusion constitute the sequential stages of the membrane fusion process, ensuring precise and controlled release of vesicle contents into the target membrane.

key steps of the synaptic vesicle cycle:

1. Neurotransmitter Release: Upon stimulation, synaptic vesicles fuse with the presynaptic membrane, leading to the release of neurotransmitters into the synaptic cleft.

2. Endocytosis: After neurotransmitter release, the empty vesicle membrane is retrieved from the presynaptic membrane through endocytosis. Clathrin-coated pits form around the vesicle, internalizing it to form an endocytic vesicle.

3. Uncoating: The clathrin coat is shed from the endocytic vesicle, which then becomes an uncoated endocytic vesicle.

4. Vesicle Refilling: The uncoated endocytic vesicle undergoes a process called vesicle refilling. Neurotransmitters are replenished within the vesicle by specific transporters, which actively import neurotransmitter molecules from the cytoplasm into the vesicle.

5. Vesicle Maturation: The refilled vesicle matures and acquires a new coat of clathrin, becoming a recycling vesicle.

6. Vesicle Re-Primed: The recycling vesicle is re-primed to become ready for subsequent rounds of exocytosis. This step involves the reloading of calcium ions and the reformation of the SNARE complex, preparing the vesicle for fusion with the presynaptic membrane.

7. Vesicle Exocytosis: Upon the arrival of a new action potential, the re-primed recycling vesicle fuses with the presynaptic membrane, leading to the release of neurotransmitters and the completion of the synaptic vesicle cycle.

In summary, the synaptic vesicle cycle involves the release of neurotransmitters, followed by endocytosis, vesicle refilling, maturation, re-priming, and subsequent exocytosis. This recycling process ensures the continuous availability of synaptic vesicles and efficient neurotransmitter release at synapses.

Gap junctions are specialized intercellular channels that directly connect the cytoplasm of neighboring cells. They are composed of protein structures called connexons, which consist of six connexin subunits arranged in a cylindrical fashion.

The function of gap junctions is to enable direct cell-to-cell communication and electrical coupling. They allow the passage of ions, small molecules, and electrical signals between adjacent cells. This direct transfer of molecules and electrical currents facilitates rapid and coordinated cellular activities, such as synchronized contractions in cardiac muscle and the spread of electrical signals in neurons.

In summary, gap junctions are intercellular channels composed of connexons, facilitating the direct exchange of ions, small molecules, and electrical signals between neighboring cells. Their function is to promote coordinated cellular activities and communication within tissues and organs.

1. Acetylcholine

   • Molecular Class: Biogenic amine/ cholinergics

   • Excitatory or Inhibitory: Can act as both excitatory and inhibitory depending on the receptor subtype and location in the nervous system.

2. Glutamate

   • Molecular Class: Amino acid

   • Excitatory or Inhibitory: Excitatory. It is the primary excitatory neurotransmitter in the central nervous system.

3. GABA (gamma-aminobutyric acid)

   • Molecular Class: Amino acid

   • Excitatory or Inhibitory: Inhibitory. It is the primary inhibitory neurotransmitter in the central nervous system.

4. Dopamine

   • Molecular Class: Biogenic amine/ phenethylamines and derivates

   • Excitatory or Inhibitory: Can act as both excitatory and inhibitory depending on the receptor subtype and brain region.

5. Serotonin

   • Molecular Class: Biogenic amine/ indoleamines

   • Excitatory or Inhibitory: Can act as both excitatory and inhibitory depending on the receptor subtype and brain region.

6. Noradrenaline (norepinephrine)

   • Molecular Class: Biogenic amine/ phenethylamines and derivates

   • Excitatory or Inhibitory: Can act as both excitatory and inhibitory depending on the receptor subtype and brain region.

7. Histamine

   • Molecular Class: amino acids

   • Excitatory or Inhibitory: Can act as both excitatory and inhibitory depending on the receptor subtype and brain region.

8. Glycine

   • Molecular Class: Amino acid

   • Excitatory or Inhibitory: Inhibitory. It serves as an inhibitory neurotransmitter in the spinal cord and brainstem.

9. Adenosine

   • Molecular Class: Purine nucleoside

   • Excitatory or Inhibitory: Inhibitory. It acts as an inhibitory neuromodulator in the central nervous system.

10. Substance P

    • Molecular Class: Neuropeptide

    • Excitatory or Inhibitory: Generally considered excitatory. It is involved in pain transmission and neurogenic inflammation.

Ionotropic receptors are a type of neurotransmitter receptor that directly allow the flow of ions across the cell membrane upon neurotransmitter binding. They are ligand-gated ion channels, meaning they have an ion channel pore that opens or closes in response to the binding of a neurotransmitter. Ionotropic receptors mediate fast synaptic transmission and produce rapid effects on the postsynaptic cell.

Metabotropic receptors, on the other hand, are a different type of neurotransmitter receptor that do not have an ion channel pore. Instead, they are coupled to intracellular signaling pathways through G proteins. When a neurotransmitter binds to a metabotropic receptor, it triggers a series of intracellular signaling events that can modulate ion channels or affect other cellular processes. Metabotropic receptors mediate slower synaptic transmission and produce longer-lasting effects on the postsynaptic cell.

In summary,

ionotropic receptors: directly allow ion flow upon neurotransmitter binding,

metabotropic receptors: activate intracellular signaling pathways to produce their effects.

The shadow reflex in barnacles involves a neuronal pathway that allows the organism to respond to changes in light intensity and adjust its position to remain in darker areas.

1. Photoreceptor Cells: Barnacles have specialized photoreceptor cells located in their eyestalks that detect changes in light intensity. These cells are sensitive to light and generate electrical signals in response to light stimulation.

2. Photoreceptor Output Neurons: The electrical signals from the photoreceptor cells are transmitted to a group of output neurons. These output neurons receive inputs from multiple photoreceptor cells and integrate the information.

3. Excitatory Projection Neurons: The output neurons then send excitatory signals to the motor neurons responsible for muscle contractions. These excitatory projection neurons transmit signals that promote muscle contraction, leading to the extension of the barnacle's body.

4. Inhibitory Interneuron: An inhibitory interneuron is present in the pathway between the output neurons and motor neurons. This interneuron receives excitatory input from the output neurons but has an inhibitory effect on the motor neurons.

5. Inverting Cell: The inhibitory interneuron is connected to an inverting cell, which, instead of inhibiting the motor neurons, activates them. The inverting cell acts as a switch, converting the inhibitory signal from the inhibitory interneuron into an excitatory signal for the motor neurons.

The physiological properties of the involved cells vary. The photoreceptor cells are specialized for light detection, converting light stimuli into electrical signals. The output neurons integrate signals from multiple photoreceptor cells and transmit excitatory information. The inhibitory interneuron receives excitatory inputs from the output neurons and provides inhibitory input to the motor neurons. Finally, the inverting cell receives inhibitory input from the inhibitory interneuron but outputs excitatory signals to the motor neurons.

The presence of an inverting cell in the circuit is crucial for the shadow reflex pathway. It allows the inhibitory signal from the inhibitory interneuron to be converted into an excitatory signal, effectively activating the motor neurons and promoting the appropriate response of muscle contraction for repositioning the barnacle in darker areas. The inverting cell ensures the proper directionality and coordination of the shadow reflex response.

Non-associative learning:

• Habituation: a repetitive stimulus that does not bear any relevance leads to a decrease in the response. This is not due to receptor adaptation or muscle fatigue.

• Sensitization: a strong, relevant (e.g., noxius or rewarding) stimulus that increases the animal‘s reactivity in general (not stimulus-specific).

Associative learning:

a) Classical conditioning, CS-US-paring,

US = punishing or rewarding stimulus.

CS = neutral stimulus prior to training.

Contiguity (temporal relationship between the two stimuli)

Contingency (the occurence of the stimuli follow a general rule)

b) Operant conditioning: The own behavioral action leads to consequences.

• The habituated response can be dishabituated by a different, strong, often relevant stimulus (similar to sensitization).

• Stimulus-specific: Only the repeatedly presented stimulus causes habituation.

• The degree of habituation is dependent on the number of stimulations.

• Spontaneous recovery can be observed after a period without habituating stimulus.

• With repeated series of habituating stimuli the decline in response ocurrs faster and faster.

Sensitization: a strong stimulus enhances the general reactivity non- specifically.

Sensitization is non-specific, but can be restricted to a certain behavioral context. Food-related, sensitization enhance responses in the context of feeding, noxoius stimuli enhance responses in the context of protective or escape behavior.

Since multiple behavioral reactions are enhanced („central arousal“), larger parts of the nervous system must be modulated.

Example Aplysia: heterosynaptic facilitation.

1. Synaptic depression = decrease in synaptic transmission

2. Synaptic potentiation = increase in synaptic transmission

a) Homosynaptic plasticity: one synapse (2 neurons) are modulated.

b) Heterosynaptic plasticity: 2 oder more synapses are part of the modulation process.

Example: convergence of two neurons onto a common postsynaptic neuron.

The simple form of habituation could be explained by homosynaptic depression of a reflex circuit.

The response of a postsynaptic neuron to a presynaptic action potential is probabilistic. The vesicles released can be, e.g., one, two or three or none. On average the number can be, e.g., two. This probabilistic release of vesicles (“quanta”) can be described as a Poisson distribution.

Conclusion:

• Arrival of an action potential increases the probability of the release of a quantum (= fusion of vesicle).

• Several vesicles are ready to be released. Every quantum causes the same effect at the postsynaptic site (quantal size Q that sums up linearly at the postsynaptic site.

• The average number of quanta released, m, is given by the product of n, the number of available quanta: m = np.

• The average response of the postsynaptic neuron to a presynaptic stimulus is the product of the quantal size and the average number of quanta per stimulus: Qm = Qnp.

• The release probability of observing 0, 1, 2, ..., n quanta is given by a binomial distribution, with parameters n and p.

1. Paired-Pulse Facilitation: When two stimuli arrive in close succession, the second stimulus can produce a stronger excitatory postsynaptic potential (EPSP), resulting in an increase in synaptic transmission.

2. Augmentation: Augmentation refers to an increase in the amplitude of EPSPs with a slower time constant. It can occur in response to prolonged or repetitive stimulation of the presynaptic neuron.

3. Potentiation: Prolonged or fast and repeated stimulation of the presynaptic neuron can lead to a sustained increase in the amplitude of EPSPs. This is referred to as potentiation.

4. Paired-Pulse Depression: When two stimuli arrive in close succession, the second stimulus produces a weaker EPSP compared to the first stimulus, resulting in a decrease in synaptic transmission.

