Neuroanatomy - Everything (PDF)

Chapter 1 & Chapter 2 Two Neuroanatomy Theories: Cajal vs. Golgi Cajal: Neuron doctrine: neurons communicate by being close and having contact, but not continuity. Each cell is independent from one another. Neurons follow cell theory. Predicted chemical signaling. Golgi: Reticular Theory (neurons m...

Chapter 1 & Chapter 2 Two Neuroanatomy Theories: Cajal vs. Golgi Cajal: Neuron doctrine: neurons communicate by being close and having contact, but not continuity. Each cell is independent from one another. Neurons follow cell theory. Predicted chemical signaling. Golgi: Reticular Theory (neurons membranes are fused together into a reticulum or network) -> communicate by continuity. Does not follow cell theory. - Cajal proven correct - However, Golgi sometimes correct -> membranes can be fused together by a pore and communicate through a gap junction Two Stains Nissl Stain: labels ALL cell bodies, good for seeing density. Good for seeing cytoarchitecture of tissue (the arrangement of neurons). Distinguishes between neurons and glia - Cons: doesn’t label the whole cell. Can’t see neurites Golgi Stain: can see the entire cell, including dendrites and axons! Silver chromate solution - Cons: cannot see all neurons. Only a small percentage. Nervous System: Central Nervous System: - Brain and spinal cord - Encased in bone - Cannot regenerate after injury Peripheral Nervous System: - All of the nerves innervating the body - Can regenerate after injury - Outside of bone Cell Biology Review & Protein Synthesis ↳Organelles: Organelle Name Function Nucleus Command center A sphere at the center of the soma. Has a double membrane with holes to release proteins. Inside nucleus: chromosomes with DNA. Each cell uses different segments of the DNA (genes) Protein synthesis occurs IN THE CYTOPLASM!  Ribosomes Production center Site of protein synthesis in the cytoplasm. Found on ER and just floating around. Polyribosomes: when many free ones are attached, (usually when many ribosomes work on one piece of mRNA to make multiple copies of a protein) Smooth ER ~Seamstress!~ Continuous with rough ER, does 3d folding, has no ribosomes, regulates ion concentrations Mitochondrion Powerhouse of cell Site of cellular respiration. Protein, fat, and sugar turns into pyruvic acid and oxygen, which in the krebs cycle, makes energy and then goes to the electron transport chain to make 17 ATP! There is the cristae and the matrix Golgi Apparatus Packaging center Post translational modifications, sorts proteins! Packages them! Lysosomes Waste management Break down waste What determines where a protein is synthesized? Where it is destined to go! Cytosol: built in free ribosomes Rough ER: produces proteins to be put into membranes usually ↳CENTRAL DOGMA DNA has genes that code for proteins DNA-> mRNA (copied into mRNA) in transcription goes out into cytoplasm translation occurs at ribosomes -> mRNA binds to ribosome -> amino acids put together sequentially each 3 nucleotides codes for an amino acid (codon) Transcription: the gene is read to make mRNA transcript-> RNA polymerase binds to the promoter with the help of transcription factors -> stop sequence at the end Introns: non coding segments of a gene RNA Splicing: Introns are removed and exons are spliced together with the spliceosome mRNA transcripts are made with the help of SNRNPs: small nuclear ribonucleoproteins Base pair with introns and then splice them -> they are then rapidly degraded Translation:  The assembly of proteins from amino acids under the direction of the mRNA The mRNA transcripts come out of the pores and travel to the cytoplasm where the amino acids are assembled Neuroanatomy Soma/cell body/perikaryon: contains the cell nucleus, is the site of protein synthesis, oval shaped. Cytoplasm: cytosol including organelles but excluding the nucleus Dendrites: projections that are thin and branch-like that extend outwards from the soma and receive inputs/ send signals to cell bodies. Way shorter than axons and taper off at the edges (not even diameter) Axon: a thicker, generally even-diameter tube that extends down from the soma. Can have projections that typically go at right angles, but each cell usually only has one axon. Axon hillock: generates action potential that conducts down the axon to the axon terminal. synapses are made on postsynaptic cells. Extends from the soma. Axon terminal: releases neurotransmitter in synaptic transmission! **only 1 axon that’s even diameter, but can have many dendrites that taper off** Neurons & Glia: about equal amounts in the body! Classifying Neurons DENDRITES: RECEIVE info! - most synapses end on dendrites (specifically, spines)! -neurotransmitters bind to special receptor proteins in cell membrane of dendrites (post synaptic) and the dendrites recognize them Have channels that may amplify the signal Dendritic Spine: - Little processes sticking off of dendrites - Some dendrites are spiny, some aren’t - SITE of synaptic transmission! - SHAPE and density of spines often determines synapse strength!!! Diseases with Dendritic Spines: Example 1: -general intellectual impairment causes sparse, wavyer, thin / spindly spines Example 2: -also: fragile X syndrome causes longer, more dense spines -length / width / density is not good or bad but dendritic spine abnormalities correlate with these two syndromes, just in different ways AXONS: transmit information! - Unique to neurons - Can be over 1 m long - Uniform diameter - No rough ER in the axon and few free ribosomes. Must receive proteins from the soma - The axon membrane has a very different protein composition from the soma - Myelinated or unmyelinated Axon terminal:  - No microtubules - Has synaptic vesicles - Lots of mitochondria because high energy demand Cytoskeleton - Made up of microtubules, microfilaments, and neurofilaments (intermediate filaments) - Microtubules = tubulin and biggest, microfilaments = actin and smallest, neurofilaments = keratin and very strong - MAPS: microtubule associated proteins. Tau is one of them, implicated in Alzheimer’s Disease. Alzheimer’s Disease: gyri shrink, sulci expand amyloid plaques, clumps of beta amyloid (outside) neurons inside neurons: neurofibrillary tangles (tau) form inside neurons -> leads to microtubule structure being compromised (inside) # of tangles found correlates with how severe the disease was Symptoms: cognitive decline memory loss disorientation loss of communication skills enlarged ventricles PROCESS OF ALZHEIMER’s: 1. Beta amyloid clumps into plaques outside of neurons 2. extra beta amyloid triggers tangle formation: (shape of tau changes bc of BA (phosphorylated by BA) and microtubules fall apart -> the SHAPE OF TAU CHANGES, thus they can’t hold the tubular molecules together properly anymore-> fall apart 3. neuron dies 4. tau accumulates (tangles) 5. distorted tau spreads to nearby neurons (prion like) -> spreads from one cell to the next and infects TAU = inside , forms tangles, loses structure and damages dendrites BA = outside, forms plaque, the trigger ↳Axoplasmic Transport need to get things from terminal to soma and vice versa Axons cannot survive when separated from soma There is slow and fast transport, since some axons are so long Utilizes MICROTUBULES Anterograde transport: proteins from soma transported to axon terminal Retrograde: axon terminal to soma THESE ARE FAST AXOPLASMIC TRANSPORT!!!!!! REMEMBER “KARD” ACRONYM ANTEROGRADE: kinesin proteins - walks a VESICLE DOWN A MICROTUBULE RETROGRADE: dynein proteins -> Signals what the axon needs DISEASES w AXOPLASMIC TRANSPORT: herpes and cold sores Anterograde & Retrograde: herpes 1. infection from saliva of infected person 2. HSV-1 enters nerve terminal at broken skin 3. retrograde transport to soma 4. replication of virus 5. recurrence of blister -> goes back down axon with anterograde transport causes blister at times of stress, reduced sleep, etc. DISEASES Rabies Disease: Retrograde Transport 1. animal bite -> virus in saliva does retrograde transport to soma 2. replicates 3. results in cell death 4. virus infects other cells 5. rabies causes Classifying Neurons: 1. # Neurites - unipolar, bipolar, multipolar 2. Length of Axon - Golgi Type 1 (long axon) Type 2 (short) 3. Type of Dendrite - spiny or aspinous, stellate or pyramidal 4. Connection with Periphery ***Primary sensory - carry information into CNS ***Primary motor - in CNS, connect with muscles or glands, carries info OUT ***Interneurons - all others -> from neuron to neuron GLIA! support cells, but with a twist brain is 50% glia generally smaller roles: electrically insulate neurons, protect neurons from infection, nourish them Astrocytes: most common fils spaces between neurons REGULATE ion concentrations around neurons guide neurons in development protect them by taking up toxins Restricts the spread of neurotransmitters after being released Myelinating Glia: Oligodendroglia and Schwann Cells electrically insulate axons with myelin (fat) the insulation speeds conduction break: node of ranvier PNS: Schwann cells, each insulates one neuron CNS: Oligodendroglial cells do many neurons! -efficient! ***REMEMBER COPS ACRONYM*** Other Non-Neuronal Cells in Brain: 1. Ependymal cells: line fluid filled ventricles, help cells migrate during development 2. Microglia: like phagocytes, remove debris 3. Arteries, veins, and capillaries, too! CNS Tumors: the most common CNS tumors are oligodendroglioma and astrocytomas (glioblastoma is particularly serious version) neuron cancers are rare because neurons don’t generally divide in the adult brain symptoms of glial tumor: nausea, headache, vomiting Chapter 3 The Neuronal Membrane at Rest The Phospholipid Membrane: Neuronal membrane has a two layers of phospholipids The heads face out (hydrophilic) and the tails face in towards one another (hydrophobic) ISOLATES the cytosol (hydrophilic) from the extracellular fluid -> has to pass through the hydrophobic interior of the membrane BARRIER to ion flow Proteins in the Membrane: determine what can and can’t enter! 