Zusammenfassung Neuro- & Sinnesphysiologie.pdf

Summary: Neuro- & sensory physiology 1. Lecture Function of nervous systems, types of nerve cells, structure of nerve cells, excitable & non-excitable parts of nerve cells, signal transduction in axons, glial cells, myelin, elec- tric properties of cellular membranes, ion channels, patch clamp, v...

Summary: Neuro- & sensory physiology 1. Lecture Function of nervous systems, types of nerve cells, structure of nerve cells, excitable & non-excitable parts of nerve cells, signal transduction in axons, glial cells, myelin, elec- tric properties of cellular membranes, ion channels, patch clamp, voltage sensors Information transfer in organisms through: - Hormones as chemical messengers (slower) → transfer speed: 0.1 m/s → but long effects (duration of effect: s – days) - Nerve Signal as electrical information transfer (faster) → signal speed: 1-120 m/s → but shorter effects (duration of effect: ms – min) - fast transfer of information leading to physiological effects of short duration are gen- eral achieved through nerve signals - slower transfer of information leading to longer lasting physiological effects are in gen- eral achieved through hormones - simplest form of a nervous system is a neural net → multipolar nerve cells are distributed between ecto- & endodermal cells (is not clearly distinguishable from the rest of the body) ▪ ectoderm: outermost layer that forms nails, hair, etc. ▪ endoderm: innermost layer that forms stomach, colon, urinary bladder, etc. - cells spread in all directions with decreasing strength via single pulses - more dense concentration of neurons around sensory organs → in evolutionary more developed organisms neurons are concentrated either in ganglia or nerve cords → specialization and fusion of body segments can lead to development of brains in limbed animals ▪ faster or more complex cascades in these parts ▪ usually around fins/arms/primitive organs ▪ ganglia = “mini brains” along the body (often in insects) → bundle of nerves - radial symmetry animals vs. bilateral symmetry animals - radial symmetry: ▪ multiple symmetry axis along the body ▪ body parts extend outward from the center of the body in an equal distri- bution ▪ e.g. starfish ▪ is the oldest form of organisms - bilateral symmetry: ▪ one symmetry axis divides the animal into two equal parts ▪ “newer” form → as these evolved, the neural networks also evolved & be- coming more complex with more structural systems ▪ sub-structured bodies with more complex neuronal structures - evolution from neuronal network to formation of ganglia to specific brains to structured, more complex neuronal systems in a sub-structured body with multiple limbs & protru- sion - processing of new sensory information & activation of effector systems can be visualized  - NMR/MRT: functional magnetic resonance imaging - PET: positron-emission-tomography - but overall really difficult to pinpoint regions of the brain to only certain action ▪ there are spatial segregations but they look the same → no structural dif- ferences nervous system and behavior - larger number of neurons in a nervous system and higher degrees of networking among neurons allow larger capacities to take up, process and use information → sum of all activities on whole animal level = behavior - number of neurons correlate in some way with cognitive capacity but not always with the size of the animals - capacity to learn ▪ many complex behaviors (self-awareness) is learned & it’s not something we’re born with - more simple nervous networks allow stereotypical reactions to specific trigger - very little modulation → its always the same - BUT simple learning/habituation is possible - complex nervous networks allow complex learning and certain freedom of choice and awareness - more complex = nervous system; more simple = nervous network anatomy of a neuron - structure: - soma with nucleus → perikaryon - dendrites - axon - synapse - accessory cells of the nervous system (glia) ▪ oligodendrocytes (CNS) ▪ Schwann-cells (peripheral nervous system) - different types of neurons - invertebrate neuron ▪ cell body with axon & dendrites - pseudounipolar cell ▪ cell body with central axon & peripheral axon to skin & muscle - bipolar ▪ axon with cell body & dendrites - characteristic of axon not always clear = neurite is the more appropriate term - neurite = any projection from the cell body of a neuron (axon/dendrite) ▪ “lazy term” ▪ not always simple to differentiate axon from dendrite/specific role of pro- jection ▪ is it a receiving/output part of the cell? (needs to be experimentally deter- mined) - special types of neurons in vertebrates - spinal motor neuron - pyramid cells in the hippocampus - Purkinje-cells of cerebellum - even though the anatomy is very different in different neurons, the overall functional anat- omy is similar → same sequence of events comparison of the invertebrate & vertebrate CNS - ganglia vs. spinal cord - process of processing is quite similar on this level ▪ neurons coming in, forming synapses, information is transmitted locally & then travels to a different part - level of comparison breaks away on higher processing levels - vertebrates have brains as their main processing part ▪ from ganglia-based to stratified/layered structure - main processing region in invertebrates stays ganglia-based Glial cells in vertebrates - neurons do not operate alone but are part of a neuronal system with all different kind of cells - other neuronal cells that do not participate in the direct transportation of signals - participate indirectly by providing support/nutrients or removing waste - Glia cells are the “glue of the nervous system” - overall more glia cells then neurons - provide physical and chemical support to neurons and maintain their environment - different types of glial cells in CNS with specific roles - Astrocytes ▪ most common type of glial cells ▪ protoplasmic astrocytes (thick with lots of branches; in the gray matter of the brain) & fibrous astrocytes (longer & slender with few branches, in the white matter of the brain) have similar jobs forming the blood-brain barrier (filtering system) regulating neurotransmitters (recycling) cleaning up (after a neuron dies; excess potassium ions) regulating blood flow to the brain synchronizing the activity of axons brain energy metabolism and homeostasis - Oligodendrocytes ▪ main purpose: help information move faster → electrical insulation wrap around axons & form protective layer → myelin sheath gap between = node of Ranvier; node that helps spread the electri- cal signal (signal hops from one node to the next)  - Microglia ▪ tiny glial cells ▪ brain’s own dedicated immune system alert to signs of injury and disease → clearing away dead cells or getting rid of toxins/pathogens ▪ housekeeping role in learning-associated bran plasticity & guiding the de- velopment of the brain - Ependymal cells ▪ make up thin membrane lining of the central canal of the spinal cord and the ventricles of the brain ▪ have little hairlike projections called cilia that wave back and forth to keep cerebrospinal fluid circulating fluid delivers nutrient and eliminates waste products form the brain & spinal column necessary to maintain homeostasis (e.g. regulating its tempera- ture) ▪ also functions as a cushion/shock-absorber between brain and skull - Radial glia ▪ type of stem cell that can create other cells ▪ contribute to the brains ability to change & adapt → neuroplasticity - different types of glial cells in peripheral nervous system (PNS) - Schwann cells ▪ function like oligodendrocytes → provide myelin sheaths for axons in PNS but one Schwann cells surrounds one axon (oligodendrocytes can spread out & myelinate a few cells) ▪ also part of immune systems of the PNS when nerve cell is damaged they can “eat”/destroy the nerve’s axon and provide path for a new axon to form ▪ can be involved in some form of chronic pain - Satellite cells ▪ surround certain neurons with a sheath around the cellular surface ▪ believed to be similar to astrocytes ▪ main purpose: regulating the environment around neuron → keeping chemicals in balance ▪ neurons with satellite cells make up clusters of nerve cells called ganglia in autonomic nervous system (NS for internal organs) & in sensory system (NS for senses) ▪ can deliver nutrients to neurons and can absorb toxins like metals Electric properties of the neuron plasma membrane (PM) - PM posses lipid bilayer that is impermeable to charged particles → is electric insulator - but active transporters (e.g. Na+/K+-ATPase) or passive carriers/channels (Sodium (N) or Potassium (K) channels) allow ions to pass through the membrane - potential difference is force/power and can be used - electrical properties are primarily regulated through Na+ & K+ - influenced by ▪ concentration difference between intra- & extracellular space ▪ permeability of the PM  - Na+/K+-ATPase maintains concentration gradient across membrane ▪ electrogenic pump = 3 Na+ out & 2 K+ in per cycle ▪ creates net differences → transports net charges → electrogenic pump! - because of their unequal distribution/gradient, whenever channel opens, a small amount of these ion pass through the membrane ▪ bc of the huge concentration differences, they are very motivated to move along their gradient - changing the permeability of the PM to charged ions important so cell can