Simple forms of learning

Non-associative learning:

• Habituation:

  a repetitive stimulus that does not bear any relevance leads to a decrease in the response. This is not due to receptor adaptation or muscle fatigue.

• Sensitization:

  a strong, relevant (e.g., noxius or rewarding) stimulus that increases the animal‘s reactivity in general (not stimulus-specific).

Associative learning:

a) Classical conditioning,

CS-US-paring,

US = punishing or rewarding stimulus.

CS = neutral stimulus prior to training.

Contiguity (temporal relationship between the two stimuli)

Contingency (the occurence of the stimuli follow a general rule)

b) Operant conditioning: The own behavioral action leads to consequences.

1. Homosynaptic plasticity: one synapse (2 neurons) are modulated. -> 1 pathway

1. Heterosynaptic plasticity: 2 oder more synapses are part of the modulation process. -> more than one pathway

Example: convergence of two neurons onto a common postsynaptic neuron.

1. Activation of PKA: The activation of PKA is triggered by an increase in intracellular levels of cyclic adenosine monophosphate (cAMP). This can occur when a neurotransmitter, such as serotonin, binds to its receptor on the presynaptic membrane, leading to the activation of adenylyl cyclase, an enzyme that synthesizes cAMP.

2. PKA Translocation: Once activated, PKA translocates from the cytoplasm to various target sites within the presynaptic terminal. This translocation is facilitated by the binding of cAMP to the regulatory subunits of PKA, releasing the catalytic subunits that are responsible for the downstream signaling.

3. Phosphorylation of Proteins: The catalytic subunits of PKA phosphorylate a variety of proteins within the presynaptic terminal. One key target of PKA phosphorylation is the voltage-gated calcium channels (VGCCs) that mediate calcium entry into the presynaptic terminal upon depolarization. Phosphorylation of VGCCs by PKA increases their activity, leading to an enhanced influx of calcium ions.

4. Calcium-Dependent Events: The increased calcium influx resulting from PKA-mediated phosphorylation of VGCCs triggers several downstream events. This includes the activation of protein kinases and the modulation of proteins involved in neurotransmitter release, such as synaptotagmin and synapsin.

5. Enhanced Synaptic Vesicle Release: The cumulative effects of PKA-mediated phosphorylation events ultimately lead to an enhancement of synaptic vesicle release. These include an increase in the probability of vesicle fusion with the presynaptic membrane and alterations in the readily releasable pool of vesicles available for release.

By modulating the activity of presynaptic proteins involved in calcium entry and neurotransmitter release, PKA regulates the strength of synaptic transmission in Aplysia. This PKA-mediated modulation of synaptic vesicle release contributes to the plasticity of synaptic connections and the cellular mechanisms underlying learning and memory in the animal.

1. Serotonin Release: Sensitization is often induced by the release of serotonin, which acts as a modulatory neurotransmitter. Serotonin is released by a facilitating interneuron onto the sensory neuron responsible for the gill withdrawal reflex.

2. Activation of Serotonin Receptors: Serotonin binds to specific receptors on the sensory neuron, initiating intracellular signaling cascades. In Aplysia, the most well-known receptor involved is the serotonin receptor 5-HT2A.

3. Activation of Adenylyl Cyclase: Activation of the serotonin receptor leads to the activation of adenylyl cyclase, an enzyme that synthesizes cyclic adenosine monophosphate (cAMP) from adenosine triphosphate (ATP).

4. Activation of Protein Kinase A (PKA): Increased cAMP levels result in the activation of protein kinase A (PKA), a key intracellular signaling molecule. PKA translocates from the cytoplasm to various target sites within the sensory neuron.

5. Phosphorylation of Proteins: Once activated, PKA phosphorylates various proteins involved in the regulation of synaptic strength. This includes the phosphorylation of ion channels, such as potassium channels, which results in their decreased activity and prolonged membrane depolarization.

6. Modulation of Calcium Channels: PKA phosphorylation also modulates voltage-gated calcium channels (VGCCs) in the presynaptic terminal of the sensory neuron. This enhances calcium influx upon action potential initiation, leading to increased calcium-dependent processes.

7. Enhanced Neurotransmitter Release: The increased calcium influx triggers enhanced neurotransmitter release from the sensory neuron onto the motor neuron involved in the gill withdrawal reflex. This results in an amplified response and sensitization of the reflex.

intact:

• Short-term memory

• Intelligence

• Motor learning

defect:

• Acquisition of new “declarative” (episodic, semantic) long-term memories (“anterograde amnesia”), certain retrograde deficits, but old memories (“childhood”) are intact.

explicit (declarative)

• conscious and intentional acquisition of knowledge or skills

• the ability to consciously recall and express what has been learned

• involves the engagement of cognitive processes such as attention, reasoning, and deliberate rehearsal

• Examples of explicit learning include learning facts, memorizing information, and acquiring explicit knowledge about specific topics

implicit (non-declarative) learning.

• without conscious awareness or intention

• acquiring knowledge or skills through implicit processes -> learning takes place without explicit instruction or deliberate effort

• occurs gradually and is manifested in changes in behavior or performance without conscious reflection on the acquired knowledge

• Examples: acquiring motor skills, learning to ride a bicycle, or developing intuitive knowledge through repeated exposure to certain patterns or stimuli

Humans can express declarative memories by language.

Maze experiments in rodents

Task 1: all arms contain food. The rat should learn to visit each arm only once to optimize the search strategy ( = working memory task).

Task 2: only four of the eight arms contain food. The rat should learn to search for food only there (= reference memory task).

Lesion of the hippocampus: rats learn to move towards the end of the arms, but cannot remember in which arms they have been.

Morris water maze

Orientation with spatial cues because platform is not visible.

The rat learns the spatial relationships between cues (= spatial learning)

Long-term potentiation (LTP) is a form of synaptic plasticity that refers to a long-lasting strengthening of the synaptic connection between two neurons. It is considered a cellular mechanism underlying learning and memory formation in the brain.

Some properties of this type of long-term potentiation:

1. Cooperativity: LTP can be induced by cooperative activation of presynaptic and postsynaptic neurons. When the presynaptic neuron repeatedly and persistently fires while the postsynaptic neuron is depolarized, LTP can be triggered. Enough afferent fibers must be activated.

2. Input specificity: LTP exhibits input specificity, meaning it is specific to the synapses that were activated during the induction process. Only the synapses that experienced a high level of activity or stimulation undergo potentiation, while neighboring synapses remain unaffected. Only those synapses are potentiated whose pre- and postsynaptic cells are coincidently active.

3. Associativity: LTP can display associativity, meaning that weakly stimulated synapses that are coincidently activated alongside strongly stimulated synapses can also undergo potentiation. This property allows for the associative linking of different inputs and strengthens their connections. Weakly activated synapses (sub- threshold) if the postsynaptic cell is coincidently activated by a different, strong input.

4. Synaptic Strength Enhancement: LTP results in an increase in the strength of synaptic transmission. It leads to a more robust and efficient communication between the presynaptic and postsynaptic neurons.

5. Persistent Changes: LTP is characterized by its long-lasting effects. Once induced, it can persist for an extended period, ranging from hours to days or even longer. This sustained enhancement of synaptic strength is thought to contribute to the long-term storage of information.

6. Involvement of NMDA Receptors: NMDA receptors play a crucial role in the induction of LTP. These receptors are a subtype of glutamate receptors and require both presynaptic glutamate release and postsynaptic depolarization for activation. The influx of calcium through NMDA receptors triggers various intracellular signaling pathways that lead to the potentiation of the synapse.

7. Role in Learning and Memory: LTP is believed to be one of the key cellular mechanisms underlying learning and memory formation. The persistent strengthening of synaptic connections through LTP is thought to contribute to the encoding and storage of new information.

Overall, long-term potentiation is a process of enduring synaptic enhancement that is input-specific, associative, and critically involved in learning and memory. It involves the activation of specific receptors and intracellular signaling pathways, leading to persistent changes in synaptic strength.

1. AMPA Receptor:

   • Role in Baseline Transmission: AMPA receptors mediate the majority of fast excitatory synaptic transmission in the central nervous system under normal conditions.

   • Initial Synaptic Response: When glutamate is released from the presynaptic neuron, it binds to and activates the AMPA receptors on the postsynaptic membrane. Activation of AMPA receptors allows the influx of sodium ions, resulting in a rapid depolarization of the postsynaptic membrane and the generation of excitatory postsynaptic potentials (EPSPs).

   • Contribution to LTP Induction: During the early phase of LTP induction, the activation of AMPA receptors is critical. The influx of sodium ions through AMPA receptors leads to depolarization and the removal of a voltage-dependent magnesium block at NMDA receptors, allowing them to be activated.

2. NMDA Receptor:

   • Requirement for LTP Induction: NMDA receptors play a crucial role in the induction of LTP. They are voltage-dependent and require both presynaptic glutamate release and postsynaptic depolarization to become activated.

   • Coincidence Detection: NMDA receptors are involved in coincidence detection. They require the presynaptic release of glutamate and the postsynaptic depolarization, which relieves the magnesium block, allowing calcium ions to enter the postsynaptic neuron. Calcium influx through NMDA receptors triggers various intracellular signaling pathways that lead to the long-lasting changes associated with LTP.

   • Synaptic Plasticity: Once NMDA receptors are activated, the calcium ions that enter the postsynaptic neuron initiate various intracellular processes, including the activation of protein kinases and the synthesis of new proteins. These processes contribute to the strengthening and potentiation of the synaptic connection, leading to long-term changes in synaptic efficacy.

In summary, the AMPA receptor is responsible for the initial synaptic response and depolarization, while the NMDA receptor plays a pivotal role in coincidence detection and the induction of LTP. The activation of NMDA receptors triggers calcium-dependent signaling cascades that lead to the molecular and cellular changes underlying the long-lasting synaptic potentiation observed in LTP.

• Pattern completion is a cognitive process.

• It involves retrieving complete patterns or memories from partial or incomplete cues.

• The brain fills in missing information to reconstruct a complete representation.

• Stored information and existing neural connections are used in the process.

• It allows recognition of familiar objects and recall of memories from partial cues.

• Pattern completion relies on associative memory and interconnected neural networks.

• Activation of a partial cue triggers the reactivation of interconnected neurons.

• It plays a role in recognizing faces, objects, recalling memories, and maintaining continuity of thought.

• Pattern completion helps make inferences and fill in missing details based on previous experiences and knowledge.