1. Channel proteins -> usually selective for a type of ion a. Gating: can be voltage gated or transmitter gated b. Some channels are always leaky! -> K+ leak channels 2. Ion pumps: maintain the gradient across the membrane!! Membrane potential: the voltage (electrical potential difference) across the neuronal membrane at any moment (Vm) whether at rest or not Given in volts - Determined by the concentration of ions on either side of the membrane - The typical resting membrane potential is -65 mV! Resting Membrane Potential: - The weighted average of equilibrium potentials! Relies on concentration gradient and charge distributions, weighted by permeability! - Factors that contribute: - High Na+ outside, high K+ inside - K+ is 40x more permeable than Na+, so it draws the membrane closer to its -80 mV Eion - GOLDMAN EQUATION How does it stay constant when the driving force on sodium is so much higher? - The driving force on sodium is higher, but the membrane is much more permeable to K+ ions due to the Kleak channels! Why is Vm closer to Ek than ENa? - Kleak channels that are constantly open and let K+ leave the cell! - Membrane is 40x more permeable to potassium than sodium! Key Points About Membrane Potential: 1. Small changes in ion concentration provoke big changes in membrane potential 2. The net difference in charge is at the surfaces (inside + outside) of the membrane -> the charge is densely packed near the membrane bc the charges are attracted to cell membrane-> CAPACITANCE: the membrane stores electrical charge 3. “Ions are driven across the membrane at a rate proportional to the difference between the membrane potential and the equilibrium potential” -> Vm-Eion (real membrane potential minus equilibrium potential ) = ionic driving force. 4. Positive ion moves into cell: Vm increases or becomes LESS negative. 5. Positive ions move out of cell: Vm decreases or becomes MORE negative. The Sodium-Potassium Pump: MAINTAINS the resting membrane potential! 1. active transport of Na+ outside of the cell and K+ inside the cell - works against the concentration gradient a. Uses ATP and phosphorylation to induce a shape change in the protein, making it open and close b. 3 Sodium out for every 2 K+ in -> thus, there is less positive charge inside and more positive charge outside Factors that Govern Ion Movement: just because a channel is open does not mean that ions will flow 1. DIFFUSION: a. Movement of ions from high to low concentration to distribute themselves evenly b. Ions will flow down the concentration gradient c. This is the chemical driving force. d. Moving ions chemically requires channels permeable to that ion and a concentration gradient across the membrane. 2. ELECTRICITY: a. Like charges repel, opposites attract! b. A big buildup of positive ions will repel one another, want to cross the membrane c. This is the electrical driving force. d. Moving ions electrically requires channels permeable to that ion and an electrical potential difference (voltage) across the membrane Terms:  1. Current: the movement of POSITIVE ions across the membrane. conductance x driving force = gion (Vm - Eion). Means how much the ions are actually flowing. If you have no channels open or no driving force, the current will be 0. It depends on both these things! ***-depends on how much it CAN flow (conductance) and how much it WANTS to flow (driving force) 2. Conductance: how well/easily the charge can move across the membrane. Conductance increases with open channels. 3. Driving force: Vm - Eion. 4. Electrical potential: voltage, or the charge exerted on a particle. Higher electrical potential difference, the more current that will flow. Relative Concentration of Ions: K+: inside. 100 mm: 5 mm outside Na+: outside. 15 mm: 150 mM outside Cl-: outside. 13 mM: 150 mM outside Ca2+: outside..0002 mM: 2 mM outside Only K+ is concentrated inside! Equilibrium Potential! - The electrical potential difference that exactly counterbalances an ionic concentration gradient - Eion. Each ion has its own unique value. Some Key Points: 1. Equilibrium potential restates the concentration gradient in electrical terms 2. Tells us what membrane potential will give zero net movement for a particular ion. Eion = Vm, there is no NET movement for that ion. 3. Ions still move when at Eion, they just don’t move in an overall / net direction. 4. Eion tells us what value the membrane is going to be drawn towards if you open channels permeable to that ion. 5. The closer the resting membrane potential is to an ion’s equilibrium potential, the less driving force, the less the ion will be pushed across the membrane. What Occurs with Equilibrium Potential: 1. You know that Ca2+ is concentrated outside the cell. If there are channels, the ion flows down the concentration gradient inside the cell. Then, the positive charge inside the cell starts to repel some Ca2+ ions, pushing them back out of the cell through the channel. When the electrical force pushing the Ca2+ out = the force of diffusion, the membrane is at equilibrium, and there is a positive charge equilibrium on the inside. Nernst Equation: - Calculates the equilibrium potential for an ION! 𝑅𝑇 [𝑖𝑜𝑛]𝑜 Eion = 2.303 𝑧𝐹 𝑙𝑜𝑔 [𝑖𝑜𝑛]𝑖 Eion= ionic equilibrium potential R = gas constant T = absolute temperature z = charge of the ion F = Faraday’s constant Log = base 10 [ion]o = ionic concentration outside the cell [ion]i = ionic concentration inside the cell Increasing T means increasing diffusion and thus increasing the potential difference achieved at equilibrium (T and Eion are proportional) Increasing the electrical charge of each particle decreases the potential difference needed to balance diffusion (Eion inversely proportional to charge of ion (z) (thus decreases Eion) Changes to Equilibrium Potential: Would the following Changes increase or decrease the equilibrium potential of A+?: - Lower A’s concentration outside cell: DECREASE Eion - A is transformed from a monovalent to divalent cation: DECREASE (electrical charge and Eion are inversely proportional) - Temperature increased: INCREASE Eion (they are proportional) Driving force cation anion - Push into cell Push out of cell + Push out of cell Push into cell Positive driving force: positive charge leaving or negative charge coming in Negative driving force: positive charge coming in or negative charge leaving 1) Negative ion, more concentrated INSIDE the cell: Eion is positive. 2) Negative ion, more concentrated OUTSIDE the cell: Eion is negative. 3) Positive ion, more concentrated INSIDE the cell: Eion is negative (think of K+) 4) Positive ion, more concentrated OUTSIDE the cell: Eion is positive (think of Na+) CURRENT: Iion = gion (Vm-Eion) For current to flow, there must be a nonzero conductance AND nonzero driving force. Equilibrium Potentials: Ek = -80 mV ENa = +61mV ECl = -65 mV ECa = +123 mV Depolarizing: Ca2+ and Na+ Hyperpolarizing: K+ and Cl- Big Chapter 3 Takeaways:  1. For a cation concentrated outside cell: a. Decrease the difference in concentration, decrease the Eion b. Increase from a monovalent to divalent ion, decrease Eion c. Increase temperature, increase Eion (because diffusion force increases) 2. For current to flow, you need a nonzero conductance AND a nonzero driving force 3. Charge difference is localized right at the membrane 4. The resting membrane potential is a weighted average of the ion concentrations/ charge distribution and their relative permeabilities (Goldman Equation) 5. The higher the driving force, the faster ions will flow out of the membrane 6. The closer the resting membrane potential is to an ion’s equilibrium potential, the smaller the driving force on that ion 7. Being “at equilibrium” does not mean that no ions are moving, there are equal charges on either side of the membrane, or there are equal concentrations of ions on either side of the membrane -> it just means that the two forces are balanced 8. If the Vm = the Eion, there will be no net movement of that ion 9. Membrane potential is relative-> it’s the difference in voltage from the inside of the cell to the outside of the cell. 10. Only a tiny fraction of the total ions in the cell make up the concentration gradient What if Ion Permeabilities Change Over time? If Na+ permeability increases, the membrane potential will become more positive, moving towards ENa If K+ permeability increase, membrane potential will become more negative, moving towards Ek Effects of Aberrant Ion Concentrations & Why Concentrations Must be Maintained: Weaver mice have a K+ channel mutation that allows both K+ and Na+ to pass through Because of increased Na+ permeability, resting potential is more positive than normal and neuron function is compromised. They move abnormally Importance of Regulating K+ Concentrations Externally: - There is potassium spatial buffering by astrocytes - tenfold rise in extracellular K+ severely diminishes resting membrane potential - without negative resting potentials, cell function is compromised-> lethal injections Chapter 4 The Action Potential - All or nothing! - Whole thing lasts 2 msec, and voltage-gated Na+ channels close after one msec - Delayed rectifiers: Vg K+ channels open after 1 msec. The Stages of the Action Potential: How do you generate an action potential? You need three kinds of channels: 1. Potassium channels that are open regardless of membrane potential (Leaking ones) (Kleak) 2. Voltage gated sodium channels (NaV) Resting Potential: Na/K pump running K+ leakage channels are open Vg Na+/K+ channels NOT open Around -65 mV Threshold: Passive Depolarization: Depolarization of the membrane to threshold (around -40 mV) Can be caused by two things, like sensory input (step on a tack and the neuron membranes actually stretch and open sodium channels) or neurotransmitter release If it reaches threshold, AP