make sure that only specific ions are able to pass through and other can’t → unspecific channels would not allow us to use the force that is build up (potential would be neutralized) - specificity is very important for potential building & usage - ions are “judged” by channel properties by charge type, size and diameter of the ion (if the ion is hydrated or dehydrated) - channels usually let specific ions through (but unspecific cation channels exist) - selectivity filters of ion channels ▪ external selectivity filter e.g. cation channels can have negative charges on the outside so negatively charged mole- cules/ions are electrostatically repelled ▪ internal selectivity filter have specific binding sides inside the channel which only stabi- lizes passage of a specific ion passage also possible by hybridization of the ion (binding of water) the patch clamp method - electrophysiological technique that can directly measure the membrane potential &/or amount of current passing across cell membrane - allows insight into function of ion channels and membrane properties at single-cell-level - process - sealing a glass pipette to the cell membrane under a microscope ▪ tip of the pipette is brought into contact with cell membrane and by apply- ing suction/negative pressure, a small patch of membrane is pulled into the tip of the pipette and a tight seal is formed - high-resistant seal or whole-cell configuration ▪ two primary configuration of the method “cell-attached”: seal between pipette and membrane has high re- sistance, allowing recording of ion channel activity directly at the membrane  “whole-cell”: additional suction to rupture the membrane and to establish electrical contact between pipette and cytoplasm; al- lows extensive manipulation of the cell’s internal environment - recording ion currents ▪ small voltage across the membrane/cell interior through amplifier ▪ by measuring the resulting ionic currents flowing through ion channels, conductance, kinetics & selectivity can be characterized of these chan- nels ▪ amplifier also allows control of voltage across the membrane → study of voltage-gated ion channels possible - membrane potential (Vm) = voltage difference over a biological membrane = difference between potential inside the cell compared to outside the cell - measurement through “voltage clamp” → electrode inside the cell - membrane potential is always inside vs. outside Ion Channels - conductivity of ion channels - equilibrating channels (Gleichgewicht) ▪ allow ion flow across membrane in both directions → equilibrium poten- tial with no net movement of ions ▪ typically no significant selectivity → permit ions to flow down their elec- trochemical gradient until equilibrium is reached - rectifying channels ▪ asymmetry in their ion conductance properties → only/preferentially al- low ion flow just in one direction over the other ▪ more permeable in one direction than the reverse direction → rectification of the ion current ▪ play a part in controlling resting membrane potential and the shaping of action potentials ▪ electrical signal is unidirectional - Gramicidines are peptides form Bacillus brevis → antibiotic effects, pore-building toxin - “artificial” ion channel → opens & closes in a voltage dependent manner - creates a perfect equilibrating channel - current flow through an ion channel is a saturation function - flow increases with increasing ion concentration but ion channel lumen can only hold a certain number ions per time unit → Imax (maximal single channel current) is reaches, when the channel is fully saturated with ions → operate just like en- zymes Regulation of ion channel function - flow of current through an open ion channel is constant until channel closes or is inacti- vated → driven through conformational changes of the channel protein - open/close → physical prevention of flow - active/inactive → channel is open but is not leading current - mechanisms (gating) - Ligand activated ion channels (A) ▪ ion channels can be opened/closed by binding of extracellular messenger molecules that bind to receptor domain on the channel ▪ different modulation possible endogenous agonist o opens the channel “normally” reversible agonist o blocks the binding site and keeps the channel closed o is reversible irreversible antagonist o blocks the binding site and keeps the channel closed irre- versibly exogenous agonist o binds at a different binding site and can also open the channel - opening of an ion channel through protein phosphorylation (B) ▪ channel protein has Aas in cytosolic domain and phosphorylation of that domain leads to ΔKonf. which opens the ion channel ▪ can be many other PTM - voltage gated ion channels (C) ▪ channels can be open through depolarization of the membrane potential above a critical threshold ▪ voltage sensor is part of the channel’s protein structure ▪ “sliding helix” hypothesis depolarizing the membrane above a threshold twists certain do- main of helix structure (S4-transmembrane domain) from its met- astable conformation positively charged Arg-side groups stabilize the channel in open position through interaction with negative charge at the next level → mechanism behind opening/closing ▪ different closing mechanisms intrinsic inactivation (refractivity) inactivation through the transported ion (binds to certain side on cytoplasmic side of channel) inactivation through protein phosphorylation of the channel pro- tein - stretch-activated ion channels (D) ▪ channel proteins can be connected to cortical actin system which is part of the cytoskeleton ▪ ΔKonf. when plasma membrane is stretched due to internal/external pres- sure ▪ present in many mechano-sensors building an ion channel - ion channels can be hetero-multimeric, homo-multimeric or can consist of pseudo-sub- units - topology of an ion cannel subunit - certain transmembrane regions but also regions that reach into cytoplasm or ex- tracellular room - hydrophobicity plots can provide insights into position of transmembrane regions and ex- tra-/intracellular domains - shows how hydrophobic/hydrophilic certain regions are - amino acid sequence of subunits of Na+/Ca+/K+ channels overlap between 27-50% among animals → probably homologs inactivation & refractivity - intrinsic inactivation (A) - inactivation through the transported ion (B) - inactions through protein phosphorylation of the channel protein (C) - more complex  2. Lecture Membrane potential, electrotonic signaling, action potential, axonal AP-transport, elec- tric and chemical synapses, neurotransmitters, excitatory and inhibitory postsynaptic potentials, ionotropic and metabotropic receptors Membrane potential - neurons transport information/signals via electricity → electricity is produced via/de- pends on flow of charged ions - hypothetical cell - if the PM is not permeable at all and K+ ions are added in different concentrations on different sides of the PM, there would be a large charge difference but no bio- logical effect - if form of transporter/channel is added and K+ ions can diffuse, ions will flow along their concentration gradient to try to reach equilibrium - because of the positive charge, two forces will start to work against each other - if it was only K+ both forces would reach equilibrium but because other charged molecules are present, which cannot permeate the PM, and add a charge to the membrane, which is slightly more positive on the outside → chemical and electrical driving forces would counteract each other (accumu- lating positive charge (electrical force) on the outside would work against the flow of K+ from inside of the cell (chemical force)) → equilibrium is reached (but far away form 0) - equilibrium potential of K+ can be calculated with NERNST equation [mV] 𝑅𝑇 [𝐾 + 𝑒𝑥𝑡𝑟𝑎𝑐𝑒𝑙𝑙. ] 𝐸𝐾 = ∗ 𝑙𝑛 + 𝑧𝐹 [𝐾 𝑖𝑛𝑡𝑟𝑎𝑐𝑒𝑙𝑙. ] → real cells behave very similarly as the hypothetical cell - measured membrane potential (VM) of real cells decreases at higher extracellular K+ concentrations and follows the calculated line of the NERNST equation almost perfectly → suggests that VM is almost entirely driven by the high permeability of the PM to K+ ▪ cell responds easily and readily to change of K+ concentration (easy depo- larization if extracellular K+ concentration rises) ▪ resting cells have a VM of -70 with ex- tracellular K+ c at 10 mmol/l - as soon as the external K+ c decreases under values that are physiologically relevant, the curves/graphs deviate from each other → other ions start to contribute more and more to the VM ▪ Na+ & Cl- ▪ NERNST equation is sufficient for up- per part of the curve (green) but as soon as the other ions participate, GOLDMANN equation is needed, which adds the other ions as well (red)  𝑅𝑇 𝑃𝐾 [𝐾 + ]𝑜𝑢𝑡 + 𝑃𝑁𝑎 [𝑁𝑎+ ]𝑜𝑢𝑡 + 𝑃𝐾 [𝐶𝑙 − ]𝑜𝑢𝑡 𝐸𝑀 = ∗ ln ( ) 𝑧𝐹 𝑃𝐾 [𝐾 + ]𝑖𝑛 + 𝑃𝑁𝑎 [𝑁𝑎+ ]𝑖𝑛 + 𝑃𝐾 [𝐶𝑙 − ]𝑖𝑛 - gives you a more physiological VM Measuring & Manipulating the membrane potential - membrane potential can be measured via microelectrodes - one inside & one outside the cell → gives difference between both spaces - normally: inside of the cell is negatively charged in contrast to the outside of the cell - by adding a second microelectrode that can push current into the cell and acts like a pow- erful ion channel, the membrane potential can be manipulated - response of the potential depending on the current which is pushed inside the cell - 2 experiments ▪ push negative current inside