A network of distributed synapses can store a neuronal pattern as a "memory" through a process known as synaptic plasticity and the concept of Hebbian learn

1. Synaptic Connections: In a neural network, individual neurons are connected to each other through synapses, which are the points of communication between neurons. Each synapse consists of a presynaptic terminal from one neuron and a postsynaptic terminal on another neuron.

2. Hebbian Learning: Hebbian learning is a fundamental principle that states "neurons that fire together, wire together." It suggests that when two connected neurons are repeatedly activated in close temporal proximity, the synaptic connection between them is strengthened. This synaptic strengthening occurs through a process called long-term potentiation (LTP).

3. Long-Term Potentiation (LTP): LTP is a form of synaptic plasticity that leads to the long-lasting enhancement of synaptic strength. When a presynaptic neuron repeatedly activates a postsynaptic neuron, it triggers a series of intracellular signaling events. This signaling cascade involves the activation of various proteins and the strengthening of the synaptic connection. As a result, the postsynaptic neuron becomes more responsive to the signals from the presynaptic neuron.

4. Distributed Synaptic Connections: In a network of interconnected neurons, a specific pattern of activation across multiple synapses can represent a particular memory or information. The pattern is encoded by the specific pattern of synaptic connections and their strengths within the network.

5. Pattern Recognition and Retrieval: When a partial cue or input activates a subset of neurons within the network, the distributed synaptic connections allow for pattern completion and retrieval of the complete memory or information associated with that pattern. The activated subset of neurons triggers the reactivation of the entire pattern through interconnected synaptic connections, allowing for pattern recognition and retrieval.

By adjusting the strengths of synaptic connections and establishing specific patterns of activation, a network of distributed synapses can store and retrieve neuronal patterns as memories. This distributed and interconnected nature of synapses provides flexibility, resilience, and capacity for information storage and retrieval in the brain.

Yes, there are molecular similarities between synaptic plasticity in Aplysia and long-term potentiation (LTP) in the hippocampus. While there are specific differences due to the distinct characteristics of these systems, some key molecules play similar roles in both forms of synaptic plasticity.

1. NMDA Receptors: NMDA receptors have a central role in both Aplysia and hippocampal LTP. Activation of NMDA receptors is critical for the induction of LTP in the hippocampus, as well as for the induction of sensitization in Aplysia. NMDA receptors contribute to calcium influx, which triggers intracellular signaling cascades that lead to synaptic plasticity.

2. Calcium Signaling: Calcium ions serve as a crucial signaling molecule in both Aplysia and hippocampal LTP. Calcium influx through NMDA receptors in the hippocampus and other calcium channels in Aplysia is involved in the activation of various downstream signaling pathways that regulate synaptic plasticity.

3. Protein Kinase A (PKA): PKA is a key signaling molecule that plays a role in both Aplysia and hippocampal LTP. In Aplysia, PKA is involved in the modulation of synaptic strength and is required for the expression of long-term facilitation. In the hippocampus, PKA activation is also implicated in the induction and expression of LTP.

4. Protein Kinase C (PKC): PKC is another protein kinase that is involved in both Aplysia and hippocampal LTP. It is an important modulator of synaptic plasticity and is activated during the induction and expression of both forms of plasticity.

5. CREB (cAMP Response Element-Binding Protein): CREB is a transcription factor that plays a role in both Aplysia and hippocampal LTP. It is involved in the long-lasting changes associated with synaptic plasticity and is implicated in the regulation of gene expression necessary for long-term changes in synaptic strength.

While there are also differences in molecular mechanisms and specific signaling pathways between Aplysia and hippocampal LTP, these shared molecular components highlight some common underlying principles of synaptic plasticity across different model systems.

• Knockout mice without NMDA receptors in the CA1 region of the hippocampus have deficits in spatial memory formation.

• The involvement of CA1 NMDA receptors suggests their importance in encoding or storing spatial memory.

• Memory is not exclusively stored in one specific region; it involves distributed networks across multiple brain regions.

• Proving the exact localization of a memory is challenging.

• Techniques like lesion studies, optogenetics, and functional imaging provide insights but cannot precisely pinpoint the location of a memory.

• Memories likely rely on coordinated activity among interconnected brain regions.

Proof of an internal clock: constant environmental conditions (without Zeitgeber) lead to a maintenance of rhythm, but with a phase shift (free running cycle).

Subjects in an constant environment while their behaviours and in the best case hormones are constantly being measured.

Is a behaviour still rhythmic -> internal clock

Behaviour loses rhythm -> no internal clock

• Zeitgeber: Zeitgeber refers to an external cue or stimulus that helps regulate and synchronize an organism's internal biological rhythms with the external environment. It serves as a "time giver" that helps set or entrain the biological clock.

• Circadian Rhythm: Circadian rhythm refers to a roughly 24-hour cycle that influences various physiological and behavioral processes in organisms. It regulates the sleep-wake cycle, hormone production, body temperature, and other biological functions. Circadian rhythms are driven by an internal biological clock and can be influenced by zeitgebers such as light, temperature, and social cues.

• Entrainment: Entrainment is the process by which an organism's internal biological rhythms, such as the circadian rhythm, align and synchronize with external cues or zeitgebers. It involves adjusting the timing and phase of the internal clock in response to environmental cues, ensuring that the biological rhythms stay in harmony with the external world.

• Free Running Cycle: The free running cycle refers to the natural rhythm of an organism's internal clock when it is isolated from external cues or zeitgebers. In the absence of external time cues, an organism's internal biological rhythm will continue to cycle, but it may not align precisely with the 24-hour day. The duration of the free running cycle may be slightly longer or shorter than 24 hours, indicating the intrinsic period of the internal clock.

In Drosophila (fruit flies), the timeless (tim) and period (per) genes play a crucial role in generating a rhythm through a cellular principle known as transcription-translation feedback loop. Here's an overview of how these genes function and contribute to the generation of a rhythm:

1. Transcription: In the morning, the CLOCK-CYCLE (CLK-CYC) protein complex binds to specific DNA regions called E-boxes in the promoter region of the per and tim genes. This binding leads to the activation of gene transcription.

2. Translation: The newly transcribed mRNA molecules of per and tim are then processed and translated into PER and TIM proteins.

3. Protein Accumulation: As the day progresses, the PER and TIM proteins accumulate within the cytoplasm of the cells.

4. Nuclear Entry: Eventually, the PER and TIM proteins form a complex and enter the cell nucleus.

5. Inhibition of Transcription: Once in the nucleus, the PER-TIM complex inhibits the activity of the CLK-CYC complex, preventing further transcription of per and tim genes.

6. Degradation: Over time, the PER and TIM proteins undergo degradation, reducing their levels in the cytoplasm.

7. Relief of Transcription Inhibition: As the PER and TIM protein levels decrease, their inhibition on CLK-CYC is alleviated, allowing the transcription of per and tim genes to resume.

8. Cycle Restart: The newly transcribed per and tim mRNA molecules are again translated into PER and TIM proteins, initiating a new cycle of accumulation, nuclear entry, inhibition, degradation, and relief.

This transcription-translation feedback loop between the PER-TIM complex and the CLK-CYC complex creates a rhythmic pattern of protein accumulation and degradation, leading to oscillations in gene expression levels. The time it takes for the PER and TIM proteins to accumulate, inhibit transcription, degrade, and relieve inhibition determines the duration of the cycle, resulting in a roughly 24-hour rhythm.

The timely and coordinated interactions between the per and tim genes and their protein products enable the generation of a cellular clock that drives the circadian rhythm in Drosophila. This principle of transcription-translation feedback loops is found in various organisms and plays a fundamental role in regulating circadian rhythms across species, including humans.

The "master clock" in mammals is located in an area of the brain called the suprachiasmatic nucleus (SCN). The SCN is a small, paired structure located in the hypothalamus, specifically above the optic chiasm, which is where the optic nerves cross.

The SCN receives optical zeitgeber input primarily through a specialized population of retinal ganglion cells called intrinsically photosensitive retinal ganglion cells (ipRGCs). These cells contain a photopigment called melanopsin, which is sensitive to light and allows them to respond to changes in light intensity and wavelength.

The ipRGCs receive light information from the environment and transmit this information to the SCN via the retinohypothalamic tract. This pathway sends direct, monosynaptic connections from the retina to the SCN, bypassing other visual processing areas. The ipRGCs communicate with the SCN, relaying information about light-dark cycles and serving as the primary conduit for optical zeitgeber input.

When light is detected by the ipRGCs, it leads to the suppression of melatonin production from the pineal gland and helps synchronize the internal circadian rhythm with the external light-dark cycle. Light exposure during the day promotes wakefulness and activity, while darkness during the night promotes sleep and rest.

The input from the ipRGCs to the SCN allows the master clock in the SCN to adjust and align the timing of circadian processes throughout the body. This synchronization with the light-dark cycle helps regulate various physiological and behavioral rhythms, including the sleep-wake cycle, hormone secretion, body temperature, and metabolism.

1. Sleep-Wake Cycle: The sleep-wake cycle is a prominent circadian rhythm that regulates the alternating patterns of sleep and wakefulness over a 24-hour period.

2. Body Temperature: Core body temperature follows a circadian rhythm, typically peaking in the late afternoon or early evening and reaching its lowest point during the early morning hours.

3. Hormone Secretion: Various hormones in the body exhibit circadian fluctuations. For example, cortisol, a stress hormone, typically follows a diurnal pattern with higher levels in the morning and lower levels in the evening. Melatonin, a hormone involved in sleep regulation, is typically released in higher amounts during the evening and nighttime hours.

4. Blood Pressure: Blood pressure can exhibit diurnal variations, typically showing higher levels during the daytime and lower levels during sleep.

5. Alertness and Cognitive Performance: Alertness and cognitive performance tend to follow a circadian pattern, with peaks during the daytime and troughs during the early morning hours (commonly known as the "afternoon slump").

6. Metabolic Processes: Various metabolic processes, such as glucose metabolism and insulin sensitivity, show diurnal variations, with increased activity during the daytime and reduced activity during sleep.

7. Digestion: The digestive system also demonstrates circadian rhythmicity, with changes in gastrointestinal motility and enzyme secretion across the day.

8. Cardiovascular Function: Heart rate, cardiac output, and other cardiovascular parameters can exhibit diurnal variations, with higher levels during the day and lower levels during sleep.

• Rhythmic behavior can be measured using actigraphy.

• Actigraphy involves recording and analyzing movement patterns over time.

• An actogram is a graphical representation of the data obtained from actigraphy.

• It displays activity levels or movement counts in a 24-hour format.

• Consecutive periods of activity and rest are depicted as alternating dark and light bars or squares.