is generated. If it doesn’t, NO AP! Rising Phase: After reaching threshold, that voltage causes voltage-gated Na+ channels to open at around -40 mV Voltage gated Na+ channels are activated -> as some open, the depolarizing current opens more. FEEDBACK! gNa >> gK! Vm moves towards Ena -> membrane potential reverses to positive OVERSHOOT: - K+ driving force is largest here! Around 40 mV peak Can’t fully reach ENa (62 mV) because there is still a good deal of K+ leakage / conductance Driving force for Na+ starts to decrease as Vm approaches ENa NaV channels inactive (globular protein) KV1 channels open - delayed rectifiers LARGE driving force now on K+, because the membrane inside is positively charged and the outside has way less K+ Falling Phase: Vm moves toward Ek -> voltage gated channels open Driving force on Na+ is increasing as Vm gets more negative -> but the sodium channels are inactivated Gk >> gNA Undershoot/Hyperpolarization: Falls below -65 mV -> gets very close to Ek because both Kv1 AND Kleak are open -> more potassium channels open than would be usually NaV channels start de-inactivating (get ready for next action potential) Kv1 channels close and get back towards resting membrane potential Driving force on Na+ is HIGHEST HERE! Voltage Gated Na+ Channels: How does the selectivity filter allow Na+ and not K+? -> each ion is accompanied by a water molecule-> the water molecule and Na+ fit into the pore, but not the water molecule and K+. Stripped of most but not all water molecules 1. Activated: When depolarized to threshold, the closed channel swings open 2. Inactivated: A globular portion of the protein swings up and occludes the pore after 1 msec. 3. Deinactivation occurs when the globular portion swings away and the pore closes. Now, a new action potential can occur Properties: - Open with little delay - Stay open for 1 msec then close - Cannot be opened again by depolarization until the membrane potential returns to a negative value near threshold What is Responsible for the Absolute Refractory Period? Falling phase - When the globular portion of the sodium channel swings up and clogs the pore. Even if there is depolarization, ions cannot flow through the channel. What is Responsible for the Relative Refractory Period? Undershoot - The relative refractory period is a period of time where it is possible to generate a new action potential; however, it is a lot harder to. This is because only some VG Na+ channels have been de-inactivated, and also, some Vg K+ channels are still open in addition to the leak channels, so the membrane is more hyperpolarized than usual, and it would take more current to reach threshold with less channels to amplify. Voltage Gated K+ Channels: Either closed (rising phase) or open (overshoot to falling phase) Function similar to sodium channels (4 polypeptide units that come together with a pore in the middle, the protein twists to allow K+ to enter the pore upon depolarization). DELAYED RECTIFIER: the potassium channels open 1msec after depolarization to rectify the membrane potential Ion Channel Toxins Tetrodotoxin - TTX ○ Derived from puffer fish ○ Blocks Na+ channels and stops action potentials -> binds to sodium channels such that it cannot open anymore -> leads to muscle paralysis and then asphyxiation -> 1 mg is lethal Saxitoxin (STX) ○ Poisoned by eating shellfish that have ingested dinoflagellates Local Anesthetics - Affect Small Axons Locally and transiently block action potentials Cocaine was the first one discovered Lidocaine: the most commonly used today -> must enter channel and bind to inside of pore Block Na+ channels -> APs in small axons are most affected because they have fewer Na+ channels, conduct less current and thus have to open more-> lucky for us, nerves responsible for pain have small axons! Frequency of Action Potentials: Rate of conduction depends on the magnitude of depolarization The more current, the more impulses / second (1 Hz to 50 Hz or Herz) LIMITS TO RATES: the maximum firing frequency is 1000 Hz - you cannot initiate another action potential for about 1 msec (absolute refractory period) Relative refractory period: lasts a few seconds after the absolute refractory period, where the current required to depolarize the neuron to threshold is elevated (it is a little bit harder to create an action potential) How is the Action Potential from One Neuron Conducted Down the Axon? Part of the axonal membrane is depolarized to threshold -> voltage gated sodium channels open -> action potential initiated -> the influx of positive charge spreads inside the axon and depolarizes adjacent segments of membrane, which then reach threshold, have their sodium channels open, and then generate action potentials that spread further and depolarize other sections of the membrane to potential. This process continues until the action potential reaches the axon terminal, and synaptic transmission is initiated THE ACTION POTENTIAL GOES IN ONE DIRECTION -> because the neuron behind it is refractory Factors Influencing Conduction Velocity: - Bigger diameter increases it -> less likely the charges get localized at the membrane - Passive depolarization increases it - Myelin and saltatory conduction blocks leakage channels and lowers the axial resistance to flow-> but increasing nodes SLOWS CONDUCTION! Has to pause and jump more! Multiple Sclerosis:  Autoimmune attack on myelin, degrades AP conduction Symptoms: limb numbness or weakness, electric shock -women more likely than men Chapter 5 Synaptic Transmission: the process of information transfer at a synapse Electrical Synapses: - Allow the direct transfer of ionic current from one cell to the next - Occur at gap junctions - Gap junction channel: when two connexons (one from each cell) meet and combine to form the channel - Allows ions from one cell’s cytoplasm to pass into the other cell - Smaller than chemical synapses - These synapses are bidirectional unlike chemical synapses! - The current from the ion causes a postsynaptic potential (1 mV)-> many sum to excite a neuron - Function: high synchronicity, especially in inferior olive Chemical Synapses: Vesicles that Release NT: Synaptic vesicles: store NT and are in the axon terminal Secretory granules: aka dense core vesicles, these are larger and appear darker in microscope. Contain peptide neurotransmitters. Proteins Involved: MEMBRANE DIFFERENTIATIONS: the accumulations of protein on either side of the synaptic cleft Active Zone: protein composition on the presynaptic side Postsynaptic Density: on the postsynaptic side, contains the neurotransmitter receptors 3 Main Types of Synapses: - Axodendritic - Axosomatic - Axospinous Classifying CNS Synapses Based on Membrane Differentiation 1. Asymmetrical / Gray’s type I synapses: the membrane differentiation on the POSTSYNAPTIC side is thicker (excitatory) 2. Symmetrical synapses / Gray’s type II: the membrane differentiation on both sides of the synapse is similar (inhibitory) Categories of Neurotransmitters 1. Amino acids: examples are GABA/ gamma-aminobutyric acid, Glu/glutamine, Gly/ glycine 2. Amines: examples are acetylcholine/ACh, dopamine/DA, epinephrine, histamine, norepinephrine/NE, serotonin/ 5-HT 3. Peptides: examples are CCK/ cholecystokinin, Dynorphin, Enk/Enkephalins, NAAG, etc. SYNTHESIS AND STORAGE: How are neurotransmitters made?: (AMINO + AMINE)  ○ glutamate and glycine are amino acids that are 20 building blocks of proteins, so they are in all cells of body, including neurons ○ GABA/amines: made by the neurons that release them -> enzymes for both amino acid and amine neurotransmitters are transported to the axon terminal where they locally + rapidly direct transmitter synthesis using precursor molecules How are they stored? (AMINO + AMINE) ○ Amino acid and amine neurotransmitters must be taken up by synaptic vesicles ○ Transporters: special proteins in the vesicle membrane that make sure neurotransmitters are concentrated inside the vesicle PEPTIDE Synthesis and Storage: a precursor peptide is synthesized in the rough ER-> it is then split in the Golgi to yield the active neurotransmitter -> secretory vesicles with the active peptide neurotransmitter bud from the golgi and travel to the axon terminal where they are stored Synthesis and Storage of Different Types of NT: Process of Neurotransmitter Release at Synapse: 1. When the depolarizing current reaches the presynaptic membrane, the synaptic vesicles are waiting, docked at the active zone. 2. Depolarization of the presynaptic membrane causes voltage-gated Ca2+ channels to open, and Ca2+ rushes into the cell because of the larging driving force. 3. Ca2+ triggers neurotransmitter release by binding to synaptotagmin in the SNARE complex, which is a sensor that triggers vesicle fusion. 4. The T-snares on the presynaptic membrane and the V-snares come together, helping the vesicle membrane to rearrange and fuse with the presynaptic membrane. 5. The vesicle fuses with the presynaptic membrane, and the neurotransmitter is released into the presynaptic terminal via exocytosis. 