membrane gets even more polarized in steps-wise manner that correlates with the strength of the current ▪ push positive current inside membrane gets depolarized in a steps-wise manner until a certain threshold is reached → strong depolarization leads to an action potential - action potential occurs in almost all neuronal cells ▪ is dependent on 2 things: needs voltage-dependent ion channels and is dependent on the depolarization of the membrane potential (strong enough, over a certain threshold) ▪ height of the threshold varies along organisms → is high than “normal” fluctuations so only “true” signals lead to the building of an action poten- tial → hyperpolarization = no action potential → depolarization = possible action potential (if threshold is exceeded) - Electric circuit of a neuronal cell - membranes acts as strong capacitor (can build up charge bc charge cannot go through the membrane) - through the introduction of ion channels, conductivity increases strongly (even without channels, membranes are slightly leaky (especially to K+)) - membrane potential tells us the strength of the potential energy and the current flow of ions (through channels & leaks) - microelectrode experiments on squid giant motoneuron axon revealed two types of volt- age gated ion channels - by using two types of toxins (tetraetylammonium (TEA) & tetradotoxin (TTX)) which block K+ and Na+ channels respectively, an action potential could be dissected into two parts ▪ normal action potential doesn’t show if the depolarization of the mem- brane happens because there is negative current going into the cell or pos- itive current going out of the cell - blocking of Na+ channels with TTX leads to upper graph & blocking of K+ channels lead to lower graph → two distinct parts  - narrow downward peak (point of polarity flip) because K+ current (out) counteracts the Na+ flow (in) - K+ becomes dominant ion flow which leads to strong membrane polarization - with microelectrodes only the sum current of all ions is actually measured → block- ers/toxins are very important for neurobiology research & also medicine Selection of physiological important ion channels - Inward Current → Depolarization (towards 0 Membrane potential) - Na+ (INa) ▪ rapid depolarization, action potential e.g. in squid giant axon close automatically very fast (fast kinetics) ▪ inhibitors Tetrodotoxin (TTX) Saxitoxin (STX) - Ca (ICa) + ▪ concentration around 1.000 times higher extracellular (mmol) than intra- cellular (µmol) has even higher potential to depolarization because of this huge concentration difference but abundance of Ca+-Channels is very low + very slow kinetics (open slowly & close slowly) → slower de- polarization ▪ moderately rapid depolarization, plateau-phase in action potential ▪ inhibitors Cobalt ions (Co2+), Nickel ions (Ni2+) → often irreversible Nifedipin (in the heart) o for people with high blood pressure → need to slow down the action of the heart; by inhibiting the Ca+-channels, the heart operates more slowly - Outward Current → Hyperpolarization/Repolarization (more negative Membrane poten- tial) - K+ (IK) ▪ delayed K current, repolarization during the action potential ▪ inhibitors Tetraethylammonium (TEA) 4-Aminopyridin (4-AMP) - Calcium-activated K+-channels (IK(Ca)) ▪ Ca+ comes mostly from inner storage & not through channels (would make no sense to first push Ca+ out & then use it inside again)  ▪ is secondary active chloride secretion ▪ inhibitors Tetraethylammonium (TEA) Barium ions (Ba2+) - voltage gated channels are used for 2 things - action potential - vesicle release in synaptic cleft Sequence of events during the action potential (AP) - whole event needs around 4 ms - 4 main parts with 2 main players - very rapid voltage gated Na+-channels & slower voltage gated K+-channels ▪ both are positive currents but looking from the inside of the cell, one is a positive current (Na+) & one is a negative current (K+) - Equilibrium potential ▪ Na+-Channel has two gates outside gate: solely voltage dependent inside gate: time dependent gate that reacts to outside gate with delay ▪ both channels get activated at the same time but K+ is just very slow - Depolarization ▪ strong inward current of Na+ because of the concentration gradient → intracellular space gets positive very fast; strong depolarization of the membrane potential ▪ K+-channels start to open while Na+-channels start to close again ▪ highest point is reached when K+ flow works against Na+ → net positive current in is overtaken by net positive current out  - Repolarization ▪ K+-flow overtakes the Na+-flow (channels are closed) → strong positive outward current ▪ K+-flow is the dominant flow - Hyperpolarization ▪ when the membrane potential is reached, the K+-flow stops and channels close → membrane gets even more negative because channels are so slow - every step of an AP can be calculated with the NERNST equation - resting membrane potential around -70/-90 - during Depolarization, the mem- brane potential is solely dependent on Na+ ▪ equilibrium potential of Na+ around +63 → if channels open, Na+ would like to flow in until that is reached (if reached, no driving force anymore) but outward flux of K+ coun- teracts and then overtakes the dominant flow position (Na+-channels are already closed again) → equilibrium potential of K+ becomes the driving force - after reaching resting membrane potential and K+ flux stops, the main driving force becomes the Na+/K+-pump ▪ no NERNST equation because it is energy dependent and not driven by chemical or electrical gradients ▪ NERNST equation always describe passive diffusion - Different types of AP - most APs look the same in humans (except heart muscles) - some other animals have different APs & have the ability to code them differently ▪ e.g. some crabs can stack APs (not only on/off) and it offers different amounts of messages Electrotonic signaling - in parts of neurons where there are no voltage-gated ion channels, APs cannot be gener- ated → non-excitable parts include e.g. dendrites & soma - current pulse injected in one part of the membrane leads to diminishing of the strength of the signal as a function of distance - the further away form the pulse/signal point, the weaker the signal gets → ions get diluted into the cytoplasm (diffusion) → strength diminishes quickly  - as important as saltatory/jumping signaling - if synapse connects with a dendrite, the signal is dependent on the electrotonic signaling → ions need to travel the dendrite & soma to reach the axon hillock/hill to start a new APs and continue signaling - length constant λ describes the size of the diminishing strength along a neurite ▪ low = only short distances can be traveled ▪ higher = greater distance possible → cells with very long dendrites (low λ) need very strong signals to overcome dis- tance and enable signal transmission - benefit for long dendrites = when multiple synapses are connected, longer dis- tances give more play room for integration of the signals local circuit theory - through electrotonic signal (diffusion of ions) the local depolarization of the membrane is often large enough to overcome the action potential threshold of neighboring regions of the membrane - only possible at excitable membranes - act like independent local circuits but because of the ion diffusion there are inter- connected and signals can travel from one local circuits to another - if (in an unnatural stimulation) an axon gets excited in the middle, the signal would travel in both ways axonal conduction velocity – saltatory transport - 2 factors dictate how well a signal can be conducted 1. density of ion channels 2. diameter of the axon - for a signal to be transmitted, omic resistance needs to be overcome - omic resistance is dictated by diameter and surface area - increase in axon diameter can lead to an increase in the velocity of electric conductance (lower resistance = increased transmission speed) - invertebrates (e.g. squid & earthworms) have very thick diameters (100-600 µm) and ver- tebrates (e.g. frogs & cats) have very thin diameters of axons (4-10 µm) - but both types have similar conduction velocities - only difference → vertebrate neurons are myelinated ▪ if e.g. the human ischias nerve would consist of unmyelinated axons, it would have to have a diameter of 20-40 mc to achieve the same conduc- tion velocity as its myelinated form does - axon diameters in non-myelinated axons decreases as a function of lower mobil- ity (faster animals have thicker axons) - saltatory transport - myelinization makes part of the axon membrane impermeable to ions and there- fore non-excitable - Nodes of Ranvier are able to transmit electric signals ▪ electrotonic signaling in spaces between two nodes → improves kinetics (not every little “local circuit” needs to be excited) and “reuses” ions → signal jump form one node to the next → fastest axon conduction velocity in mammal myelinated axons: 120 m/s  - there are voltage gated ion channels under myelin sheet even though it does not make sense ▪ can be activated/depolarized but no flow of ions possible ▪ two different cell types do not communicate with each other Electric Synapses vs. Chemical Synapses - two different functional types - electric synapses - joint cell membranes through gap junctions (in some organisms (e.g. bacteria) can be actual holes) - special proteins (connexons, out of 6 subunits (connexins)) connect two cells with each other and allow ion flow ▪ fit on top of each other - there are most of the time constitutive connected and constitutive open - are equilibrating (most of the time) ▪ equilibrated channels can transmit signal in both directions with the same probability → no one way filter - chemical synpases - pre- & post-synaptic cells are not connected to - synaptic cleft is place for releasing and receiving signals in from chemicals - usual process ▪ signal come to pre-synapse and voltage gated (usually Ca+-)channels are opened → Ca+ flows into the cell and triggers release of vesicles filled with transmitters ▪ transmitters diffuses through synaptic cleft and can bind to receptors of the post-synapse - different types of receptors in the post-synaptic cell 1. ionotropic receptors ▪ receptor & ionopore/ion channel in one 2. metabotropic receptors ▪ receptor is decoupled from the ion channel ▪ intracellular communication between receptor and ion channel (e.g. through G-protein-signaling-cascade) with a little delay Feature electric synapse chemical synapse synaptic cleft no 10-20 nm cytoplasmic contact yes no components gap junctions Transmitter-vesicles postsynaptic receptors excitation transport through ion current chemical transmitters synaptic delay < 0,1 ms up to 10 ms excitation directionality bidirectional unidirectional Occurrence older form/less prominent dominant form of synapses Coding of electric and chemical signals - electric signals are binary → on/off - by modulating frequency, different signals are transmitted ▪ amplitude↑ or duration↑ → output signal↑ ▪ stronger signal = stronger frequency = stronger output/transmitter release - receptor attenuation = strength of receptor potential decreases even though sig- nal input stays the same ▪ type of sensory learning ▪ reason why e.g. we don’t feel clothes on our body all the time body learns that these non-changing signals do not need to be transmitted Neurotransmitters - are extracellular messengers that transport information in synapses (contact sites of neu- rons) - many different types of neurotransmitters but few different groups with the same struc- tures - Biogenic Amines - Neuropeptides - Amino acids - Soluble gases → a lot of neurotransmitters are N-containing (seem to be derivates/derived from amino acids; have very similar synthesis pathways - Synthesis of neurotransmitters - most are synthesized in smooth endoplasmic reticulum (smaller molecules) - are packed into vesicles and transported along the axons to the release site (pre- synaptic terminal)  - precursors of neurotransmitters & protein transmitters (are bigger molecules) are synthesized on ribosomes on rough endoplasmic reticulum → get taken up into ER and are posttranslationally modified and then packed into vesicles and trans- ported - soluble gases are the odd ones out ▪ are metabolically produced by enzymes located in the cytosol of neurons ▪ leave the cells through diffusion (are small, uncharged molecules so they can easily penetrate the plasma membrane) ▪ can participate in retrograde signaling signal travels backwards from the target cell back into original source (flow backwards) feedback loop → neurons could modulate themselves could maintain overall excitement levels in neuronal tissue ▪ but can still participate in anterograde signaling (flow from one cell to the next one) axonal transport - axons are packed with organelles → a lot of mitochondria - a lot of ATP is needed - long filaments going along the axon (thick or thin possible) - neurofilaments for structure - microfilaments → transport-system for vesicles - vesicles filled with neurotransmitters are transported from soma to the synapse - empty vesicles filled with endocytosed membrane material is transported back to the soma - anterograde transport = from soma to synapse - transporter molecules are kinesin - retrograde transport = from synapse to soma (back transport) - transporter molecules are dynein → transporter molecules wander along the filaments & drag the vesicles along local recycling of neurotransmitters in the synapse - needed to try to decrease the cost - regulation is needed ▪ only release the amount of transmitters that is absolutely necessary ▪ tricky balance - recycling of transmitters ▪ recycling/uptake & fast stop of the signal - Acetylcholine (ACh) vs. GABA - both are stored in vesicles in the pre-synapse - ACh is broken down very quickly by ACh-esterase after being released ▪ products acetate & choline can be resorbed in the pre-synapse & moved into biosynthetic apparatus (e.g. ER), where they are fused together again & repackaged into vesicles → no prolonged activation so transmission is highly structured and defined - GABA is not cleaved, but directly taken up by pre-synapse into the cytosol ▪ no extra step/enzyme necessary ▪ can also get taken up from nearby cells & used as nutrients  → both bind equally well to respective receptors so activation of the synapse is as fast as possible - but kinetics of GABA is much slower ▪ GABA has to diffuse from the receptor and is not cleaved specifically ▪ overall concentration of GABA is much higher - neurons can overall sense, how much neurotransmitters are present (inside pre-synapse) - percentage of neurotransmitters is always lost through diffusion, so they have to be replenished - mechanism behind is still very unclear - Acetylcholinesterase inhibitors are main active ingredient in many insecticides - by manipulating the breakdown of ACh, you have a very effective tool for manipu- lating the strength of the signaling - blocking split/recycling of ACh leads to longer depolarization → cramps - very strong inhibitors needed ▪ but Colorado potato beetle has overcome these (and every other pesti- cide) 2 main methods for adaptation o metabolic adaptation (overcompensation/production of a lot ACh-esterase) o target site adaptation (actual change of the enzyme struc- ture so inhibitor cannot bind anymore) drugs & neurotransmitter-receptors Drugs Effect possible mechanism in CNS LSD Hallucinogen Antagonist of serotonin receptors THC distorted perception binds to inhibitory receptors in cerebellum & hip- pocampus Amphetamine, Stimulant activates and destroys dopaminergic neurons MDMA that regulate sleep, sexual functions, mood, pain sensibility & motoric functions in different brain regions Opiates analgetic (pain killer), binds inhibitoric opiate-receptors that act over distorted perception G-proteins to influence among other, pain recep- tion & homeostatic functions of the body Cocaine, Crack local anesthetic, Hallu- Dopamine re-uptake inhibitor, strong overexcita- cinogen tion of the CNS, euphoria, wakefulness nicotine Stimulant activates (low dose) or inhibits (high dose) nico- tinergic receptors, stimulates the release of adrenaline form the adrenal glands → whole range of different effects on the CNS via different mechanisms → whole system is very sensitive to manipulation - a lot of these drugs have their origin in nature - in nature there are used e.g. for predation or as defense mechanism - then used/abused by humans Integration of synaptic inputs → summation - almost never 1:1 communication of neurons - one can talk to many and one can listen to many → convergent & divergent - a lot of different incoming synapses from in- coming neurons - all depolarizations (excitatory; leads to EPSP) & hyperpolarizations (inhibitory; leads to IPSP) work against each other all the time ▪ whole neuron is completely covered → large amount of input of different signals all the time - axon hillock is the point where actual action potential is formed → point where all the incoming signals are summarized (sum of input) - always two forces that work against each other ▪ time & distance of electrotonic signal- ing/diffusion with time and distance, sig- nals decrease ▪ excitatory & inhibitory signals work against each other → simple depolarization does not lead to an overcoming of threshold Excitatory & Inhibitory Synapses - excitatory postsynaptic potential (EPSP) - temporary depolarization of postsynaptic membrane caused by flow of positively charged ions - inhibitory postsynaptic potential (IPSP) - temporary hyperpolarization of postsynaptic membrane caused by flow of nega- tively charged ions - different examples of synapses 1. same neurotransmitter in the same animal can lead to different outcomes de- pending on the post-synapse ▪ heart muscle cells do not have Na+-channels → ACh only leads to K+-efflux meaning it leads to hyperpolarization (bc positive charge is leaving → cell becomes more negative) 2. same neurotransmitter can lead to different flows of ions ▪ D- & H-cells both use ACh as a neurotransmitter & in both cases, Cl—chan- nels are activated ▪ D-cells = high intracellular Cl--concentration; H-cells = low intracellular Cl--concentration → when channels open, ACh leads to depolarization in D-cells (neg. charge leaves meaning cell becomes more positive) & to hyperpolariza- tion in H-cells (neg. charge flows in) 3. same cell can lead to different signal transmission based on the neurotransmitter ▪ depending on the neurotransmitter (Glutamate = EPSP; GABA = IPSP), dif- ferent signals can be transmitted Receptor types in the post-synapse - ionotropic receptors (A.) - transmitter-receptors and ionopore in a single protein Pros Cons - very fast & reliable - cannot be modulated very easily → always - very simple → not dependent on other works the same molecules for correct function - metabotropic receptors (B.) - transmitter-receptor coupled to an effector molecule that initiates metabolic re- actions, e.g. the production of second messenger (cAMP) or protein phosphoryla- tion - ligand-binding part & ionopore are separated (can be spaced out quite far) - dependent on intracellular communication (e.g. G-coupled receptors) for activa- tion of the ion-channel Pros Cons - slow (good in some cases) - slow (bad in some cases) - everything can be modulated - whole system is quite vulnerable ▪ a lot of different molecules are involved ▪ a lot of different molecules are needed which concentrations can be modu- for correction function lated and lead to different reactions ▪ “easy” target bc many different steps are necessary - very energy intensive ▪ a lot of different steps need ATP → post-synapses often have a mix of these different receptors types and not only strictly one of them  - amplitude of IPSP is very similar but kinetics are very different - much longer lasting effects with B but also a lot of lag time → metabotropic receptors can prime the whole system for more than just a quick change - overall kinetics are very different in vertebrates and invertebrates - human: EPSP with A = 5 ms - Drosophila: EPSP with A = 1 ms → kinetics are clearly defined in vertebrates (e.g. humans) but can vary quite a lot in dif- ferent invertebrates ▪ e.g. crabs can modulate kinetics in different situations → more freedom ▪ less freedom maybe bc of endothermic & ectothermic lifestyle endotherms optimized to work best under certain set of conditions ectotherms need to adapt to very different sets of conditions so they need this additional freedom/flexibility → BUT transmitters may activate both metabotropic receptors and ligand-gated ion channels to produce both fast & slow PSPs at the same synapse  3. Lecture Neuronal circuitry, pre- & postsynaptic signal modulation, micronetworks, reflexes, on- togenetic development of the vertebrate nervous system, central, peripheral and enteric nervous systems, invertebrate nervous systems Neuronal circuits - neurons can have multiple synapses and build circuits which specific tasks - divergence: neurons can influence the electric activity of multiple target cells ▪ single neuron sends output to multiple other neurons ▪ information form on neuron is distributed & influences a broader network of neurons ▪ amplification of signals & coordination of responses possible - convergence: electric activity of a single neuron can be modified by input from multiple other neurons ▪ multiple neurons send their input to a single neuron ▪ a single neuron can therefore integrate information from various sources ▪ integration of signals and sensory processing possible presynaptic neuromodulation - overall part of the modulation of neurons & neuronal networks - process, in which the activity & efficacy of neurotransmitter release is regulated by vari- ous signals - modulation can alter the amount of neurotransmitter released in response to an action potential → influencing signal transmission and communication - presynaptic inhibition - reduces release of neurotransmitters form pre-synapse → decreasing excitatory or inhibitory signals send to the postsynaptic neuron  - mechanisms: ▪ activation of presynaptic receptors neurotransmitters are released from interneurons which leads to the opening of K+-channels and/or closing Ca+-channels → out- come is the same (hyperpolarization of the pre-synapse) reduces Ca+-influx → decreases neurotransmitter release ▪ activation of inhibitory interneurons release of inhibitory neurotransmitter via interneurons onto pre- synapse → reducing neurotransmitter by inhibiting their activity - functions & significance: ▪ helps prevent over-excitation & maintain network stability ▪ fine tuning of neural circuits - presynaptic facilitation - increases release of neurotransmitter form the presynaptic terminal → enhancing excitatory or inhibitory signals send to the postsynaptic neuron - mechanism: ▪ activation of presynaptic receptors: neurotransmitters are released form interneurons which leads to activation of second messenger systems → increased/prolonging Ca+-influx or enhance neurotransmitter release directly ▪ action of facilitatory interneurons interneurons can release facilitatory neurotransmitter & thereby enhancing activity → increased neurotransmitter release - function & significance : ▪ enhancing specific synaptic inputs → strengthening neural pathways ▪ important for synaptic plasticity, learning, memory, … - pre- & postsynaptic inhibition - mechanism to reduce activity of neurons → modulating flow of information - presynaptic inhibition: reduces neurotransmitter release form the presynaptic neuron → decreasing signal sent to the postsynaptic neuron - postsynaptic inhibition: reduces excitability of the post-synapse making it less likely t fire an action potential - feed-forward inhibition: ▪ circuit mechanism ▪ excitatory neuron activates an inhibitory neu- ron which then inhibits a downstream excita- tory neuron signal gets split into two ▪ function: sharpening response preventing over-excitation - feedback inhibition: ▪ circuit mechanism ▪ excitatory neuron activates an inhibitory neu- ron which then inhibits the same excitatory neuron or another neuron in the same network ▪ function: stabilizing neural activity (preventing runaway excitation) regulating rhythmic activity (oscillations in neural networks) ▪ all sensory motor neurons have a feedback inhibition process - different possible motifs of forming micro-networks - example of excitatory & inhibitory feed-forward signaling: “knee-jerk” reflex - “knee-jerk” = patellar reflex ▪ intrinsic reflex that triggers contraction of the extensor muscles of the thigh and thus an extension at the knee joint  - steps: ▪ stimulus detection: tap on patellar tendon stretches the quadriceps muscle stretch is detected by muscle spindles → sensory receptors within muscle ▪ sensory signal transmission: muscle spindles generate action potential which travels to sen- sory neurons to the spinal cord ▪ excitatory feed-forward signaling: in the spinal cord, sensory neurons build synapses directly with motor neurons for the thigh muscle → monosynaptic connection (only one synapse between sensory input & motor output excitation of motor neurons → action potential that travels to thigh muscle → kick outward via contraction → ensures rapid & direct response → quick reflex via direct activation of motor neurons by sensory neurons ▪ inhibitory feed-forward signaling: sensory neurons at the same time also form synapses with inhibi- tory interneurons in the spinal cord inhibitory interneurons form synapses with motor neurons that ac- tivate the antagonist muscle (hamstring) → hamstring remains re- laxed preventing counteraction to contraction of thigh muscle → prevents contraction of the antagonist muscle ensuring that the leg ex- tends smoothly → desired movement is not counteracted so efficiency is not reduced, and possible injury is prevented → reflex pathways are very complex and need strict modulation - simple reflexes only involve two neurons (effector & affector (sensory & motor neuron)), some reflexes are highly complex & multiple neurons, neuron types & whole organs are involved - e.g. escape reflexes found in many insects - reflex modulation is needed for e.g. stretch reflexes - when a muscle is stretched when rested → contraction for stability (standing up) - during voluntary movements, the intensity of the stretch/contraction is re- duced/reversed → prevents impending movements development of the vertebrate nervous system → Neurulation - Neurulation = formation of neural/central tube in the embryo - process that begins the manifestation of the central nervous system in all verte- brates - central tube gives rise to the central nervous system - involves series of coordinated events (cellular shape changes, movements, differentia- tion) development of the human CNS - neural tube undergoes series of expansion & divisions that form distinct regions of the brain - involves transformation form initial three primary brain vesicles into five secondary brain vesicles - primary brain vesicles ▪ initially neurol tube forms prosen- cephalon (forebrain), mesencephalon (midbrain) & rhombencephalon (hind- brain) - secondary brain vesicles ▪ primary vesicles further subdivide into 5 secondary vesicles ▪ will eventually rise to the major struc- tures of an adult brain  - 5 vesicle stages are crucial for correct formation of different parts of the brain - 1a: Telencephalon (part of forebrain) ▪ vesicles rise to cerebral hemispheres (cerebral cortex, basal ganglia & ol- factory blub) ▪ cerebral hemispheres are responsible for higher cognitive function, motor control, sensory perception, … - 1b: Diencephalon (part of forebrain) ▪ vesicles develop into thalamus, hypothalamus, epithalamus & subthala- mus ▪ thalamus = relay station for sensory information ▪ hypothalamus = regulates homeostasis (temperature control, hunger & hormone release - 2: Mesencephalon (part of midbrain) ▪ midbrain does not further subdivide into secondary vesicles ▪ remains as mesencephalon & develops into structures as tectum & teg- mentum ▪ midbrain involve functions like vision, hearing, motor control, sleep/wake cycles & arousal - 