• Actograms are used to identify and analyze rhythmic behavior, such as the sleep-wake cycle or circadian rhythms.

• They are valuable tools in sleep research and the study of biological rhythms.

the retinohypothalamic tract is a neural pathway that connects the retina to the hypothalamus, specifically the SCN. It transmits light information from specialized retinal ganglion cells called ipRGCs, playing a key role in regulating the circadian rhythm and coordinating the body's internal clock with the external light-dark cycle.

Masking:

• Using blackout curtains or wearing a sleep mask: By blocking out external light during sleep, these measures help mask the influence of light on the sleep-wake cycle. They create a darker environment that promotes better sleep and reduces the impact of light as a zeitgeber.

• Wearing earplugs or using white noise machines: These measures can mask external auditory stimuli, such as noise from traffic or neighbors, which may disturb sleep and impact the quality of rest.

• Using blue-light blocking glasses: Blue light emitted by electronic devices can interfere with the natural sleep-wake cycle by suppressing melatonin production. Wearing blue-light blocking glasses in the evening can help mask the disruptive effect of blue light and promote better sleep.

Entrainment:

• Morning sunlight exposure: Exposing yourself to natural sunlight in the morning helps entrain your circadian rhythm. The bright light in the morning sends a strong zeitgeber signal to your body, indicating the start of the day and helping you feel more awake and alert. This exposure can regulate your internal clock and promote better daytime functioning.

• Regular meal times: Consistently eating meals at specific times throughout the day can help entrain the circadian rhythm associated with digestion and metabolism. Regular meal timing signals the body to anticipate and prepare for nutrient intake and promotes better metabolic regulation.

• Exercise routine: Engaging in regular exercise at consistent times, such as morning or early evening, can help entrain the circadian rhythm associated with physical activity. Regular exercise promotes wakefulness, energy expenditure, and overall well-being, aligning with the natural cycles of the body.

• Establishing a bedtime routine: Creating a consistent routine before bedtime, such as reading a book or taking a warm bath, helps signal to the body that it's time to wind down and prepare for sleep. This routine can aid in entraining the circadian rhythm associated with sleep onset and improve sleep quality.

The suprachiasmatic nucleus (SCN) circuit can be described as a "system" because it consists of multiple interconnected components that work together to perform a specific function. A system typically refers to a set of elements or parts that are organized and interact in a coordinated manner to achieve a collective purpose.

1. Neuronal Population: The SCN consists of a specific group of neurons located in the hypothalamus that serve as the central pacemaker for circadian rhythms.

2. Input Pathways: The SCN receives inputs from various sources, including the retinohypothalamic tract (light information), neural pathways from other brain regions, and input from other bodily systems.

3. Output Pathways: The SCN sends output signals to other brain regions and peripheral tissues, influencing their activity and coordinating the timing of physiological processes.

4. Intracellular Signaling: Within SCN neurons, there are intricate signaling pathways involving various molecules, receptors, and ion channels that contribute to the generation and maintenance of rhythmic activity.

1. Precision: The variability in phase among individual clock neurons allows for more precise timing and coordination of circadian rhythms. The SCN acts as a central pacemaker, and having a diversity of phases in its constituent neurons helps in accurately timing various physiological and behavioral processes. This diversity ensures that the timing of specific events, such as hormone secretion or sleep-wake cycles, is finely regulated.

2. Robustness: The presence of different phases in individual clock neurons increases the robustness and stability of the circadian system. If all cells were intrinsically firing at the same phase, the system would be more vulnerable to disruptions. However, by having a range of phases, the SCN can maintain its function even if a subset of neurons is affected or compromised. This redundancy in the system helps ensure that circadian rhythms persist despite external influences or internal variations.

3. Adaptability: The diversity of phases allows the SCN to adjust and adapt to changes in external cues or environmental conditions. The SCN needs to synchronize its rhythm with the light-dark cycle, and having different phases in its neurons allows for flexibility in entrainment. It enables the system to respond to shifts in light exposure, such as when traveling across time zones, by adjusting the phase relationship among the neurons to align with the new environmental conditions.

In summary, the presence of different phases in individual clock neurons of the SCN contributes to the precision, robustness, and adaptability of the circadian system. This diversity of phases allows for fine-tuning of timing and coordination, enhances the resilience of the system, and enables appropriate adjustments in response to environmental changes.

1. Neural Pathways: The SCN sends neural signals to other brain regions involved in controlling behavior and physiological processes. It projects to areas such as the pineal gland, which regulates melatonin production, and the hypothalamus, which influences hormone secretion and various homeostatic functions.

2. Hormonal Pathways: The SCN regulates the release of certain hormones that can impact peripheral organs and brain regions. For example, the SCN controls the timing of cortisol release from the adrenal glands, which influences metabolism and stress response. It also influences the release of other hormones, such as growth hormone and prolactin.

3. Autonomic Nervous System: The SCN can modulate the activity of the autonomic nervous system, which controls functions such as heart rate, blood pressure, and digestion. By influencing autonomic outflow, the SCN can indirectly regulate the physiological processes of peripheral organs.

4. Circadian Clocks in Peripheral Organs: The SCN can synchronize or entrain the circadian clocks present in peripheral organs. Peripheral organs, including the liver, kidneys, and gastrointestinal system, have their own internal clocks that are influenced by the SCN. The SCN can send timing signals to peripheral clocks via neural, hormonal, or other signaling pathways, ensuring coordination and alignment of circadian rhythms throughout the body.

These routes of control allow the SCN to exert its influence on peripheral organs and brain regions involved in behavior and physiological regulation. The SCN acts as the central pacemaker, coordinating and synchronizing circadian rhythms across the body, ensuring proper timing and integration of various biological processes.

1. There is no obvious order in the perceptual olfactory space!

2. There are no „primary odors“!

3. There seems to be no simple connection between percept and the volatile chemical compound!

4. Olfactory percepts are mostly synthetic, not analytic, i.e., we have a limited ability to discriminate compounds in a complex mixture of odorants. But there are dominant key odorants (“main components”) determining smells (important for food industry).

1. Each olfactory sensory neuron expresses typically one olfactory receptor.

2. A given receptor can bind multiple odorants. The range of odorants can be broad (“broadly tuned receptors”, e.g., to many alcohols) or narrow (“narrowly tuned receptors”, e.g., to very specific pheromones).

3. A given odorant molecule can often bind to multiple receptors.

4. The ligand receptor interaction causes depolarization leading to a particular action potential frequency AND a particular response latency.

5. The combination of these responses encodes odor identity and odor intensity.

• recurrent inhibition (“gain control”), e.g. example in case of over-stimulation.

• lateral inhibition (“contrast enhancement”) between glomeruli.

• Odor-onset and offset responsiveness of mitral cells though recurrent inhibitory feedback.

• Reorganization of action potential firing patterns of mitral cells until they reach a steady state (“de-clustering” or “de- correlation”).

• Synchronization of subsets of mitral cell action potentials (enhances “bandwidth” of information about a certain odorant”.

1. Salty

2. Sour

3. Sweet

4. Bitter

5. Umami (sodium glutamate)

sugars (fructose, sucrose, maltose), proteins (monellin), aspartam, sachharin, sucralose

Ions (KCl, Mg2+, Chinin, coffein, denatonium).

Salts

Acids

Type I cell

Type II cell

Type III cell

comprise approximately half the total number of cells in a taste bud. They have narrow, irregularly shaped nuclei, are electron-dense and have wing-like cytoplasmic extensions that ensheath other taste bud cells. Type I cells seem to have glia-like functions. They express enzymes and transporters that are required to eliminate extracellular neurotransmitters and ion channels that are associated with the redistribution and spatial buffering of K+.

Approximately one-third of the cells in a taste bud are type II cells. These cells function as chemosensory receptors for sugars, amino acids and/or bitter stimuli as they express taste G protein-coupled receptors (GPCRs) and their downstream effectors. Most type II cells express one class of taste GPCR — namely, taste receptor type 1 (T1R) or T2R — and correspondingly respond only to one taste quality (for example, sweet or bitter, but not both. It should be noted that T1R1, T1R2 and T1R3 are often co- expressed in taste bud cells, and, accordingly, responses to both sweet and umami stimuli can be detected in the same cells. The type II cells in a taste bud can differ in their expression of taste GPCRs such that each taste bud can respond to multiple taste stimuli.

the least numerous; they represent 2–20% of the cells in a taste bud, and their incidence varies regionally in the oral epithelium. For instance, taste buds on the anterior tongue (fungiform taste buds) often contain no more than a single type III cell, whereas taste buds in the posterior tongue may contain as many as ten. These cells display slender profiles and oblong nuclei. They do not express taste GPCRs but do contain the machinery required to detect sour taste. Type III cells have ultrastructurally recognizable synapses with features such as clear and dense-cored vesicles, SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins and densities in which the membranes of the taste cell oppose nerve fibres. By contrast, type II cells lack synaptic vesicles and communicate with closely apposed afferent fibres via non-vesicular transmitter release (ATP!).

• Amilorid-sensitive sodium channel

• voltage independent

• permanent open.

Effect of anion?

Can strongly influence taste (Na-saccharin, Na-acetate!)

Candidate: ENaC = epithelial sodium channel

Older (outdated) model: H+ can pass the amilorid-sensitive channel, H+ can block K+ channels

More recent data indicate other candidates:

PKD2L1 and PKD1L3 subunits (both TRP channels, interact to proper localize to the membrane)

2 families of taste receptors:

• T1R

• T2R.

~ 30 genes for T2R receptors, all are for bitter!

Bitter tasting solutes include many non-toxic and toxic alkaloids, hydrophilic quinine and some divalent ions. Involves a receptor protein linked to G-protein and activation of phospholipase C, which results in substrate hydrolysis to IP3, releasing Ca2+ from intracellular stores.

Sweet solutes and non-sugar sweeteners interact with a receptor membrane protein through a G protein, which activates phospholipase C. A second messenger, inositol triphosphate (IP3), is synthesized which releases Ca2+ from intracellular stores. Accumulation of Ca2+ depolarizes the cell, releasing neurotransmitter at the synapse.

• Type I cell: comprise approximately half the total number of cells in a taste bud. They have narrow, irregularly shaped nuclei, are electron-dense and have wing-like cytoplasmic extensions that ensheath other taste bud cells. Type I cells seem to have glia-like functions. They express enzymes and transporters that are required to eliminate extracellular neurotransmitters and ion channels that are associated with the redistribution and spatial buffering of K+.