6. Vesicle is recycled via endocytosis! HOW does the release of peptide neurotransmitters differ from that of amino acids and amines? NOT released at active zones, they’re released at a distance from where Ca2+ enters the cell. Need more depolarizing current so the internal Caa2+ concentration can build up higher and trigger release away from the active zone. HOW are Neurotransmitters RECEIVED at the Postsynaptic neuron? TWO TYPES OF RECEPTORS: transmitter-gated ion channels and G-protein coupled receptors Transmitter-Gated Ion Channels: Generate EPSP and IPSP! Postsynaptic potentials are not all the same size!!! EPSP: a transient postsynaptic membrane depolarization caused by the presynaptic release of NT ○ Cause Na+ or K+ to rush into cell or Ca2+ ○ This occurs with ACh-gated and glutamate-gated ion channels (amine / amino acid) IPSP: a transient hyperpolarization of the postsynaptic membrane caused by presynaptic release of neurotransmitters IF permeable to Cl- or K+: the postsynaptic cell will be hyperpolarized This is “inhibitory” because it brings the membrane potential away from threshold ○ This occurs with glycine-gated or GABA-gated (amino acid) channels Synaptic Integration & Quantal Analysis: - Quantum: A quantum refers to the NT contents of one vesicle. - miniPSP: is the potential change in the postsynaptic neuron caused by the release of one vesicle or quantum. - All vesicles have the same amount of NT. NTs cause a change in the potential of the postsynaptic neuron when they bind receptors. - Quantal analysis: The postsynaptic response can be quantified in terms of discrete changes in potential based on how many quanta were released EPSP Summation: simplest form of synaptic integration - Spatial summation: adding together many EPSPs generated simultaneously at different synapses on a dendrite - Temporal summation: adding together EPSPs generated at the same synapse in quick succession G-protein coupled receptors THREE STEPS 1. Binding of neurotransmitter to receptor protein  2. Activation of g-proteins 3. Activation of effector systems G-Protein Structure: One polypeptide 7 alpha helices Two extracellular loops form transmitter binding sites Two intracellular loops bind to / activate g proteins How the G-Protein Works: 1. Each g protein has 3 subunits: alpha, beta, and y 2. Resting state: GDP molecule is bound to the a subunit, and the whole complex floats on interior surface of membrane 3. If the g protein bumps into the right receptor type that is also ACTIVATED by transmitter: GDP is switched for GTP 4. The active g protein splits into two parts, activated Ga subunit with the GTP and then the Gby unit 5. Both subunits go on to influence effector proteins 6. Ga subunit breaks down GTP into GDP and phosphate, and the two subunits come back together 2 Types of G Protein: GS (stimulate effector proteins) and Gi (inhibit effector proteins) Two Types of Effector Proteins: G-Protein-gated ion channels and G-protein-activated enzymes Length Constant and Factors Affecting IT: ○ This distance, where the depolarization is about 37% of that at origin, is called the dendritic length constant -> the longer the length constant, the more likely it is that EPSPs generated at distant synapses will depolarize the membrane at axon hillock (135) -> it is an index of how far depolarization can spread FACTORS affecting the value of λ: ○ Internal resistance (ri): the resistance to current flowing longitudinally down the dendrite ○ Membrane resistance: (rm): the resistance to current flowing across the membrane ○ λ will increase as rm increases because less current will leak out ○ λ will decrease when internal resistance increases because more will flow out across the membrane Ri: depends on width of dendrite / electrical properties of cytoplasm -> pretty constant in mature neuron Rm: depends on # open ion channels -> CAN CHANGE -> so the dendritic length constant is NOT REALLY CONSTANT How to Increase Length Constant: 1. Add VG channels throughout dendrite 2. Use an NT to activate a GPCR and alter excitability of the membrane by closing a channel 3. Shunting inhibition DECREASES length constant! Shunting Inhibition & IPSP: - Having an inhibitory synapse after an excitatory one “shunts” it, preventing the current from flowing through the soma to the axon hillock - IPSPs reduce the size of EPSPs, making it less likely to fire action potentials - Makes it so you can’t have a higher Vm in the soma than what you started with! Chapter 6 Four Rules of Neurotransmitters: 1. Must be synthesized and stored in presynaptic neuron 2. Must be released by presynaptic neuron upon stimulation 3. In experiments, must produce a response in postsynaptic cell that mimics the response that occurs naturally when the neurotransmitter is released from the presynaptic neuron 4. There’s a mechanism for removal / inactivation of neurotransmitter candidate substance Dale’s Principle: states that a neuron has only one neurotransmitter ○ However, some neurons have amino acid or amine in addition to a peptide Cotransmitters: two or more neurotransmitters released from one terminal CHOLINERGIC NEURONS How is Acetylcholine made? Choline acetyltransferase enzyme (ChAT) is made in the soma and brought to axon There, ChAT synthesizes ACh, and ACh transporters concentrate it in the vesicles ChAT transfers acetyl group from acetyl CoA to choline (found in extracellular fluid), making acetylcholine and CoA How do you get choline? -> a neuronal membrane transporter requiring Na+ takes up choline into the axon terminal and concentrates it highly in a very small space General Process of Making ACh with Transporter Proteins: First, the choline membrane transporter drives the intracellular concentration of choline up using energy from the Na+ concentration gradient (2 Na go in). Then, ChAT enzyme takes choline + acetyl CoA and makes acetylcholine. The acetylcholine transporter then uses countertransport to push ACh into a vesicle. This vesicle then releases its contents during synapse, and ACh can be received by receptors on the postsynaptic cell. Rate-limiting step: the amount of choline limits how much ACh can be made -> so transporting choline is rate-limiting step How is Acetylcholine degraded? Acetylcholinesterase (AChE) secreted into the synapse, breaks ACh into choline and acetic acid IN SYNAPTIC CLEFT  Plasma Membrane Transporters: use a cotransport mechanism. Carry two Na+ ions into the cell with one transmitter molecule -> use some of the energy from the steep Na+ gradient to drive the concentration of neurotransmitter up Vesicular Membrane Transporters: use a countertransport mechanism. Use ATP pumps to keep the contents acidic CATECHOLAMINERGIC: - Dopamine, norepinrphrine, and epinephrine - Precursor: tyrosine - Rate-limiting enzyme: TH - Decrease catecholamine release/ accumulate presynaptic: inhibit TH - Lots of catecholamine release: increase TH How to Make Catecholamines: 1. Dopa (made from TH from precursor tyrosine) is converted into dopamine (DA) by dopa decarboxylase enzyme (amount of DA made is dependent on the amount of dopa available, not the enzyme) 2. Dopamine beta hydroxylase enzyme then makes norepinephrine from dopamine -> but the DBH enzyme is in synaptic vesicles, not cytosol, so it’s made there in noradrenergic axon terminals 3. Phentolamine N-methyltransferase (PNMT) then converts NE to epinephrine (adrenaline), but this happens back in the cytosol! How Does Degradation of Catecholamines Differ from that of Acetylcholine? DON’T get degraded in the synaptic cleft They are reuptaken by selective uptakers of the neurotransmitters Drugs like amphetamine and cocaine block catecholamine uptake, prolonging the actions in the cleft In the terminal: could be reloaded into a vesicle for use or destroyed by monoamine oxidase (MAO) on the membrane of mitochondria SEROTONERGIC - Made from tryptophan How is Serotonin Made?: Tryptophan is made into 5-hydroxytryptophan (5-HTP) by tryptophan hydroxylase enzyme (adds OH group) 5-HTP then converted to 5-HT by 5-HTP decarboxylase enzyme (removes carboxyl group) AMOUNT OF TRYPTOPHAN present from diet affects the amount of serotonin that can be made Degradation of Serotonin: similar to catecholamines A transporter removes it from axon terminal and reuptakes it, then reloads it or degrades it by MAO DRUGS: SSRI (selective serotonin reuptake inhibitor) -> allows AMINO ACIDERGIC NEURONS (AMINO ACID NEUROTRANSMITTERS) Glutamate, glycine, and gamma-amino-butyric acid (GABA) are in MOST CNS SYNAPSES Glutamate and Glycine: Glutamate and glycine normally in cells (they’re one of 20 amino acids that make proteins), they just exist in higher quantities in cells where they are used as neurotransmitters The TRANSPORTER shows you whether or not it is glutamatergic: in glutamatergic cells, the transporter loads glutamate into vesicles until the concentration is 50 mM Glutamate: major excitatory neurotransmitter GABA: Glutamic acid decarboxylase removes carboxyl group from glutamate, making GABA GABAergic neurons main source of synaptic inhibition in the nervous system How are Amino Acid neurotransmitters degraded? Na+ dependent transporters uptake them into the presynaptic terminal or glia GABA transaminase enzyme metabolizes GABA in the glia or terminal! OTHER NEUROTRANSMITTERS: ATP: (in CNS and PNS): Usually is a co-transmitter in vesicles with other neurotransmitters catecholamine especially, but also GABA, glutamate, ACh, DA, and peptide transmitters ATP can also excite neurons by gating cation channels -> binds to purinergic receptors, and is degraded by extracellular enzymes Endocannabinoids: Small lipid molecules that can be released from postsynaptic neurons and be received at presynaptic neurons -> retrograde messengers -> regulate regular forms of synaptic transmission Action potentials casue calcium gated channels to open, ca enters cell, and elevated [Ca2+]i stimulates synthesis of these molecules ○ They’re not packaged in vesicles like other neurotransmitters! ○ They are membrane permeable and can go diffuse to other cells ○ Bind selectively to CB1 cannabinoid receptor CB1 Receptors: G-protein coupled receptors that reduce opening of calcium channels in pre synaptic neurons Thus, endocannabinoids are released when neurons are really active Nitric Oxide (NO): Small and membrane permeable May be another retrograde messenger TRANSMITTER-GATED CHANNEL TYPES: Nicotinic ACh receptor: At the neuromuscular junction in skeletal muscle  Has 5 subunits (pentameric) -> ∝βyδ, with two ∝ and one of each else Each of these subunits has 4 segments that will coil into alpha helices -> the segments are hydrophobic ACh needs to bind to both spots on the ∝ subunits to open the channel Nicotinic receptors: ligand-gated ion channels ○ Generally, they allow the flow of multiple ions (Na+, K+, and, in some instances Ca2+) ○ These are the ACh receptors primarily found in the NMJ. Since they are ion channels, they can quickly transduce a chemical signal into an electrical signal. Muscarinic receptors: GPCRs ○ Generally, can cause both the opening and the closing of ion channels that lead to very slow EPSPs and IPSPs. ○ In the muscarinic ACh receptor signaling cascade, they let K+ out of the cell, leading to hyperpolarization. ○ These mediate the slowing down of the heart rate in the Otto Loewi experiment. Drugs that inhibit muscarinic receptors mimic activation of the sympathetic division of the ANS. Drugs that activate muscarinic receptors mimic activation of the parasympathetic division of the ANS. GABA and glycine receptors: Also pentameric receptors Glutamate receptors: only have four subunits (tetrameter) The M2 alpha helix segment on this receptor doesn’t span the membrane! It forms a hairpin on the intracellular side **they have these M1-M4 regions in common where the polypeptides coil into alpha helices** (165) AMINO-ACID GATED CHANNELS: responsible for most CNS fast transmission Glutamate-Gated Channels: 3 Types Named for their Selective Agonists: AMPA, NMDA, and kainate AMPA-gated and NMDA-gated: mediate fast excitatory transmission in brain Ampa gated channels: Permeable to Na+ and K+ Causes a depolarization when activated (more Na+ enters than K+ leaves) NMDA gated channels: Also coexist with AMPA receptors, and these channels cause glutamate-mediated EPSP DIFFERENCE from AMPA: permeable to Ca2+ and voltage dependent When this channel opens, ca2+ and na+ enter the cell but the magnitude of the current depends on the postsynaptic membrane potential-> at low membrane potential, the pore is clogged by Mg2+ ions that only leave the pore when the membrane is depolarized Requires glutamate AND depolarization in order to open GABA-Gated and Glycine-Gated Channels: Both receptors gate a chloride channel Benzodiazepines and barbiturates: bind to the GABA channel other sites -> only have an effect when GABA is also present -> Drugs being present cause more inhibitory Cl- current and stronger IPSPs Ethanol: binds to particular types of subunits, meaning it only causes stronger IPSPs in certain areas of the brain GABA: synaptic inhibition in CNS OTTO LOEWI: - Discovered chemical synaptic transmission - Two hearts are connected: stimulate heart #1 at vagus nerve, slows heart beat. - If the valve is open: the second heartbeat will slow, too!!!! - “Vagus stuff”: acetylcholine! - It was binding to the muscarinic receptors - -ach binds to receptor, GDP/GTP exchange. Beta gamma subunit bumps against potassium channel that was originally closed and OPENS THE K+ CHANNEL. K+ FLOWS OUT, hyperpolarizing the membrane (making it less electrically active) Protein Phosphatases: remove phosphate groups Order of How Fast Transmission is: Fast to Slow 1. Gap junctions 2. Activation of ligand/NT-gated ion channels 3. Activation of G proteins that open ion channels (shortcut pathway) 4. Activation of protein kinases (that are activated by GPCRs) that then open ion channels CASCADES FIRST EXAMPLE: cAMP Stimulatory Pathway 1. Norepinephrine binds to B receptor. 2. If a G protein is bound, B receptor activates stimulatory g protein. The alpha subunit switches out GDP for GTP and is now activated. It dissociates from the beta gamma unit 3. Alpha subunit stimulates the membrane bound effector enzyme, adenylyl cyclase 4. Adenylyl cyclase converts ATP to cAMP 5. cAMP in the cytosol activates protein kinase A (PKA) 6. Protein Kinase A phosphorylates things -> for example, if it phosphorylates a K+ channel, it will close, making the membrane more excitable. SECOND EXAMPLE: cAMP Inhibitory Pathway 1. Norepinephrine binds to a different GPCR, the a2 receptor 2. If there is an inhibitory G protein bound, GDP will be replaced with GTP, leading to activation of the inhibitory g protein 3. The activated alpha subunit dissociates, leads to the downregulation of adenylyl cyclase 4. Less cAMP is made, cannot activate PKA to phosphorylate channels THIRD EXAMPLE: IP3/DAG Pathway (branching pathway)  1. Neurotransmitter binds to GPCR, and if the G protein is bound, it is activated, converting GDP to GTP on the alpha subunit such that it is activated and dissociates 2. Activated alpha subunit binds and activates PLC effector protein 3. PLC cleaves PIP2 from membrane into Ip3 and DAG 4. IP3 is water soluble, travels to the ER lumen, where it binds and opens Calcium gated ion channels, calcium rushes out. Calcium then binds to calmodulin, forming the calcium calmodulin complex, which activates calcium-calmodulin dependent kinase 5. DAG is lipid soluble, stays in membrane, activates protein kinase C Phosphorylation and dephosphorylation Protein kinases in downstream cascades are important Transfer ATP to proteins Protein phosphatases remove the phosphate groups Advantages of G-Protein coupled receptor transmission: signal amplification Widespread effects Chapter 7 Anatomical References: - Anterior / rostral: towards nose - posterior/ caudal: towards tail - rostral/caudal follow neuraxis -> anterior just means in front of the creature and is synonymous with ventral in spinal cord. Posterior means behind creature and is synonymous with dorsal in spinal cord. - Dorsal: back - Ventral: stomach - Medial: closer to midline - Lateral: farther from the midline - Ipsilateral: same side of body - Contralateral: opposite side - Decussation: axons crossing the midline Planes of Section: Sagittal: down midline is the sagittal plane -> a midsagittal section divides it into two halves, and you’re looking at sagittal pane Horizontal: think of the horizon! This cut can go through both ears and both eyes. Coronal: think of crown Transverse: perpendicular to the neuraxis-> starts off as coronal in bipeds, as you bend back, it stays perpendicular to the neuraxis, becomes horizontal Spinal Cord: - The roots fuse to form spinal nerve - Afferent Dorsal roots: carries info into the spinal cord -> like that you’ve stepped on a tack (collect in dorsal root ganglia) - EFFERENT Ventral roots: carries info away from the spinal cord -> like to the muscles that move your foot -> collect in ventral horn  - DIVA Matter: - White matter: on the outside in spinal cord, inside in -> axons - Gray matter: on the inside in spinal cord, outside in brain -> neurons Gray Matter: in HORNS ! Dorsal horn, intermediate zone, ventral horn White Matter: in COLUMNS ! dorsal column, lateral column, ventral column Spinal canal: fluid filled space Ventral horn-> ventral root -> muscle Skin -> dorsal root -> dorsal horn The Meninges First Membrane: dura mater Outermost membrane Leatherlike consistency, tough bag Second membrane: arachnoid membrane Spiderweb like layer Usually no space between dura and arachnoid -> but if the blood vessels in dura rupture, you have subdural hematoma Third membrane: pia mater Closest to the brain, meaning “gentle mother” (186) Separate from the arachnoid by the cerebrospinal fluid-> subarachnoid space has fluid, floats the brain. There may be blood vessels that dive into the substance of the underlying space The Ventricular System - Lateral ventricles, third ventricle, cerebral aqueduct, then fourth ventricles - Lateral ventricles = ram’s horn! Curl into temporal lobe - CSF is generated in the choroid plexus, travels through the ventricular system (lateral, third, cerebral aqueduct, then fourth), then exits and goes into subarachnoid space  - Hydrocephalus: when there’s a blockage from the choroid plexus to subarachnoid space and the ventricles swell -> insert tube into lateral ventricle and drain the fluid Neurulation: 3 layers of cells first: ectoderm (nervous system & skin), mesoderm (bones and muscles), and endoderm (viscera) Neurulation: process by which the neural tube forms from the neural plate Groove in the neural plate (rostral to caudal) forms (neural groove) The walls of the groove: neural folds The neural folds move together and fuse dorsally to form neural tube THE WHOLE CNS DEVELOPS FROM NEURAL TUBE Neural crest: the ectoderm tissue that is pinched off when the neural tube forms -> forms PNS Neural tube = CNS Neural crest = PNS Two Diseases: Anencephaly: failure of the anterior neural tube to close -> fatal condition affecting forebrain / skull Spina bifida: posterior neural tube doesn’t close -> the posterior spinal cord may not form from neural plate, or the meninges / vertebrate may not be covering end of spinal cord (not fatal, but needs a lot of care) Cortex: - 5 mm thick, over 1 m2 if flattened! - Sulci = grooves, gyri = bumps  - Increases surface area-> humans have a lot of cortex compared to other species! More association areas / information processing Three Primary Ventricles: - Rostral end of neural tube forms three vesicles that become the whole brain - Prosencephalon: forebrian - Mesencephalon: midbrain - Rhombencephalon: hindbrain THREE PRIMARY VESICLES: Rostral end of neural tube: cells divide at a rapid pace to form the three primary vesicles! ○ Forebrain, midbrain, hindbrain -> prosencephalon, mesencephalon, rhombencephalon Forebrain: largest part of brain Diencephalon (core) ○ Thalamus ○ Hypothalamus Buried underneath in core, near midline Telencephalon (around diencephalon) ○ Cortex (outside) ○ Basal telencephalon (basal ganglia) (inside) ○ Contains structures buried between cortex Structures buried between cortex and thalamus The corpus callosum: in a coronal view, directly above the lateral ventricles. Connects the left and right hemispheres. Internal capsule: white matter ventral to the corpus callosum, on either side of the lateral ventricles / third ventricle. Midbrain: Tectum (roof) ○ Contains colliculi (4 bumps -> superior colliculi (eye info) and inferior colliculi (ear info)) Tegmentum (floor) -> SUBSTANTIA NIGRA (PARKINSON’S) in the midbrain, and the red nucleus is here as well. Contains the cerebral