3a: Metencephalon (part of hindbrain) ▪ differentiates into pons & cerebellum ▪ pons = motor control & sensory analysis ▪ cerebellum = motor coordination, balance, learning of motor skills - 3b: Myelencephalon (part of hindbrain) ▪ forms medulla oblongata responsible for regulating vital autonomic func- tions (heart rate, breathing, blood pressure) bone marrow and spinal nerves - brain + bone marrow = CNS - bone marrow is an extension of the CNS - spinal nerves are mixed nerves that emerge form the spinal cord through spaces between vertebrae - sensory parts of the spinal nerves already belong to the peripheral nervous system - have sensory and motor functions - CLARKE’s nucleus/nucleus dorsalis - group of neurons located in the dorsal gray horn of the spinal cord - contains neurons, whose axons pass information about body posture directly to cerebellum without crossing the CNS ▪ conveys information form the lower limbs/trunk to the cerebellum - contributes to coordination of voluntary movements & posture dorsal root ganglion/spinal ganglion - contains soma of sensory neurons → dendrites end in peripheral regions of the body - makes synaptic contact to neurons in the thalamus or the bone marrow (e.g. motor neu- ron reflexes) - ventral column of the spinal neuron contains efferent (motoric; from brain to body) nerve fibers - grey matter includes all the synapses nerve vs. neuron - nerve = bundle of axons (nerve fibers) which are bound together by connective tissue - transmit signals between the brain, spinal cord & other parts of the body - can contain both sensory (afferent) neurons (transmitting sensory information to CNS) & motor (efferent) (transmitting commands form CNS to muscles & glands) - neuron = specialized cell - fundamental building block of the nervous system - responsible for transmitting information through body in the form of electrical sig- nals/action potentials - consist of cell body (soma), dendrites (receive signals from other neurons) & axon (travel/transmission) - neurons receive, integrate & transmit signals somatic vs. autonomous motoric system → PNS - both divisions of the peripheral nervous system (PNS) responsible for controlling different types of motor functions - somatic motoric system → voluntary - controls voluntary movements of skeletal muscles ▪ include movements like walking, running, lifting objects, facial expressions - includes pathways that originate in motor cortex in the brain & travel through the spinal cord to the skeletal muscles - somatic motor neurons are under conscious control → voluntarily movements - autonomous motoric system → involuntary - controls involuntary movements of smooth muscle, cardiac muscles & glands ▪ regulates activities that are essential for maintaining internal homeostasis (heart rate, digestion, respiration & secretion of glands) - autonomic motor neurons operate involuntarily - actions are often unconscious and reflexive ▪ responding to internal & external stimuli to maintain physiological balance - involve two-neuron chain ▪ CNS-neuron form synapses with PNS-neuron - further division possible ▪ sympathetic nervous system fight-or-flight system prepares the body for intense physical activity mobilizes energy reserves, increases heart rate & directs blood flow to muscles & vital organs while decreasing non-essential ac- tivities include co-transmitters o are peptides that are released along with classical neuro- transmitters o can modulate & modify the effect of primary neurotrans- mitters ▪ parasympathetic nervous system rest-and-digest system promotes maintenance activities & conserves energy enhances digestion, lowers heart rate & promotes relaxation & re- covery after stressful situations ▪ enteric nervous system second/abdominal brain runs through almost entire gastrointestinal tract complexity & neurotransmitters very similar to CNS includes AUERBACH plexus o neural network located in the GI tract o lies within muscularis externa of esophagus, stomach, small & large intestine o consists of dense network of ganglia (clusters of neuronal cell bodies) & nerve fibers that run parallel to the length of the GI tract o primarily controls motor function (peristalsis (wave-like contractions) & segmentation (mixing movements)) → facilitates digestion & food movement o coordinates contraction & relaxation of smooth muscle cells in muscularis externa to propel food & absorb nutri- ents o modulation through both the sympathetic (decrease of peristalsis through noradrenalin) & parasympathetic  (increase of peristalsis through acetylcholine) nervous systems includes MEISSNER-Plexus o located within submucosa (layer of connective tissue be- neath the inner lining of the GI tract o consists of smaller ganglia & nerve fibres o regulates secretory function (enzymes, mucus, fluid into lumen) o modulation through the parasympathetic nervous system (acetylcholine) includes Mucosal-Plexus o located within the mucosa (innermost layer of the GI tract lining) o consists of nerve fibres & ganglia o regulates local sensory & secretory functions o coordinates responses to luminal contents, chemical stimuli & mechanical stimuli o regulation of electrolyte & water secretion/reabsorption invertebrate central nervous system - huge variety but there are common features and general organizational patterns - organized in ganglia with high interconnectedness - neurons are very similar to neurons in vertebrates (in structure & function) - brain is the main ganglia region - but large ganglia are also spread throughout the body → large independence of functions of different body parts (e.g. insects often “stay alive” after being beheaded)  4. Lecture imaging methods, the vertebrate brain, the brain stem, cranial nerves, control of facial musculature (expressions), automatization of motion patterns, cerebellum Cerebrum = large brain (with cortex, basal ganglia, hippocampus, amygdala) Corpus collosum = colossal commissure (nerve bundles that connect the left & right cerebrae/hem- isphere) Diencephalon = thalamus & hypothalamus (con- necting centers) Brain stem = with midbrain, pons (bridge) & me- dulla oblongata Cerebellum = small brain NMR – nuclear magnetic resonance - you gain primarily information about the structure of the brain - scans rely on magnetic properties of certain atomic nuclei = spin - physical phenomenon - nuclei in a strong constant magnetic field are perturbed by weak oscillating mag- netic field & respond producing an electromagnetic signal with frequency charac- teristic of the magnetic field at the nucleus → when these nuclei are placed in an strong external magnetic field, “nuclear magnets” align with/against the field → distinct energy states - during scans, fluctuation in these strong magnetic fields are introduced (flipping the field) - not the whole field but just certain spots/slices - adds energy to certain atoms - adding and releasing this energy (after realigning in the overall magnetic field) can be measured - very sensitive equipment can pick up this energy in a special-informed manner - by modulating the frequencies, the spots/slices, the angles, etc. whole picture of the brain can be constructed form the magnetic spins - measuring energy that radiates form different tissues types (high fat content, high water content) an image that represents the inner structure of complex organs at certain depth can be build ▪ different tissues reacts differently - single scans compiled into stacks allow 3D-image of an organ (e.g. the brain) = computer tomography X-ray computed tomography - CT or CAT scans - weak to moderately strong X-rays to make images of the inside of the body - contrast dye helps highlight some areas better - can help highlight & emphasize blood vessels  - 3D-images out of different angles etc. to make stacks & help form whole structure - much lower resolution/less sensitive to motion than NMR/MRI - BUT MRI/NMR are much more expensive & takes more time ▪ CT (2-3 min) vs. NMR (30-45 min) → for diagnostics, CT scans are first choice & NMR only for further or more detailed prob- lems/questions (often both methods are used) PET – positron-emission-tomography - primarily information about function rather than structure - functions: - neurons are purely aerobic → they always need O2 - by injecting labeled O2 (18O-Dexoxyglucose; labeled water), the function (usage of O2) can be analyzed → areas that are more yellow, use O2 very fast meaning high metabolic activity - changes in local blood supply can be measured through the breakdown rate of oxygen isotopes - local blood supply is high in regions where neuronal activity is high - BUT best: combined analysis of the whole body gives information about the structure & the function Topology of the human brain – functions - Topology = structure function connection - a lot of the brain is very similar amongst humans but especially the Cortex involves a lot of neuronal plasticity therefore individual structures - Brain stem (Medulla, Pons (Hirnstamm)) - processing sensory & motoric signals - regulation of vegetative functions - Diencephalon (Thalamus, Hypothalamus) - filtering of sensory information & transla- tion into consciousness in the cortex - also used for unconscious regulation of the homeostatic bodily functions (Thala- mus) → gate to the brain - Basal ganglia - starting point of the regulation of con- scious movement patterns - in & around the brain