• Type II cell: Approximately one-third of the cells in a taste bud are type II cells. These cells function as chemosensory receptors for sugars, amino acids and/or bitter stimuli as they express taste G protein-coupled receptors (GPCRs) and their downstream effectors. Most type II cells express one class of taste GPCR — namely, taste receptor type 1 (T1R) or T2R — and correspondingly respond only to one taste quality (for example, sweet or bitter, but not both. It should be noted that T1R1, T1R2 and T1R3 are often co- expressed in taste bud cells, and, accordingly, responses to both sweet and umami stimuli can be detected in the same cells. The type II cells in a taste bud can differ in their expression of taste GPCRs such that each taste bud can respond to multiple taste stimuli.

• Type III cell: the least numerous; they represent 2–20% of the cells in a taste bud, and their incidence varies regionally in the oral epithelium. For instance, taste buds on the anterior tongue (fungiform taste buds) often contain no more than a single type III cell, whereas taste buds in the posterior tongue may contain as many as ten. These cells display slender profiles and oblong nuclei. They do not express taste GPCRs but do contain the machinery required to detect sour taste. Type III cells have ultrastructurally recognizable synapses with features such as clear and dense-cored vesicles, SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins and densities in which the membranes of the taste cell oppose nerve fibres. By contrast, type II cells lack synaptic vesicles and communicate with closely apposed afferent fibres via non-vesicular transmitter release (ATP!).

1. Labeled Line: The concept of labeled line refers to the idea that each specific sensory modality, such as vision, hearing, touch, taste, or smell, is represented by a distinct and dedicated pathway in the nervous system. According to this concept, sensory information from a specific modality is transmitted through a specialized pathway, or "line," which is labeled with that particular sensory modality.

2. Across Fiber Pattern: In contrast to the labeled line concept, the across fiber pattern theory proposes that sensory information is encoded not by dedicated pathways for each modality but by the combined activity of a population of neurons. According to this theory, each sensory receptor responds to multiple types of stimuli, and the perception of a particular sensory experience arises from the pattern of activity across a population of neurons.

1. Combinatorial Code:

   • Combinatorial code refers to a coding scheme in which multiple elements or features are combined in various combinations to represent different stimuli or concepts. In this coding scheme, individual neurons or groups of neurons selectively respond to specific combinations of features, and the pattern of their activity represents a particular stimulus or concept.

   • For example, in the domain of olfaction (smell), different odorants can activate a large number of olfactory receptors. However, the perception of a specific odor arises from the unique combination of receptors that are activated and the pattern of their activation. Each receptor can contribute to the perception of multiple odors, and the brain interprets the specific combination of activated receptors to identify and discriminate between different smells.

   • The generation of a combinatorial code involves the integration of multiple sensory inputs or features and the subsequent activation of specific neurons or neural populations that are responsive to particular combinations. This coding scheme allows for a high degree of information representation and discrimination, as different stimuli can be distinguished based on the specific combinations of features that are present.

   • Advantages of combinatorial coding include:

     • High information capacity: Combinatorial codes can represent a large number of stimuli or concepts by combining different elements or features in various ways.

     • Discrimination and specificity: Specific combinations of features can be selectively encoded, enabling precise discrimination between similar stimuli.

     • Flexibility: Combinatorial coding allows for flexible and adaptive representation, as the same elements or features can be recombined to represent different stimuli or concepts.

2. Sparse Code:

   • Sparse code refers to a coding scheme in which only a subset of neurons or neural populations is active or involved in representing a particular stimulus or concept. In sparse coding, the majority of neurons remain inactive, while only a few neurons become highly active in response to a specific stimulus.

   • This coding scheme often occurs when stimuli or concepts are highly specific or distinct. For example, in visual recognition, certain neurons in the visual cortex may respond selectively to specific visual features, such as vertical lines or curves, while remaining unresponsive to other features. The activation of these sparse populations of neurons represents the presence of those specific features in the visual input.

   • The generation of a sparse code involves a process of competition and selection, where only a limited number of neurons with the highest selectivity or responsiveness to a given stimulus become active, while others remain silent.

   • Advantages of sparse coding include:

     • Efficiency: Sparse codes require fewer active neurons, resulting in a more efficient use of neural resources.

     • Noise reduction: By selectively activating only a few neurons, sparse coding can reduce the impact of background noise and increase the signal-to-noise ratio.

     • Robustness: Sparse codes can be more robust to variations or noise in the input, as only specific and highly responsive neurons are involved in representing a stimulus.

• Overall, combinatorial coding and sparse coding offer different advantages in representing and processing information. Combinatorial coding provides a rich and flexible representation with high information capacity, while sparse coding offers efficiency, noise reduction, and robustness to variations in the input. Both coding schemes contribute to the neural mechanisms that enable perception, cognition, and the interpretation of sensory information in the brain.

1. Topographic Neuronal Representation:

• Neurons organized based on spatial relationships between stimuli or body parts.

• Neighboring neurons represent adjacent regions in physical space.

• Example: Primary somatosensory cortex exhibits a topographic representation of the body surface.

1. Chemotopy:

• Neurons organized based on chemical properties of stimuli, not spatial relationships.

• Neurons respond to specific chemical cues, but their arrangement doesn't reflect physical proximity.

• Example: Olfactory system employs chemotopy, where receptors with similar chemical properties are dispersed and overlap in their activation patterns.

• Chemotopy does not preserve spatial relationships between stimuli.

Mammals:

1. Olfactory Receptors: Mammalian OSCs contain specialized olfactory receptor proteins embedded in their cell membranes.

2. Odorant Binding: Odorant molecules from the environment enter the nasal cavity and dissolve in the mucus, reaching the olfactory epithelium.

3. Receptor Activation: When odorant molecules bind to specific olfactory receptors on OSCs, it triggers a series of biochemical events.

4. Signal Transduction: The binding of odorants activates a cascade of intracellular events, involving G-protein coupled receptors and the activation of the enzyme adenylate cyclase.

5. cAMP Production: Adenylate cyclase produces cyclic adenosine monophosphate (cAMP) as a secondary messenger.

6. Ion Channel Activation: cAMP opens cyclic nucleotide-gated (CNG) ion channels, allowing an influx of calcium and sodium ions into the OSCs.

7. Depolarization: The influx of ions depolarizes the OSC, generating an action potential.

8. Transmission to the Brain: The action potential is transmitted to the olfactory bulb in the brain via the olfactory nerve, where further processing and perception of the odor occur.

Insects:

1. Odorant Receptors: Insects possess olfactory sensory neurons (OSNs) that express various odorant receptor proteins.

2. Odorant Binding: Odorant molecules from the environment enter the sensory hairs or sensilla on the insect's antennae.

3. Receptor Activation: When an odorant molecule binds to a specific odorant receptor on an OSN, it initiates a signaling process.

4. Ion Channel Activation: Odorant receptor activation triggers the opening of ligand-gated ion channels, such as cyclic nucleotide-gated (CNG) or ionotropic receptors.

5. Ion Flux: The ion channels allow the influx of calcium and/or sodium ions into the OSN, depolarizing the cell.

6. Action Potential Generation: Depolarization leads to the generation of an action potential in the OSN.

7. Transmission to the Brain: The action potential travels along the axon of the OSN, forming synapses in the insect's antennal lobe or other higher brain regions, where the olfactory information is processed.

While the overall process of transducing olfactory signals involves receptor activation, ion channel opening, depolarization, and transmission to the brain in both mammals and insects, the specific molecular mechanisms and the anatomical structures involved differ between the two groups.

• Location:

  Olfactory glomeruli are located in the olfactory bulb, which is a region of the brain directly above the nasal cavity.

• Structure:

  Each olfactory glomerulus is a spherical cluster of nerve terminals and synapses formed by the axons of olfactory sensory neurons.

• Organization:

  Olfactory glomeruli are arranged in a distinct pattern within the olfactory bulb, forming a spatial map or glomerular layer.

• Function:

  The main function of olfactory glomeruli is to serve as convergence sites for information from specific types of olfactory sensory neurons that express the same olfactory receptor.

• Odor Encoding:

  When odorant molecules bind to specific olfactory receptors on the olfactory sensory neurons, the corresponding glomeruli associated with those receptors are activated.

• Spatial Representation:

  Olfactory glomeruli contribute to the spatial representation and mapping of different odorant molecules in the olfactory bulb, allowing the brain to distinguish and discriminate between various smells.

• Processing:

  Within each glomerulus, there are complex interactions between the incoming olfactory sensory neuron axons and the dendrites of second-order neurons (mitral and tufted cells), which process and integrate olfactory information.

• Projection:

  After processing in the olfactory bulb, information from the olfactory glomeruli is further transmitted to higher brain regions involved in olfactory perception and interpretation.

In summary, olfactory glomeruli are specialized structures in the olfactory bulb that receive and process olfactory information, contributing to the spatial representation and integration of different smells in the brain.

1. Combinatorial Coding: The combination of different odorant receptors can generate a vast number of unique receptor activation patterns. The brain can interpret and discriminate between these patterns to perceive distinct odors. By employing combinatorial coding, where different receptors can be activated in various combinations, the olfactory system can generate a larger odor space than the number of individual receptors.

2. Receptor Sensitivity: Odorant receptors are not limited to responding to a single odorant molecule but can have a degree of sensitivity and respond to multiple structurally similar odorants. This broadens the range of odors that can be detected and distinguished.

3. Amplification and Signal Integration: The olfactory system has mechanisms to amplify and integrate signals. Even a weak activation of a specific receptor can be amplified through downstream signaling processes, enhancing the detectability of subtle differences between odors.

4. Temporal Patterns: Odor perception is not solely based on the activation of individual receptors but also relies on temporal patterns of activity. Different odors can evoke distinct patterns of activation across populations of receptors over time, contributing to odor discrimination.

5. Olfactory Memory and Learning: Human olfactory perception is influenced by olfactory memory and learning. Experience and exposure to different odors can shape and refine the brain's ability to discriminate between them, enhancing odor discrimination abilities beyond what can be achieved solely based on the number of receptors.

1. Genetic Manipulation: Fruit flies have a well-established toolkit for genetic manipulation. They have a short generation time, a large number of offspring, and well-characterized genetics, making it easier to study the role of specific genes and manipulate their expression in the olfactory system.

2. Simple and Accessible Olfactory System: The olfactory system of fruit flies is relatively simple compared to mammals, yet it shares fundamental principles with higher organisms. The fly's olfactory system consists of defined anatomical structures, making it easier to study and understand the underlying neural circuits and molecular mechanisms involved in olfaction.