aqueduct! Hindbrain: second biggest Rostral (closer to midbrain, biggest part)  ○ Cerebellum: develops from the rhombic lips ○ Pons (lots of nuclei) Caudal ○ Medulla (medulla oblongata) ○ Contains medullary pyramids -> corticospinal tract comes here HOW ANATOMY IS CONNECTED: In Coronal Section: Lateral ventricle: directly lateral/ next to it is the caudate nucleus In the temporal lobe (the bottom of the ram’s horn): Medial wall of lateral ventricle in temporal lobe is the hippocampus (which develops from telencephalon) - In the telencephalon! Third Ventricle: at the anterior portion, directly lateral is the thalamus At the posterior portion, directly lateral is the hypothalamus (periventricular zone) - In the diencephalon! Cerebral Aqueduct: between the tectum and the tegmentum Fourth ventricle: roof = cerebellum, floor = medulla Brain stem: made up of medulla, pons, and midbrain (not cerebellum) Hindbrain: medulla, pons, and cerebellum (not midbrain) Basal Ganglia: - Caudate is ALWAYS lateral to the lateral ventricles - In the BASAL TELENCEPHALON - Globus pallidus: most medial Lobes of the Brain: Dorsal to lateral ventricles: cerebral cortex Ventral and lateral to lateral ventricles: basal telencephalon : pons and medulla Third ventricle: continuous with lateral, surrounding by thalamus and hypothalamus Dorsal to cerebral aqueduct: tectum Ventral to cerebral aqueduct: tegmentum Dorsal to fourth ventricle: cerebellum Ventral tofourth ventricle Neurogenesis: Study of Neurogenesis in Adult Human Brain: Inject terminally ill patients with BrdU -> bromodeoxyuridine Substitutes for thymidine (A-BrdU instead of A-T) -> incorporated into DNA of dividing cells and passed on to daughter cells Post-mortem search for BrdU positive neurons with antibodies Sad experiment :( -> tremendous amount of respect for individuals Found that these neurons were wired into circuits, ahd differentiated, migrated, and connected with other neurons Where are New Neurons Generated ? Areas adjacent to the ventricles ! ○ Hippocampus ○ Olfactory system ○ NOT found throughout the entire ventricular system! How to Increase Neurogenesis? Physical exercise -> brain is a biological organ -> more blood to brain can promote neurogenesis -> chemical messages to brain increase neurogenesis ○ Exercise changes DNA methylation and acetylation, changing rate of transcription and translation of BDNF growth factor, which leads to increased transcription rates, more neurogenesis and plasticity Learning -> challenging yourself with complex tasks Death of existing neurons (MS, Alzheimer’s, Huntingtons, Stroke) Impair Neurogenesis: Stress Aging How to Visualize Living Brain: 1. MRI (magnetic resonance imaging) -> noninvasive, magnet 2. fMRI -> uses MRI imaging and imaging blood oxygen level dependent imaging -> more blood flow to more active areas 3. PET (positron emission tomography) -> inject radioactive compound that binds to specific proteins (dopamine / GABA receptors) -> can take an image of the brain -> more invasive, but can be more precise-> used to see tau accumulation sites in Alzheimer’s. PET based on the fact that more active neurons use more glucose, fMRI based on the fact that more active neurons use more oxygen Chapter 9 Eye Anatomy (structures/function) Cornea: the clear, external part of the eye. Contains no blood vessels, and it is nourished by the aqueous humor behind it. Continuous with the sclera Sclera: “white of the eye” that forms the wall of the eyeball. Contains three extraocular muscles that help move the eye Pupil: opening that allows light to enter the retina Iris: the colored part of the eye surrounding the pupil-> has muscles that can vary the size of pupil Orbit: bony eye socket in the skull Conjunctiva: membrane that folds back from the inside of the eyelids-> hids extraocular muscles Lens: responsible for adjusting to see for near and far objects (accomodation). The lens is suspended by zonule fibers. Divides the interior of the eye into two units containing either aqueous humor or vitreous humor. Retina: at the back of the eye, this is where light is transduced into an electrical signal. Contains the photoreceptors. Optic disk: responsible for the blind spot! In the nasal retina, this is where the optic nerve leaves the eye. Blood vessels cast a shadow on the retina & enter here. Aqueous humor: between the cornea and the lens, nourishes the cornea Vitreous humor: between the lens and the retinal layers at the back of the eye. Responsible for maintaining the shape of the eyeball Fovea: center of the retina that has the highest acuity + highest cone density! Optic Nerve: carries axons from the retina to exit through the back of the eye and pass through the orbit all the way to the pituitary gland PATH THROUGH THE EYE Cornea -> aqueous humor -> iris/pupil -> lens -> vitreous humor Image Formation (process/refractive index/greatest change) Refraction: light travels between two mediums and bends towards the light to the difference in the index of refraction Light bends to the perpendicular at an increase in index of refraction Biggest change in the index of refraction is from the air to the cornea!! (n = 1.00 → 1.38) Bigger Δn, more refractive power Light travels slower in water than in air and the cornea is made up of water. Therefore, the index of refraction for the cornea is greater than the index for air outside of the eye Why Does a Swim Mask Help You See Underwater? Restores the delta n / difference in refraction by putting an air pocket in front of the eye When you open your eyes underwater, light goes from water to the cornea, and the index of refraction is much smaller, so there is not as much refraction -> the light rays aren’t converged onto one point. The Image Formation Problem: Having a small pupil would give really sharp vision, but you would need lots of light in order to see Having a big pupil would allow you to see in low light but you would have really blurry vision This is why we have refraction! Accommodation (what adjusts/how does it adjust) When the eye adjusts to distance (close/far) When a near object is being seen, the light rays diverge from a point, so more refraction is required to bring them into focus! -> increase curvature = increase refractive power! Near Object Far Object Ciliary Muscles Flex Ciliary Muscles Relax Zonule Fibers Slacken Zonule Fibers Tighten Fatter/Rounder Lens Less Round / Flat Lens Increase Refraction Less Refraction Near-sighted vs Far-sighted (bending/correction) Hyperopia (far-sightedness) Myopia (near-sightedness) Can’t see near objects which require more refraction Can’t see far objects which need less vision Too little refraction Too much refraction The image is behind the retina Image focused in front of retina Length: eye too short (short kids are hyper) Length: eye too long Convex lens Concave lens There is too little / not enough accommodation by the There is too much accommodation (even the least lens amount, the image is focused in front of eye) Photoreceptors (types/compare & contrast) NOT TRADITIONAL NEURONS! Don’t fire action potentials! Rods Cones -92 million rods -5 million cones  -have more disks and thus photopigment, making them -less sensitive to light more sensitive to light -scotopic light -photopic light -concentrated on the peripheral retina-> we have the -concentrated on the fovea, less on periphery best vision on periphery in scotopic light -many rods-> one ganglion cell One or few cones -> one ganglion cell (high acuity) -not sensitive to color -responsible for color detection-> 3 different photopigments Consequences of Rod/Cone Distribution: Page 311 At photopic light levels: 1. High spatial acuity on the fovea 2. Bad at discriminating colors on the peripheral retina (less cones there) At scotopic light levels: 1. Our central vision is blind (because the cones are here) ->More sensitive to low levels of light on the peripheral retina because of many rods 2. Unable to see color differences in scotopic light (rods aren’t color sensitive) How Rods and Cones are Connected to Ganglion Cells: 1. Rods: in the peripheral retina, many rod photoreceptors provide input to one ganglion cell! This makes the peripheral retina (rods) better at detecting dim light! 2. Cones: in the central retina, one PR goes to one ganglion cell -> better for high-resolution vision/ acuity! **how rods and cones are connected to ganglion cells determines their functions!** Why do Cones Function Best in Photopic Light & Vice Versa? - In photopic conditions: rods will always be bleached and oversaturated, so they can’t detect further changes in light. However, cones require more energy to be bleached, which is why they’re better in photopic conditions. - In scotopic conditions: cones can’t function because there isn’t enough light to bleach GPCRs. Rods can function because they have more disks and thus more photopigment, and many rods -> one ganglion cell (amplification). Dark Current (ion type/Vm) Photoreceptors have leaky influx of Na+ current through channels Vm of Photoreceptors is around -30 mV (rather than the normal -60 resting mV) cGMP holds Na+ channels open As Na+ enters, so does Ca2+ causing the release of glutamate from photoreceptors Do NOT produce action potentials!! Photopigments (color types/wavelength sensitivity) Cones in our retina have one of three opsins that give photopigments their color sensitivity Blue cones (short wavelength activated by light with a wavelength of 430 nm) Green cones (medium wavelength activated by light with a wavelength of 530 nm) Red cones (long wavelength activated by light with a wavelength of 560 nm)  Helmholtz trichromacy theory: the brain assigns colors based on a comparative readout of the three cone types. When all three types of cones are equally active, we perceive white. No color looks simultaneously red and green or blue and yellow What is Color? Young-Helmholtz Trichromacy theory: the color we perceive is based on the relative