stem - control basal movement patterns & bio- logical rhythms - gatekeeper for suppressing “unneces- sary” activity in the brain (important to keep a lid on things) - Hippocampus - key memory center but not for long-term memories - Amygdala  - coordination of autonomous functions, emotional interpretation of sensory infor- mation, fear - Cortex (Großhirnrinde) - Thinking, consciousness, memory storage - Cerebellum (Kleinhirn) - Coordination of movement, motoric learning brain stem - contains thick bundles of afferent & efferent nerve fibers & several ganglia - important for coordination of motoric patterns of the skeletal musculature - control of balance & posture - medulla contains pH- & pCO2-sensitive neurons that regulate acid/base-status & ventila- tion frequency - 3 main parts - Hypothalamus → sorting station - range of cranial nerves & synapses going out - a lot of ganglia (a lot in the medulla oblongata) cranial nerves - nerves that emerge directly form the brain & brainstem - 12 pairs - relay information between the brain & the body - special senses of vision, taste, smell & hearing - I. Offactory sensory/Nervus olfactorius: - sense of smell → transmits signals from the nose to the brain - uses similar amount of neuronal power as the ocular system, but doesn’t go through the same processing in the Thalamus ▪ has a more direct route into the consciousness → very unfiltered (no dilu- tion) - sensory nerve - II. Optic Nerve/Nervus opticus: - vision → transmits signals from the retina to the brain - sensory nerve - III. Oculomotor Nerve/Nervus oculomorius: - stimulates eye- & eyelid-movements & iris - parasympathetic nerve → somatomotoric (motor nerves, voluntary movements) & vegetative (involuntary physiological features) - IV. Trochlear Nerve/Nervus trochlearis: - stimulates the superior oblique muscle - somatomotoric nerve - V. Trigeminal Nerve/Nervus trigeminus: - splits into Nervus opthalmicus, Nervus maxillaris & Nervus mandibularis - transmits sensory information from the entire face to the brain & affects chewing ▪ touch all over the face - sensory & branchiomotoric nerves - small excurse: SNAKES ▪ Snakes use the same neuronal architecture here but it leads to another, special organ for seeing infrared (pit organ) special resolution possible ▪ modified by accumulating huge densities of thermoreceptors (which hu- mans use to fell hot/cold) ▪ give up a lot of their processing power of their cortex and part of their neu- ral power for this one sense/organ - VI. Abducens Nerve/Nervus abducens: - affects the lateral ocular muscles - somatomotoric nerve - VII. Facial Nerve/Nervus facialis: - stimulates facial expression musculature ▪ emotional expression - also transmits taste sensation & affects all salivary glands (except parotid gland) - branciomotoric, vegetative & sensory nerve ▪ mix of voluntary & autonomic/subconscious movements (involved in re- flex pathways) - has taken over these functions quite late in vertebrate evolution ▪ has fewer functions in invertebrates than in vertebrates primarily mam- mals - VIII. Auditory Vestibular Nerve/Nervus vestibulocochlearis: - transmits information form the cochlea & vestibular system - sensory nerve - IX. Glosspharyngeal Nerve/Nervus glossopharyngeus: - transmits signals form the posterior part of the tongue to the brain, pressor signals of carotid-sinus to brain stem & stimulates throat muscles ▪ important for swallow reflex ▪ throat movements - also stimulates parotid gland (major salivary gland) - sensory, brachiomotoric & vegetative nerves - X. “Rambling” Nerve/Nervus vagus - main nerve of the parasympathetic nervous system (takes care of the whole sys- tem) ▪ a lot of different nerves are required for the same effect in the sympathetic nervous system - involved in the physiological regulation of many connected organs - sensory, branciomotoric & vegetative nerves - XI. Accessory Nerve/Nervus accessories - motoric stimulation of Musculus trapezius & Musculus sternocleidomastoideus ▪ controls up & down movements of the skull - starts in the bone marrow but runs parallel to the bone marrow in skull cavity & exits at the base of the skull - somatomotoric nerve  - XII. Hypoglossal Nerve/Nervus hypoglossus - controls tongue movements - somatomotoric nerve 7th cranial nerve – control of facial musculature - quite conserved in all mammals → very strongly developed in social an- imals - owners & pets can “read” each other through these expressions - shows importance throughout evolution of mammals ▪ “silent” communication possible - control of facial expression through the motor cortex - controls a lot of different muscles on the face - face & head are heavily muscularized (26 different muscles) ▪ they stimulate tissues at the border of the skin ▪ move the skin but no joints (more like smooth muscles found around or- gans rather than skeletal muscles) ▪ have no fascia (strong connective tissue) → really exposed → all controlled through this one nerve - this one nerve is able to produce very wide contraction throughout the face but also very targeted movements control of movements - movement control through basal ganglia - are group of nuclei located deep in the brain - contain of Striatum, Globus Pallidus, Subtha- lamic Nucleus & Substantia Nigra - system of the Hypothalamus & different dense nuclei act as a break between the Cortex, that wants to send out movements to the body & the body - for movement to occur, one has to overcome this break - of course many other functions (e.g. hormonal functions) but not important here - all parts are interconnected & influence each other - Cortex want to activate, but first all the other systems have to be inactivated - green = excitatory (Glutamin) - red = inhibitory (GABA) - orange/yellow = can modulate others or be itself the target → either excitatory or inhibitory (Dopamin) - nucleus subthalamicus (NS) control base motoric - substantia nigra in the midbrain control fine motoric  - image shows “normal” functions without movement - different steps necessary for movement to occur - block of the ventrolateral thalamus needs to be overcome - 0. Globus pallidus gives the whole system the signal/input to change and to lift the block for movement - 1. Neurons from one part (Pars externa) stimulate base motoric by inhibition of NS - 2. NS normally stimulates Pars Interna - 3. Pars Interna inhibits ventrolateral thalamus ▪ as long this block is intact, no movement can occur bc no excitatory sig- nals can pass to the cortex → by activating Globus pallidus & therefore inhibiting NS, excitatory step 2 & inhibiting step 3 dis- appear → part of the block is lifted → fast route for the basal motoric but secondary route is necessary to actually move in a con- trolled manner - inhibition of NS (1) not only downregulates excitatory stimulation of Pars interna (2) but also the excitatory stimulation of the Pars reticularis - 4. Pars reticularis also inhibits ventrolateral thalamus (2 inhibition loop) - 5. Substantia nigra normally blocks itself and the Globus pallidus through dopaminergic signals (inhibitory via D1 receptors) → lifts the blocks on the ventrolateral thalamus - negative self-inhibition that has a continuing effect on the Pars interna ▪ therefore you get the same inhibitory effect as before - 7. BUT also trade off through excitatory signals via D2 receptors → partially bypass inhib- itory effect - depending which dopaminergic signal is stronger, you get either inhibition or ex- citement - always competition → leads to gradual responses ▪ otherwise you don’t get smooth increase/decrease in signals ▪ without dopaminergic feedback/control, whole system would activate with great force → difficult control of much - whole system is not only influenced by the basal ganglia but also by the cerebellum - complicated set of movements through the motoric cortex but a lot of the initial neuronal power (when moving in a complex way for the first time) is then moved to the cerebellum → moving without thinking about it ▪ can also detect errors and offer correction by comparing the intended movement to the actual movement ▪ you can live without cerebellum but you become clumsy (is the base of some diseases) → cerebellum takes over the learning the movements so complex movements become easier → cerebellum allows adaptation of complex movements to new situations (e.g. dart player with angled glasses → brain can correct movement very quickly and adapt know movement to hindered eyesight) → allows fine tuning of complex behaviors & facilitate mo- toric learning structure of the cerebellum - cerebellum has a cortical structure (layers of different/specific cell types) - contain “PURKINJE”-cells - contain the largest dendritic trees - allow interconnection between different layers - strongly connected to all the ganglia for the movements (lifting block) → can intake information from this ganglia system but also infor- mation form sensory systems and can process this information and affect neurons → can bypass cortex and input their own information (needed for reflexes) - also contains “mossy fibre” synapses - get intake from different cell types and signals get modulated (pre-synaptic inhi- bition & facilitation) - convey detailed sensory information form the periphery & motor commands → input is crucial for cerebellum to integrate & process sensory & motor signals  5. Lecture evolution of the vertebrate cortex, thalamus, hypothalamus, limbic system, the will to act (deliberate motorics), biological rhythms, sleep, learning, intelligence evolution of the cortex - cortex = cerebral cortex - part of the end brain (telecephalon) - contains cell bodies of neruons = grey matter (substantia grisea) ▪ afferent & efferent fibers of these neurons = white matter (substantia alba) - phylogenetically youngest & most developed region of the brain - functions: processing sensory perception, seeing, reading, hearing, speaking, planning & executing voluntary movements, consciousness, complex thinking, personality → higher-order brain functions (perception, cognition & motor control) - is a six-layered neocortex - each layer has characteristic distribution of dif- ferent neurons & connections with other cortical & subcortical regions - I.: few neuron soma, lateral axons, glial cells - II.