3. Behavioral Assays: Fruit flies exhibit robust and easily measurable olfactory behaviors, such as olfactory-mediated attraction, aversion, or learning and memory. These behaviors can be readily studied using simple behavioral assays, allowing for high-throughput screening and analysis of olfactory responses.

4. Neuroanatomy and Connectome: The detailed neuroanatomy and connectome of the fruit fly brain, including the olfactory circuits, have been extensively mapped. This provides a valuable resource for understanding the organization and connectivity of the olfactory system, aiding in the investigation of odor processing and circuit function.

5. Conservation of Key Olfactory Genes: Many of the key genes and signaling pathways involved in olfaction are highly conserved between fruit flies and mammals. Discoveries made in fruit flies regarding olfactory mechanisms and genes often have relevance and applicability to other organisms, including humans.

6. Cost and Space Efficiency: Fruit flies are small, require minimal space and resources for maintenance, and have a short lifespan. These factors make large-scale studies feasible and cost-effective, enabling researchers to perform extensive genetic and behavioral analyses.

The combination of genetic tractability, well-defined olfactory system, behavioral assays, neuroanatomical knowledge, genetic conservation, and efficiency make Drosophila melanogaster an excellent model organism for investigating the fundamental principles of olfaction and advancing our understanding of olfactory mechanisms in both flies and higher organisms.

1. Population Code:

   • Information is represented by the collective activity patterns of a population of neurons.

   • Each neuron's activity contributes to the overall representation.

   • The combined activity of multiple neurons represents specific features or stimuli.

2. De-clustering in Population Code:

   • De-clustering refers to reducing or dispersing the clustering of neurons with similar response properties.

   • It aims to increase the diversity of response properties across the population.

   • De-clustering enhances the coding capacity and discrimination of stimuli.

   • It can be achieved through mechanisms such as experience-dependent plasticity, network dynamics, or balancing excitation and inhibition.

In summary, the population code refers to the collective activity patterns of a population of neurons representing specific information, while de-clustering in this context refers to the reduction or dispersion of clustered response properties within the population, promoting greater discrimination and coding capacity.

Broadly Tuned Receptor:

• A broadly tuned receptor is one that responds to a wide range of stimuli or exhibits a broad sensitivity to various molecules or features.

• It is less specific and can be activated by multiple, structurally diverse stimuli.

• For example, in olfaction, a broadly tuned receptor may respond to a wide range of odorants with different chemical structures.

Narrowly Tuned Receptor:

• A narrowly tuned receptor is one that responds to a specific subset of stimuli or exhibits a high specificity to certain molecules or features.

• It is highly selective and responds to a limited range of stimuli with similar chemical structures or specific features.

• For example, in olfaction, a narrowly tuned receptor may be highly specific to a particular odorant or a class of structurally similar odorants.

The tuning of receptors can vary along a spectrum, with some receptors exhibiting intermediate levels of selectivity. Broadly tuned receptors provide a broader range of responses and are involved in recognizing a diverse set of stimuli. In contrast, narrowly tuned receptors offer high specificity and are essential for discriminating between similar stimuli or detecting specific features.

Sleep can be defined across animal species and differentiated from paralysis, coma or simply inactivity.

1. Sustained periods of behavioral quiescence.

2. Increased arousal thresholds (stronger stimuli are required to evoke a behavioral response). Both states are easily reversible, which is different from coma or anesthesia.

3. Homeostatic regulation. Sleep duration is not strongly influenced by how much sensory input we have or how active we are. However, sleep loss is compensated for. After sleep loss, animals and humans sleep longer.

4. Different “patterns” of brain activity during periods of sleep and wakefulness. Sleep is characterized by “brain states”.

5. Decreased metabolism and other peripheral, vegetative functions (body temperature, breathing Rhythms, etc.).

6. Characteristic body posture.

The wake state of humans is maintained by sensory stimulation. Sleep is induced by fatigue, leading to less sensory stimulation, which reduces brain activity.

But: Giuseppe Moruzzi and Horace Magoun proved in 1949 this idea wrong:

Sectioning the ascending sensory pathways in the brain stem did not interfere at all with sleep and wakefulness.

However, lesions of the reticular formation of the brain stem caused behavioral stupor and sleep-like EEG patterns.

Second finding: It depends on where the reticular formation is sectioned: if it is cut above the pons, sleep is induced. If it is cut through the pons, sleep is inhibited!

These can be distinguished in humans using EEG measurements: global recordings of sum activity of neurons in the cerebral cortex.

Electrodes fixed with conductive substance. Standardized contact points on the skull.

Amplifier detects differences in voltage between two electrodes (in μV). Records sum activity of many neurons located directly under the skull.

Through shifts in ion concentrations very small electrical fields arise. Only if thousands of neurons are synchronously active a signal can be detected.

There are different characteristic types of rhythms:

• 10 – 30 Hz: Beta-rhythm, active cortex.

• > 30 Hz: Gamma-rhythm, „states of attention, concentration.

• 8 – 12 Hz: Alpha-rhythm, state of quiescence and wake state with closed eyes.

• 4 – 7 Hz: Theta-rhythm: distinct sleep phases (Non-REM sleep phase 1).

• < 4 Hz: Delta-rhythm: deep sleep, pathological coma.

The different sleep stages cannot only be differentiated by EEG patterns, but are also reflected in muscle tone (visible in electromyogram and in eye movements, visible in electro-oculogram).

Sleep stages 1-4 are called “Non-REM sleep”. Neuronal activity is low, metabolic rate and brain temperature are at their lowest. Activity of the sympathicus decreases, heart rate and blood pressure decline. Activity of parasympathicus increases, evidenced by constriction of pupils. Muscle tone and reflexes are intact.

Sleep stages 1-4 are called “Non-REM sleep”. Neuronal activity is low, metabolic rate and brain temperature are at their lowest. Activity of the sympathicus decreases, heart rate and blood pressure decline. Activity of parasympathicus increases, evidenced by constriction of pupils. Muscle tone and reflexes are intact.

1. Sleep stage 1: transition from wakefulness to the onset of sleep. Lasts several minutes. Awake people show low-voltage EEG activity at 16-5Hz. As they relax, alpha waves occur. In the transition to stage 1, slower frequencies (theta rhythms) occur. Slow, rolling eye movements and some activity of skeletal muscles.

2. Sleep stage 2: burst of sinusoidal waves called “sleep spindles” (12-14 Hz) and high-voltage biphasic waves (K complexes), which occur against background of low wave activity.

3. Sleep stage 3: high-amplitude, slow delta waves (0.5-2 Hz).

4. Stage 4, slow wave activity increases and dominates the EEG record. Stages 3 and 4 are sometimes calles “slow-wave sleep”.

REM (rapid eye movement) sleep is an active form of sleep. The EEG reverts to a mixed-frequency pattern, similar to stage 1 of Non-REM sleep. REM sleep is also called paradoxical sleep, because discharge patterns of neurons are similar to active wakefulness. Some neurons fire even more than during wakefulness.

Some bursts of activity originate in the pontine reticular formation, propagate through the lateral geniculate nucleus and further to the occipital cortex. Therefore, these activity bursts are called “ponto-geniculo-occipital spikes” (PGO spikes). They also occur in awake brains during abrupt and alerting stimuli (startle response).

Brain temperature and metabolic rate rise. All skeletal muscle tone is lost (atonia). Only muscles controlling eye movements, middle ear ossicles and diaphragm remain active.

Classical experiments by Moruzzi and Magoun:

• Electrical stimulation of the midbrain reticular formation promotes the waking state. Damage to this region causes a comatose state.

• The midbrain reticular formation is normally inhibited by a neuronal system in the medulla oblongata. Disconnecting this inhibition by disconnecting transecting the brain stem at the level of the pons produces a mostly awake animal.

Conclusion: There are wake-promoting neurons and sleep-promoting neurons that interact with each other.

• Stimulation of the posterior hypothalamus, rostral to the midbrain produces an arousal that resembles stimulation of the midbrain. These neurons release the transmitter histamine. Destruction of these histaminergic neurons increase sleep. Antihistaminic drugs promote sleep (see below: more recent data show that hypocretin (= orexin) is also an important transmitter).

• Stimulation of the anterior hypothalamus and the adjacent basal forebrain induces sleep. Lesions produce a reduction in sleep. These neurons release the inhibitory transmitter GABA.

Conclusion: Sleep & wake are controlled by different parts of the brain

Sleep initiation: Mediated by the GABA-ergic, inhibitory neurons in the anterior hypothalamus called Non- REM-on cells. They start the Non- REM sleep (see middle column left, Non-REM-on cells)!

They inhibit the histaminergic cells of the posterior hypothalamus and cells of the nucleus reticulates pontis oralis in the midbrain that mediate arousal. Non-REM-on cells are active durinbg Non-REM sleep and inactive during REM sleep and waking.

Conclusion: Non-REM sleep is induced by cells that are inactive during wake and REM sleep. These states exclude each other.

Non-REM sleep initiation: Mediated by the GABA-ergic, inhibitory neurons in the anterior hypothalamus called Non- REM-on cells. They start the Non- REM sleep (see middle column left, Non-REM-on cells)!

They inhibit the histaminergic cells of the posterior hypothalamus and cells of the nucleus reticularis pontis oralis (around the thalamus) in the midbrain that mediate arousal. Non-REM-on cells are active durinbg Non-REM sleep and inactive during REM sleep and waking.

Conclusion: Non-REM sleep is induced by cells that are inactive during wake and REM sleep. These states exclude each other.

Non-REM sleep is characterized by EEG spindles and slow waves, produced by synchronized cortical neurons. These synchronizations are generated by rhythmic firing of thalamic relay neurons that project to the cortex. The rhythmic firing results from the actions of GABA-ergig neurons in the nucleus reticularis.

Why? The rhythmic firing of thalamic and cortical cells occludes the transmission of sensory information through the thalamus and the cortex!

Conclusion: Non-REM sleep is induced by cells that are inactive during wake and REM sleep. Sensory input to the cortex is blocked.

REM sleep is characterized by low- voltage EEG without spindles and slow waves, i.e., not synchronized cortical neurons.

REM-on cells are part of the midbrain arousal system. They activate the GABA-ergic neurons of the nucleus reticularis, and these cannot generate rhythmic bursts anymore. Thereby, cortical cells cannot become synchronized any more. Asynchronously firing thalamo-cortical cells are visible as low-voltage EEG.

The major brain regions controlling REM sleep are visible in the sagittal section across the brain stem and forebrain.