activation of the three different cones! Color is not a physical property of objects! -> objects reflect specific wavelengths of light. The ratios of activation determine color!! Red is not a single wavelength, and the wavelength is not absorbed only by one type of cone Color Blindness Green/Red photopgiments tend to be sex-linked so connected to the X chromosome Blue photopigment is correlated with chromosome number 7 Dichromats → people missing one type of cone. Protanopia: no red, tritanopia: no blue, green dichromat: less sensitive to green, confuse red/green Monochromats → people missing two types of cones. Blue monochromats, the world varies only in lightness. Rod Monochromats → people that only have rods, no cones. Can’t see color, see in scotopic light only. Anomalous Trichromacy → green cone mutation/ deuteranomaly mutation in green cone pigment. Don’t see much difference between red and green cone pigments because the absorption waves are too close -> perceive the full range of colors that trichromats do, but sometimes disagree in precise color. Red-green color vision → more common in men resulting from a defect on the single X chromosome they inherit from their mother. Women have it if both parents contribute an abnormal X chromosome Colorblind (anomalous trichromats → 6% of men) have normal genes normally to encode blue pigment and either red or green pigment but they also have a hybrid gene that encodes a protein with an abnormal absorption spectrum between red and green pigments Achromatopsia = lack of color vision Inner vs Outer Retina: COUNTERINTUITIVE Light travels through all the layers of the retina before it hits the photoreceptors, then the signal travels back out! “Inner” retina: ganglion cell layer “Outer” retina: photoreceptor layer Outer nuclear layer (photoreceptors)-> outer plexiform layer (photoreceptors, horizontal, bipolar)-> inner nuclear layer (horizontal, bipolar, amacrine) -> inner plexiform layer (amacrine, bipolar, ganglion)-> ganglion cell layer Plexiform = synapse; nuclear = cell bodies Light travels through all layers, the signal is transduced back in the opposite direction! INNER-> OUTER RETINA Ganglion -> amacrine -> bipolar -> horizontal -> photoreceptor Phototransduction (describe/net effect) Net effect = hyperpolarize! cGMP: 2nd messenger. cGMP PDE: effector enzyme. Transducin: g protein. Rhodopsin: GPCR! 1) Light activates photopigment rhodopsin (bleached opsin) 2) Photopigment activates g-protein transducin 3) On the alpha subunit, GDP is replaced with GTP 4) Transducin increases the rate of cGMP phosphodiesterase (cGMP pde) activity 5) cGMP gets hydrolyzed to GMP by cGMP phosphodiesterase so there is net less cGMP 6) Na+ channels close as there is less cGMP to keep them open 7) Less dark current leading to hyperpolarization **in cones, this process is similar, but there are 3 opsins one for each photopigment** Adaptation (describe) Pupillary Light Adaptation: both pupils constrict to light even if light is only shone in one eye. Consensual Light Adaptation -switch to cones from rods -restrict pupil -Ca2+ feedback Ca2+ feedback mechanism: Three things to keep in mind: **cGMP is synthesized by guanylyl cyclase form GTP **cGMP gated Na+ channels also admit Ca2+ **Ca2+ inhibits guanylyl cyclase from making cGMP 1. Light level increases, causing ion channels to close (hyperpolarization and Vm=-60 mV) 2. Less Na+ and Ca2+ is admitted If the light level is sustained:  3. Ca+ normally inhibits guanylyl cyclase so there is greater GC activity that normal 4. More conversion of GTP to cGMP occurs by guanylyl cyclase 5. More cGMP means that more Na/Ca2+ channels are open 6. The cell depolarizes back to -30 mV but now with more light **the same amount of light in a light-adapted eye will cause less hyperpolarization than in a dark-adapted eye** **the quantity of light intensity the eye can see is the same, but the range is shifted towards higher intensities** **membrane potential saturates at -60 mV as the light level is increased** Dark Adaptation - switch to rods from cones - dilate pupil - Ca2+ feedback Ca2+ feedback mechanism: Three things to keep in mind: **cGMP is synthesized by guanylyl cyclase form GTP **cGMP gated Na+ channels also admit Ca2+ **Ca2+ inhibits guanylyl cyclase from making cGMP 1. Light level decreases, causing ion channels to open (depolarization and Vm = -30 mV) 2. More Na+ and Ca2+ is admitted If the light level is sustained: 3. Since there is greater Ca2+ influx, there is more inhibition of Guanylyl Cyclase 4. Less Guanylyl Cyclase activity leads to less creation of cGMP 5. Less cGMP leads to less Na/Ca influx 6. Cell hyperpolarizes Characteristics of the Fovea (density of cones/# of cones per ganglion/specializations) HIGH ACUITY because…. ○ Cones concentrated here ○ No blood vessels or other retinal layers here -> they are pushed out of the way ○ Few photoreceptors project to each ganglion cell Retinal Circuits (direct/indirect/which cells fire AP) **Only ganglion cells fire action potentials!** Receptive field: the area on the retina where, when light is applied, the firing rate of the neuron changes -light outside the receptive field for a neuron will have no effect on its firing rate! -bipolar & ganglion have center-surround RFs! Direct: cone photoreceptor -> bipolar cell -> ganglion cell -only photoreceptors respond directly to the light! IN DARK: PR depolarized -> releases a lot of glutamate IN LIGHT: PR hyperpolarized -> releases little glutamate Indirect pathway: -the surrounding photoreceptors provide input to the center photoreceptor through horizontal cells! Dark in surround: surround photoreceptors release glutamate -> horizontal cells release GABA -> this has an inhibitory effect on center photoreceptor **lateral inhibition enables the antagonistic center surround mechanism -> the response of a bipolar cell’s membrane potential to light in the center is opposite that in the surround** ON/OFF Bipolar Cells (effect of light/type of NT/ type of receptor) “Off” bipolar cells → ionotropic glutamate receptors (light = off) MAINTAINS THE SIGN Want dark in center, light in surround Response to dark: ionotropic glutamate receptor binds to glutamate and opens Na+ channels. Sodium influx leads to depolarization of the cell in the dark Response to light: less glutamate and binding with ionotropic glutamate receptor leading to less sodium influx and greater hyperpolarization “On” bipolar cells → metabotropic glutamate receptors (light = on) REVERSES THE SIGN Want light in center, dark in surround Response to dark: metabotropic glutamate receptor binds to glutamate and the subunit closed sodium channels. No sodium influx leads to hyperpolarization Response to light: less glutamate leads to less binding with the metabotropic glutamate receptor and less shutting of sodium channels. Therefore, there is depolarization. Example Scenarios: 1. Light on cone 1 (center), not on cone 2: -cone 1 hyperpolarizes to light, releasing little glutamate -cone 2 is depolarized in the surround, so it releases glutamate onto the horizontal cell, which releases GABA and FURTHER inhibits the center cone. -cone 1 is even more hyperpolarized / releases even less glutamate than if the horizontal cell weren’t active -a bipolar ON cell would be maximally depolarized, and a bipolar OFF cell would be maximally hyperpolarized 2. Light on cone 1 & cone 2 -cone 1 is the same as before -> hyperpolarizes, releasing little glutamate -now, cone 2 is also hyperpolarized. The horizontal cell releases less GABA -cone 1 sends more glutamate than before to the bipolar cell (because it isn’t also being inhibited laterally, it’s slightly more depolarized than before) -an off-bipolar cell is LESS hyperpolarized than before and an on-bipolar cell is LESS depolarized than before **light everywhere = a less hyperpolarized off-center BP, less depolarized ON-center BP** **putting light on the surrounding AND center cancels out some of the cell’s response!!** Types of Ganglion Cell RF (3 types/percentages/which are color sensitive) OFF BIPOLAR -> OFF GANGLION ON BIPOLAR -> ON GANGLION Magno (biggest) Larger receptive fields Not color sensitive because they receive input from many cone types Fast action potentials that act as a transient burst in the optic nerve Contribute to low resolution vision Can detect subtle differences in contrasts over fields  5% Parvo Smaller receptive fields well suited for discrimination of fine detail Most are color sensitive 90% of the ganglion population Respond with a sudden discharge as long as the stimulus is on nonM-nonP (smallest) Not much is known about them but some are light sensitive. Lowest -> Highest Response for an OFF-center ganglion cell: Dark on surround, light on center-> light everywhere -> dark everywhere (partial inhibition from surround is overcome)-> dark mostly / only on center **Pattern is reversed for an ON-center ganglion cell!