-VI.: pyramidal- & non-pyramidal cells (inter- neurons) in varying ratios - axons of the pyramidal cells innervate other cor- tical cells & the brain stem/bone marrow ▪ are the only efferent tracks of the cere- bral cortex! - allows for specialized layers and for parallel pro- cessing (different types of information can be processed simultaneously in different layers) - vertical integration possible ▪ neurons arranged in columns across lay- ers allows for integration of information form various sources → cortical columns each neuron in a column respond to the same type of stimulus or pro- cess similar information - horizontal connections: layers II & III facilitate hor- izontal connections between different cortical re- gions for integration & association of information across the cortex - some layers allow feedback to the thalamus or other areas to modulate the input based on con- text & experience → feedback loops help refine sensory processing & adapt to changing conditions → layered structure has no apparent function; mammalian layered cortes is not as efficient as the bird unlayered cortex (layers might be an evolutionary accident) → just because animals have some trait does not mean that that trait is optimal - has folded structure → folds increase the surface are as a function of volume (most is not visible from the outside) - smooth surface = lissencephalic brain (e.g. rats) - uneven surface = gyrencephalic brain (e.g. humans) ▪ contains gyri & sulci → ridges and grooves on the surface gyri = raised ridges/folds on the surface sulci = grooves/furrows that separate the gyri - larger number of neurons & more complex circuitry can be maintained - The more advanced the living being, the more folds in the brain → biggest evolutionary step between ape & human: cortical surface in humans is 4 times larger than in chimpanzees!! - Comparison of vertebrate brains - different mammals have the same basic structure, but different parts of the brain are differently well developed ▪ parts develop differently from the different regions in the neural tube - mammalian cerebral cortex = 6-layerd neocortex & hippocampus ▪ formed form dorsal phillial half of the fore- brain (regulated by developmental gene emx-1) ▪ in birds, this region forms different layer of the brain → forms unlayered hyerstriatum & the optic chiasma ▪ in other sauropsids (“Landwirbeltiere”; birds & reptiles); the striated dor- soventricular ridge shows similar structures as the mammal neocortex like the amygdala human brains vs. bird brains - similarities: - high cognitive abilities (problem-solving, tool use, social behaviors) - specialized brain regions (dedicated to specific functions (sensory, motor, etc.) - complex neural circuits (support learning, memory & sophisticated behaviors) - differences: - structure ▪ humans have well-developed neocortex (6-layerd structure; unique to mammals) ▪ birds lack neocortex but have a pallium → different organization but also support complex behaviors - brain organization ▪ human cerebral cortex = highly convoluted with gyri & sulci ▪ birds have relatively smooth brain with fewer folds BUT very densely packed, compensating for the lack of surface convolution - brain regions ▪ humans have prefrontal cortex for social behavior & decision making ▪ birds have a nidopallium caudolaterale for analogous functions - sensory processing ▪ humans: visual cortex located in occipital love; auditory cortex in temporal lobe mammal auditory cortex has 6 layers with different types of cells that con- nect to the thalamus ▪ birds: highly developed visual & auditory pro- cessing regions with supporting excellent vi- sion & hearing birds have similar connections with similar cells in their brain but there are not arranged in layers - relative brain size: ▪ humans have larger brain relative to body size ▪ birds have a high brain-to-body mass ratio despite overall smaller brain, they have highly dense neurons → overall differences in brain structure & brain organization reflect independent adapta- tions to the respective niches The Human Cerebrum - cerebrum = “Großhirn” - largest & most complex part of the brain → responsible for higher brain functions - parted into left & right hemisphere (each controlling opposite side of the body - left = language & analytical tasks - right = spartial & creative tasks → both hemispheres are connected via thick band of nerve fibers called Corpus Callosum to allow communication between the two sides  - cerebral cortex is divided into 4 main lobes - frontal lobe ▪ located at the front of the brain ▪ responsible for executive functions (decision-making, problem-solving, planning, voluntary motor activity) ▪ includes prefrontal cortex (complex behaviors & personality) + primary motor cortex (controls voluntary movements) - parietal lobe ▪ behind the frontal lobe ▪ processes sensory information (touch, temperature, pain) ▪ includes primary somatosensory cortex (interprets sensory data from the body) - temporal lobe ▪ beneath frontal & parietal lobes ▪ involved in auditory processing, language comprehension & memory for- mation ▪ contains primary auditory cortex & areas critical for understanding lan- guages - occipital lobe ▪ at the back of the brain ▪ responsible for visual processing ▪ contains primary visual cortex (interprets information form the eyes) - cortex makes up 80% of total brain mass - contains 20 Mrd./2*1010 neurons → 1 mg ≈ 1 µl contain 15.000 neurons → different functions can be assigned to different parts of the brain via PET scans - can lead to problematic/misleading results - while certain brain areas are indeed specialized for particular tasks, a oversimpli- fication does not fully capture the complexity & interconnectedness of the brains function Thalamus & Hypothalamus - both components of the forebrain in the diencephalon; part of the limbic system - Thalamus - located near the center of the brain, above the brainstem & below the cerebral cortex - central integration, control & coordination organ of the sensitive & sensory sys- tems - functions: ▪ sensory relay station it receives sensory inputs & transmits them to appropriate areas of the cerebral cortex for processing ▪ motor function relaying information between motor cortex & basal ganglia ▪ regulation of consciousness & sleep helps filter sensory information & regulate flow of information to the cortex - Hypothalamus - below the Thalamus, just above the brainstem (floor of the third ventricle of the brain) - relatively small - essential control center for the autonomic nervous system ▪ controls basic state of the body, its temperature, blood pressure, blood distribution, fluid balance, calorie utilization, … - functions ▪ homeostasis Thermoregulation, water balance & thirst, hunger, sleep-wake-cy- cles ▪ endocrine system regulation by regulating pituitary gland (“Hypophyse”; hormonal control) stress response, growth & development, reproduction ▪ autonomic nervous system control affecting heart rate, blood pressure, digestion & respiratory rate ▪ behavioral & emotional response behaviors related to survival: feeding, mating, aggression important for expression of emotions & regulation of emotional re- sponses → both Hypothalamus & Thalamus are involved in feedback mechanism to maintain physiologi- cal balance (get input from the body & regulates its state accordingly) the limbic system - phylogenetically very old part of the brain - not a single, clearly defined anatomical structure, but rather a network of inter- connected structures - controlling functions of drive, learning, memory, emotions & vegetative regulation of food intake & digestion & reproduction → functional unit of the brain for processing of emotions (curiosity, anger, fear, joy, disgust, sad- ness, interest, contempt, guilt, shame) & the formation of instinctive behavior (“Triebverhalten”) → important for formation of memory, motivation & behavioral responses freedom in will & behavior - human and bird cortex has large sensoric & motoric re- gions but also large associative regions → special feature in humans: associative regions are much larger than sensory & motoric regions (not even the case in other primates) - brain of fish, amphibians & reptiles have a “purely limbic” - target motor skills as the result of complex processing steps that run sequentially and in parallel in different neuronal systems complex tasks of the brain 1: biological rhythms - biological rhythms can be divided into different periods - infradian rhythms → periods longer than 1 day