Nuclei in the pontine region (= pons) critical for triggering REM sleep are shown in a coronal section: nucleus reticularis pontis oralis / caudalis (RPO / RPC).

Lesions of the regions block REM sleep or components of REM sleep.

Neurons located in the RPO/RPC trigger the switch from Non-REM to REM sleep.

Three classes: a) PGO-on cells (fire in bursts to initiate PGO spikes in cells of the lateral geniculate nucleus). These cells are regulated by b) REM-off cells (cells in the raphe nuclei of the brain stem, release serotonin = 5-HT). They become blocked if REM sleep is induced. REM-waking-on cells fire during waking and during REM sleep. They produce rapid eye movements during REM and head/neck/kimb movements during wakening. REM-on cells inhibit 5-HT cells and noradrenergic neurons in the raphe nucleus and nucleus ceruleus.

1. Conservation of metabolic energy?

   But: metabolic rate during sleep is only 15% less than during quit wakefulness. Rest is also possible during wakefulness!

2. Cognition?

   Sleep deprivation drastically impairs intellectual performance!

3. Thermoregulation?

   Heating the hypothalamus induces sleep in animals. However, evidence not strong.

4. Memory consolidation?

   Strong evidence that during sleep replay of neuronal patterns promotes consolidation of memory.

5. Clearance of radical oxygen species?

   Very recent evidence that during sleep cellular clearance processes take place!

1. Sustained periods of behavioral quiescence.

2. Increased arousal thresholds (stronger stimuli are required to evoke a behavioral response). Both states are easily reversible, which is different from coma or anesthesia.

3. Homeostatic regulation. Sleep duration is not strongly influenced by how much sensory input we have or how active we are. However, sleep loss is compensated for. After sleep loss, animals and humans sleep longer.

4. Different “patterns” of brain activity during periods of sleep and wakefulness. Sleep is characterized by “brain states”.

5. Decreased metabolism and other peripheral, vegetative functions (body temperature, breathing Rhythms, etc.).

6. Characteristic body posture.

1. Sustained periods of behavioral quiescence.

2. Increased arousal thresholds (stronger stimuli are required to evoke a behavioral response). Both states are easily reversible, which is different from coma or anesthesia.

3. Homeostatic regulation. Sleep duration is not strongly influenced by how much sensory input we have or how active we are. However, sleep loss is compensated for. After sleep loss, animals and humans sleep longer.

4. Different “patterns” of brain activity during periods of sleep and wakefulness. Sleep is characterized by “brain states”.

5. Decreased metabolism and other peripheral, vegetative functions (body temperature, breathing Rhythms, etc.).

6. Characteristic body posture.

EEG measurements: global recordings of sum activity of neurons in the cerebral cortex.

1. Electrooculography (EOG): This measures eye movements using electrodes placed around the eyes. It helps determine the different stages of sleep, including rapid eye movement (REM) sleep and non-rapid eye movement (NREM) sleep.

2. Electromyography (EMG): EMG records muscle activity by placing electrodes on the chin and/or other muscles. It helps identify muscle tone changes, such as muscle atonia during REM sleep, which is associated with normal paralysis during dreaming.

3. Electrocardiography (ECG/EKG): ECG measures the electrical activity of the heart. It records heart rate, rhythm, and any abnormalities during sleep.

4. Respiratory Parameters: Various measurements are taken to assess breathing patterns and respiratory effort during sleep. These may include:

   • Nasal and oral airflow: Monitors the flow of air through the nose and mouth.

   • Thoracic and abdominal effort: Measures the movement of the chest and abdomen during breathing.

   • Oxygen saturation (SpO2): Monitors the level of oxygen in the blood.

   • Capnography: Measures the concentration of carbon dioxide in exhaled breath.

5. Snoring: Microphones or sensors can be used to detect and record snoring sounds, which may provide insights into the presence of sleep-disordered breathing.

6. Body Position: Sensors or video monitoring may be employed to track body position changes during sleep, as some sleep disorders can be position-dependent.

7. Limb Movements: Leg movements, such as periodic limb movements of sleep (PLMS) or restless legs syndrome (RLS), can be recorded using sensors placed on the legs.

the peptide hypocretin (= orexin) seems to be crucial for inducing sleep, GABA from the ventrolateral preoptic area (VLPO) of the hypothalamus induces the wake state.

the potential “sleep switch” located in the hypothalamus affects many brain regions, and many transmitter substances are involved.

1. REM sleep is characterized by low- voltage EEG without spindles and slow waves, i.e., not synchronized cortical neurons.

2. Non-REM sleep is characterized by EEG spindles and slow waves, produced by synchronized cortical neurons. These synchronizations are generated by rhythmic firing of thalamic relay neurons that project to the cortex. The rhythmic firing results from the actions of GABA-ergig neurons in the nucleus reticularis.

Strong evidence that during sleep replay of neuronal patterns promotes consolidation of memory.

Memory consolidation refers to the process by which newly acquired information and experiences are stabilized and stored in long-term memory. It involves the transformation of initially fragile and labile memories into more stable and enduring forms.

Sleep plays a crucial role in memory consolidation. During sleep, particularly during the deeper stages of non-rapid eye movement (NREM) sleep and the rapid eye movement (REM) sleep stage, the brain undergoes processes that enhance memory consolidation.

Overall, sleep, and its distinct stages, provide a conducive environment for memory consolidation. By replaying and reorganizing newly acquired information, enhancing synaptic connections, and promoting the interaction between key brain regions, sleep contributes to the formation of durable and retrievable memories. Insufficient or disrupted sleep can impair memory consolidation and affect learning abilities.

a) Population coding of place cells within an environment. During spontaneous exploration of an environment, place cells are activated in their relative place fields (colored circles), with some cells coding for overlapping location (firing activity represented below). The location of the animal in the right part of the environment is given by the activity of the population composed of neurons 3, 4 and 5.

(b) In subsequent sleep, and mostly at time of harp wave ripples (notified by blacks stars above LFP signal), reactivations of place cells activated during previous exploration occur (Note that there is still no direct evidence that each SPW-Rs is associated with a reactivation). Since the correlation pattern is strongly maintained during SPW-Rs occurring during the first hour of subsequent sleep, the detection of the firing activity of one specific place cell (#4) can be used to associate intracranial stimulation to the whole cell assembly coding for the related location.

(c) Schematic behavioral output of the association of the engram with a positive valence during sleep. Free exploration of the open field showed homogeneous exploration before pairing. Then during 1 h of sleep, the pairing procedure depicted in panel b. is applied with electrical rewarding stimulation. At awakening, mice went directly towards the place field of the previously paired neuron, and thus to the location represented by the cell assembly it belongs to in this particular context.

• Homeostatic properties of sleep refer to the regulatory mechanisms that maintain the balance and stability of sleep-wake cycles.

• Sleep homeostasis involves the homeostatic regulation of sleep need and the drive for sleep.

• Sleep debt or sleep pressure accumulates the longer an individual stays awake, leading to a stronger drive for sleep.

• Adenosine, a neurotransmitter that builds up in the brain during wakefulness, plays a key role in promoting sleep pressure.

• Sleep-promoting neurotransmitters, such as GABA and adenosine, are more active during sleep, while wake-promoting neurotransmitters, such as norepinephrine and histamine, dominate during wakefulness.

• The balance of these neurotransmitters contributes to the homeostatic regulation of sleep.

• Homeostatic regulation ensures that the body maintains a balance between restorative sleep and wakefulness.

• Disruptions to sleep homeostasis, such as chronic sleep deprivation or sleep disorders, can have adverse effects on health and performance.

Slow brain waves, specifically the slow-wave activity (SWA) characterized by slow oscillations known as delta waves (0.5 to 4 Hz), are prominent during the deep sleep stages, also known as slow-wave sleep (SWS). The occurrence of slow brain waves during deep sleep phases is associated with several factors:

1. Thalamocortical Network: Slow waves during deep sleep arise from the synchronized activity of neurons in the thalamus and cortex. The thalamus acts as a pacemaker, generating rhythmic activity that is then propagated to the cortex. The thalamocortical network plays a crucial role in the generation and propagation of slow oscillations.

2. Neuronal Synchronization: During deep sleep, there is a high degree of synchronization among neurons in the thalamocortical network. This synchronization is facilitated by inhibitory mechanisms that suppress neuronal activity, leading to the slow, synchronized oscillatory pattern seen in delta waves.

3. Sleep Homeostasis: Slow waves are influenced by sleep homeostasis, reflecting the need for restorative sleep. The amplitude and frequency of slow waves are related to prior wakefulness and sleep pressure. The longer an individual has been awake, the higher the SWA and the greater the occurrence of delta waves during subsequent sleep.

The effects of slow brain waves during deep sleep are believed to be associated with the restorative functions of this sleep stage:

1. Memory Consolidation: Slow-wave sleep is associated with memory consolidation, particularly for declarative memories. The synchronization of neuronal activity during slow waves supports the reactivation and consolidation of recently acquired information.

2. Physiological Restoration: Deep sleep, characterized by slow waves, is associated with physiological restoration. It is believed to promote physical recovery, including the repair and rejuvenation of various bodily systems, consolidation of immune function, and hormone regulation.

3. Energy Conservation: Slow-wave sleep is associated with reduced metabolism and energy conservation. The synchronized slow oscillations require less energy compared to the more active wakeful or REM sleep states. This energy conservation may allow resources to be allocated for other essential physiological processes.

In summary, slow brain waves, specifically delta waves, are a hallmark of deep sleep stages. They arise from synchronized activity within the thalamocortical network and reflect the restorative and energy-conserving functions of deep sleep. These slow waves are implicated in memory consolidation, physiological restoration, and the overall maintenance of health and well-being.

1. Conservation of metabolic energy?

   But: metabolic rate during sleep is only 15% less than during quit wakefulness. Rest is also possible during wakefulness!

2. Cognition?

   Sleep deprivation drastically impairs intellectual performance!

3. Thermoregulation?

   Heating the hypothalamus induces sleep in animals. However, evidence not strong.

4. Memory consolidation?

   Strong evidence that during sleep replay of neuronal patterns promotes consolidation of memory.

5. Clearance of radical oxygen species?

   Very recent evidence that during sleep cellular clearance processes take place!

External ear (outer ear)

Middle ear

Inner ear (cochlea)

collects sound of different frequencies best when they originate at different positions with respect to the head.

air-filled pouch extending from the pharynx, connected by the Eustachian tube. Three bones:

• malleus (hammer)

• incus (anvil)

• stapes (strirrup).

Embedded in the temporal bone, lined with connective-tissue (endosteum and periosteum).

Three fluid-filled tubes, ~ three coils in humans, ~ 9mm across: Scala vestibuli, Scala media, Scala tympani.

Embedded in the Scala media is the organ of Corti, That carries hair cells extending into the tectorial membrane.

Scala vestibuli and Scala tympani contain normal perilymphe, Scala media K+-rich endolymphe.

Only inner hair cells provide afferent input to the central nervous system.

The outer hair cells receive efferent information from the central nervous system and actively amplify the signal.

1. External ear (outer ear):

   collects sound of different frequencies best when they originate at different positions with respect to the head.

2. Middle ear:

   air-filled pouch extending from the pharynx, connected by the Eustachian tube.

   Three bones:

   • malleus (hammer)

   • incus (anvil),

   • stapes (strirrup)

3. Inner ear (cochlea):

   Embedded in the temporal bone, lined with connective-tissue (endosteum and periosteum).

   Three fluid-filled tubes, ~ three coils in humans, ~ 9mm across:

   • Scala vestibuli

   • Scala media

   • Scala tympani.

   Embedded in the Scala media is the organ of Corti, That carries hair cells extending into the tectorial membrane.

   Scala vestibuli and Scala tympani contain normal perilymphe, Scala media K+-rich endolymphe.

1. Sound Waves: Sound waves are mechanical vibrations that propagate through a medium, such as air or water. When an external sound source, such as a musical instrument or a voice, creates vibrations in the air, it leads to the formation of sound waves.

2. Ear Anatomy: The ear is divided into three main sections: the outer ear, middle ear, and inner ear.

   • Outer Ear: The outer ear consists of the pinna (visible part of the ear) and the ear canal. Its function is to collect and funnel sound waves towards the middle ear.

   • Middle Ear: The middle ear includes the eardrum (tympanic membrane) and a chain of small bones called the ossicles (malleus, incus, and stapes). When sound waves reach the eardrum, they cause it to vibrate. These vibrations are then transmitted to the ossicles.

   • Inner Ear: The inner ear contains the cochlea, a spiral-shaped structure responsible for converting mechanical vibrations into neural signals. The cochlea is filled with fluid and contains specialized hair cells.

3. Hair Cells: Within the cochlea, there are two types of hair cells: inner hair cells and outer hair cells. These hair cells are sensory receptors that convert mechanical vibrations into electrical signals.

   • Mechanical Transduction: When the ossicles transmit vibrations to the fluid-filled cochlea, it causes movement of the fluid. This movement stimulates the hair cells.

   • Hair Cell Activation: The movement of the fluid bends the hair bundles on the hair cells, which opens ion channels on their surface. This allows ions to enter the cells, generating electrical signals.

4. Auditory Nerve: The electrical signals generated by the activated hair cells are then transmitted to the auditory nerve. The auditory nerve is a bundle of nerve fibers that carries the electrical signals from the cochlea to the brain.

5. Auditory Pathway: The auditory nerve fibers transmit the electrical signals from the cochlea to various auditory processing centers in the brain, including the brainstem, thalamus, and auditory cortex. These areas process and interpret the neural signals, allowing us to perceive and understand the sound.

Only inner hair cells provide afferent input to the central nervous system.

The outer hair cells receive efferent information from the central nervous system and actively amplify the signal

Different frequencies of sound are encoded in the auditory system through a process called tonotopy, which involves the spatial arrangement and response properties of neurons in the cochlea and auditory pathway.

1. Cochlea: The cochlea, a spiral-shaped structure in the inner ear, plays a vital role in frequency encoding. As sound waves enter the cochlea, they cause different regions of the cochlear partition to vibrate more vigorously depending on the frequency of the sound.

2. Basilar Membrane: The basilar membrane is a membrane within the cochlea that runs along its length. It varies in stiffness along its length, becoming narrower and stiffer towards the base (near the oval window) and wider and more flexible towards the apex.

3. Tonotopic Organization: The basilar membrane's stiffness gradient creates a tonotopic organization, where different regions of the membrane are sensitive to different frequencies. High-frequency sounds (e.g., high-pitched sounds) preferentially activate the base of the cochlea, while low-frequency sounds (e.g., low-pitched sounds) primarily stimulate the apex.

4. Hair Cell Activation: Along the basilar membrane, there are specialized hair cells that are responsible for converting mechanical vibrations into electrical signals. Hair cells are arranged in rows along the cochlear partition and are most sensitive to specific frequencies.

5. Frequency-Specific Neurons: The electrical signals generated by hair cells are transmitted to neurons in the auditory nerve. These neurons, known as auditory nerve fibers, have characteristic frequencies to which they are most responsive. High-frequency sounds tend to activate nerve fibers near the base of the cochlea, while low-frequency sounds activate fibers closer to the apex.

6. Auditory Pathway: The frequency-specific information encoded by the auditory nerve fibers is then transmitted through the auditory pathway to higher-level auditory centers in the brain, including the brainstem, thalamus, and auditory cortex. In these areas, further processing and analysis of the frequency information occur, leading to the perception and recognition of different pitches and tones.

In summary, different frequencies are encoded in the auditory system through the tonotopic organization of the cochlea and the corresponding response properties of hair cells and auditory nerve fibers. This tonotopic representation allows the brain to distinguish and interpret various frequencies, contributing to our ability to perceive and differentiate different pitches and tones.

The term "best frequency" refers to the characteristic frequency at which a particular auditory neuron or receptor has its highest sensitivity or response. It represents the specific frequency or range of frequencies to which the neuron or receptor is most responsive.

"Active hearing" refers to the process by which organisms actively manipulate their auditory system to enhance their ability to detect, locate, and perceive sounds in their environment. It involves active control and movement of the sensory apparatus, such as the ears or other sound-receiving structures, to optimize auditory perception.

Otoacoustic emissions (OAEs) are low-level sounds generated by the cochlea in response to auditory stimulation. These sounds can be measured using sensitive microphones placed in the ear canal. OAEs provide valuable information about the functioning of the inner ear, specifically the health and integrity of the outer hair cells.

The generation of otoacoustic emissions involves a process known as cochlear amplification, which is facilitated by the active mechanics of the cochlea.

1. Outer Hair Cells: The outer hair cells (OHCs) are specialized sensory cells in the cochlea that play a crucial role in the amplification and fine-tuning of auditory signals. These cells are arranged in rows along the basilar membrane of the cochlea.

2. Cochlear Amplifier: When sound waves enter the cochlea, they cause vibrations along the basilar membrane. This mechanical energy displaces the hair bundles of the OHCs, activating them.

3. Feedback Loop: The OHCs are connected to the tectorial membrane above them, forming a feedback loop. When the OHCs are activated by the mechanical vibrations, they undergo changes in length and stiffness.

4. OHC Motility: The activation of OHCs triggers a process called electromotility or OHC motility. This process involves changes in the cell's length, which results in the active amplification of the traveling wave along the cochlea.

5. Emission Generation: The amplification produced by the active motility of the OHCs leads to a regenerative feedback loop within the cochlea. This feedback loop generates low-level sounds, known as otoacoustic emissions, which can be detected in the ear canal.

It's important to note that otoacoustic emissions can be classified into different types based on their characteristics. Spontaneous otoacoustic emissions (SOAEs) occur without any external stimulation and are present in a subset of individuals without hearing loss. Evoked otoacoustic emissions (EOAEs) are elicited by specific auditory stimuli, such as clicks or tones.

Otoacoustic emissions serve as a valuable clinical tool for assessing the function of the cochlea, particularly the outer hair cells. They are used in diagnostic audiology to evaluate hearing sensitivity, screen newborns for hearing disorders, and monitor the effects of certain medications or noise exposure on the auditory system.

1. Interaural Time Difference (ITD): ITD refers to the difference in the arrival time of a sound at each ear. When a sound source is off-center, the sound reaches one ear slightly before it reaches the other ear. The brain uses this time difference to estimate the azimuth (horizontal angle) of the sound source.

2. Interaural amplitude Difference (ILD): ILD, also known as interaural intensity difference, pertains to the difference in sound intensity or level between the ears. When a sound source is off-center, the head acts as a barrier, causing a shadowing effect that reduces the sound level reaching the far ear. The brain uses this level difference to estimate the azimuth of the sound source.

3. Spectral Cues: Spectral cues involve the frequency content and filtering of sounds that reach the ears. As sound waves interact with the head and outer ears, certain frequencies are selectively attenuated or enhanced, creating spectral cues that can aid in sound localization.

   • Head-Related Transfer Function (HRTF): HRTF refers to the filtering effect of the head, pinnae (external ears), and torso on incoming sound. The unique filtering characteristics for different sound directions provide spectral cues that help determine the elevation (vertical angle) and front-back location of a sound source.

4. Monaural Cues: Monaural cues are cues that can be perceived by one ear alone and provide information about the location of a sound source.

   • Spectral Notches: Certain frequencies may be attenuated or suppressed when sound waves interact with the shape of the outer ear and ear canal. These spectral notches can serve as monaural cues for sound localization.

5. Head Movements: Active head movements are a crucial parameter for sound localization. By moving the head, an individual can obtain dynamic auditory information that aids in determining the direction and location of a sound source.

The brain integrates these auditory cues, including ITD, ILD, spectral cues, monaural cues, and head movements, to create a spatial representation of sound. This allows us to perceive the direction, distance, and position of a sound source in our environment.

The receptive field of a neuron is the area of the retina whose stimulation with light causes a change in the response in that neuron!

Only ganglion cells generate action potentials! All other cells in the retina transmit signals electrotonically!

1. Cone Photoreceptors: The retina contains three types of cone photoreceptor cells: red-sensitive cones, green-sensitive cones, and blue-sensitive cones. These cones are responsible for detecting different wavelengths of light and initiating the visual signal.

2. Horizontal Cells: Horizontal cells are interneurons in the retina that play a role in lateral inhibition, which enhances contrast and sharpens visual information. Horizontal cells receive input from multiple photoreceptor cells and provide lateral inhibition to nearby cells.

3. ON-Center Bipolar Cells:

   • Excitatory Connection: ON-center bipolar cells receive direct synaptic input from the central region of cone photoreceptor cells through their dendrites. When light falls on the central region of the receptive field, it leads to depolarization of the cone cells and subsequent depolarization of the ON-center bipolar cell.

   • Inhibitory Connection: Surrounding the central region of the receptive field, there are horizontal cell processes that receive input from the surrounding cone photoreceptor cells. When light falls on the surrounding region, horizontal cells release inhibitory neurotransmitters onto the dendrites of the ON-center bipolar cells, suppressing their activity.