** Color Opponent Ganglion Cells - Parvo cells and some nonM-nonP cells are sensitive to differences in wavelengths of light - Color Opponent Cells: response of one color in the RF center is cancelled by showing a different color in the surround  - There is red/green opponency and blue/yellow opponency Example: red on center, green off surround - Red light covering whole field: still excites the neuron above baseline, but less so -> the green cones partially absorb red wavelengths and partially inhibit the center - White light: contains red and green wavelengths. If you shine it on the whole RF, the center and surround are equally activated, so there is no response. Colored Light on M-Ganglion Cells: - Still respond to the light! Just don’t have color-specific responses. Eye Disorders 1. Strabismus: disorders of the extraocular muscles of sclera, eyes point in different directions 2. Cataracts: clouding of the lens -> remove and place with an artificial one 3. Glaucoma: intraocular pressure in aqueous humor compresses optic nerve axons, and you lose vision from periphery to inside 4. Detached retina: blow to the head or shrinking vitreous humor causes retina to detach because the vitreous humor can get behind it 5. Retinitis pigmentosa: photoreceptors degenerate. Affects peripheral vision 6. Macular degeneration: lose central vision 7. Presbyopia: “old eye”: hardening of the lens because new cells are generated, but not lost -> causes the eye to be less elastic Chapter 10 Retinofugal Pathway Optic nerve → Optic chiasm → Optic tract → Lateral Geniculate Nucleus (LGN) → Optic Radiation → Primary Visual Cortex (V1) Peripheral visual field “temporal” visual field: imaged onto nasal retinas! Cuts to the Retinofugal Pathway Cut to the left optic nerve: blindness in left peripheral (lose info from left eye) Cut to the right optic nerve: blindness in right right peripheral (lose info from right eye) Cut to the left optic tract: cut off right visual hemifield Cut to the right optic tract: cut off left visual hemifield Midline cut of chiasm: complete loss of peripheral vision in both eyes (damaged crossing fibers) Lesions in optic radiation cause partial or complete blindness in the contralateral visual field LGN (input/layers/input ventral to each layer): in dorsal thalamus Input to the LGN comes 80% from the visual cortex and 20% from the eyes (optic tract/ganglion cells) Right hemifield: goes to the left LGN (left temporal and right nasal) Left hemifield: goes to the right LGN (right temporal and left nasal) Contralateral visual field info! The Optic tract also innervates: - Hypothalamus for sleep/wake - Midbrain pretectum: pupil size - Superior colliculus: saccadic eye movements Layers of the LGN: 6 ipsi, (P) (dorsal) 5 ipsi, (P) 4 contra, (P) 3 ipsi, (P) 2 ipsi, (M) 1 contra, (M) (ventral) 2-3 see “i to i” Left nasal: right LGN on layers 1, 4, and 6 Right nasal: left LGN on layers 1, 4, 6, Left temporal: left LGN on layers 2, 3, 5 Right temporal: right LGN on layers 2, 3, 5 Koniocellular layers: Get their input from the nonM-nonP ganglion cell layers! VENTRAL to each LGN layer and get input from the same eye as the above LGN layer -> K3 gets Parvo input from the ipsilateral eye! Retinotopy: neighboring cells in the retina project to neighboring cells in the LGN / V1 -> there is a “mapping” V1 anatomy (layers/inputs/output) Occipital lobe -> Brodmann's area 17/ striate cortex / primary visual cortex I (rarely has cells/neurons) II (binocular) III (pyramidal, binocular) IVA (monocular) IVB (pyramidal, monocular) IVCα(stellate, monocular) IVCβ(stellate, monocular) V (pyramidal, binocular) VI (pyramidal, binocular) Inputs to V1  Magnocellular neurons project to IVCα and IVB Parvocellular neurons project to IVCβ and 2 & 3 Koniocellular neurons project to 2 & 3 MOST INPUTS TO LAYER 4C! Outputs from V1 IVB: dorsal stream/parietal lobe (from M cells) Layers II & III: ventral stream/occipital/temporal (from P cells) V: superior colliculus (tectum, controls eye movement) VI: LGN Only pyramidal neurons send input out (not stellate). No output from layers 1 or 4c. Ocular Dominance Columns: DEPTH PERCEPTION In layer 4c, there are columns where information is separated based on which eye it came from Outside 4c, above a left eye monocular region, the region will receive input from both eyes, but the input will be dominated by the left eye Combining left and right eye input helps us with depth perception Cytochrome Oxidase Blobs: COLOR PERCEPTION (found where/color sensitivity/input) Layers II and III (and some to V & VI) Cytochrome oxidase is important as it acts in cellular metabolism as an enzyme Neurons with lots of cytochrome oxidase are called blobs Blob RF: some circular, some color-opponent, some double opponent (higher firing rate than interblobs) Blobs = color detecting, centered on ocular dominance stripes THE BLOBS DON’T GO THROUGH ALL LAYERS-> NOT COLUMNS!!!!! Blob vs Interblob Properties Blobs are monocular Receive input from koniocellular layers as well as parvo/magno from IVC Don’t have orientation or direction selectivity Wavelength selective!!!!  Interblobs are the regions between these blob neuron groups that are binocular and have orientation/direction selectivity. Get parvo input from IVCB V1 Receptive Fields (layer 4C properties/monocularity/binocularity/other layers) Layer 4 Receptive Fields: Layer 4c: The receptive fields are similar to those of the LGN -> monocular, antagonistic center-surround RFs IVCa: insensitive to wavelength IVCb: has center-surround color opponency Outside layer 4: (binocular, orientation selective, direction selective) Orientation Selectivity: FORM PERCEPTION (cell response v orientation/type of perception used) Perform form perception 2 types: simple & complex Responses can be graded Perpendicular: worst response. On perpendicular axis to ocular dominance columns! Complex cells: ON and OFF responses are given throughout the receptive field, binocular, orientation selective Simple cells: specific ON and OFF receptive fields make them orientation selective, binocular Direction Selectivity: MOTION PERCEPTION (differences from orientation selectivity) Subset of orientation selective receptive fields Prefer a certain orientation of the light, and for it to move in a certain direction Move bar up: responds a lot -> move a bar down, doesn’t respond at all Broad tuning! -> the perceived direction is based on the relative activation of cells with different direction preferences Solid line: direction selective Dashed + solid: orientation selective responses STREAMS BEYOND V1 1. Magnocellular pathway (motion) -> dorsal stream -> parietal lobe 2. Blob pathway (color) 3. Parvo-interblob pathway (shape) **blob and parvo-interblob combine to make the ventral stream-> temporal lobe** Parallel Streams (two types/responsible for/anatomical directions) Dorsal Stream (magnocellular pathway): MT/V5 (has direction of motion columns) Towards parietal lobe “Where” (motion perception) Direction Selective cells Even without motion, V1 neurons respond Magnocellular LGN -> 4Ca -> 4B -> area V5 Ventral stream (parvo-interblob and blob pathways): V4 to IT Towards temporal lobe “What” (form/color perception) Orientation and Color Selective Projection to IT ○ Respond to faces ○ Prosopagnosia: can’t recognize faces ○ FFA: fusiform face area ○ OFA: occipital face area ○ AFP: anterior face patch Parvocellular/Koniocellular LGN → 4B → 4Cb → 2&3 → area IT (V4) Disorders of Perception (akinetopsia/prosopagnosia) Akinetopsia: see the world in snapshots -> lesion to area MT / V5 Prosopagnosia: can’t recognize faces -> area IT (V4)/ FFA Chapter 11 Sound Waves (frequency/amplitude) Sound = small, audible, periodic fluctuations in air pressure Frequency: Related to the pitch you perceive Defined as the # of waves in a unit of time Unit = Hertz (Hz) Low frequency = low pitch, high frequency = high pitch Amplitude or Intensity: Related to the loudness that you perceive Defined as the height of the peak of sound wave or the magnitude Unit = Length unit (cm, inches) Low amplitude = soft, higher amplitude = louder Inner, Middle, Outer Ears (structures) Outer: pinna and the auditory canal -> AIR-FILLED Important for funneling sound into the ear Difference in time that direct & reflected sounds reach the eardrum tells you about the vertical localization -> sound sourcing Middle: ossicles (malleus, incus, stapes) and then tympanic membrane (eardrum) → AIR-FLUID Variations in air pressure hit the tympanic membrane and are converted into movement of the ossicles. The ossicles move the footplate of stapes, pushing inward at the oval window Inner: the Cochlea 3 Fluid-Filled Chambers: Scala vestibuli, media, and tympani Spectrogram: plot of the components of real words! Frequency and intensity over time-> real words are complex and people have different spectrograms Audiogram: plot of frequency vs. sound pressure -> plots the threshold of hearing! Log scale! Play a frequency and keep increasing amplitude until you can hear it! General Process of Sound Movement: 1. Pinna funnels in sound waves that travel down the length of the auditory canal 2. Sound waves move the tympanic membrane, which vibrates the three ossicles 3. The bottom of the malleus is pushed inward, and lever action causes the footplate of stapes to push in at the oval window 4. The amplified pressure at the oval window helps to move fluid inside the cochlea. 5. When the oval window pushes in, perilymph moves, causing the round window to bulge out. Perilymph is pushed into the scala vestibuli FIRST 6. Endolymph is also displaced within the scala media. The movement of fluids generates a traveling wave on the basilar membrane, starting at the base and moving towards the apex 7. Movement of the basilar membrane causes hair cells to bend (transduction occurs!) Get rid of cochlear amplifier/ossicle movements: can’t hear low intensity sounds!! Middle Ear (eardrum, ossicles, round/oval windows) 1. Impedance matching: functions to amplify sound pressure to create sufficient fluid movement in the inner ear a. Impedance of air is low, but of fluid it is high (reflects energy back out)  b. Large amplitude, low energy sound waves in air are transformed into small amplitude, higher energy waves i the fluid of inner ear by: c. 30 fold difference in area of tympanic membrane vs. stapes -> energy is focused onto a smaller area at the footplate, increasing the force d. Leverage action between malleus and incus: takes large, weak fluctuations and turns them into smaller, high energy waves e. Need more pressure to move fluid because it’s incompressible and denser than air 2. Attenuation Reflex a. Stapedius muscles and tensor tympani muscle contract restricting the movement of ossicles for high intensity, and low frequency sounds b. Reduces sounds vibrations of the ossicles to dampen sound loudness c. Has the biggest effect on low frequency sounds, high intensity Purposes / Proposed Functions of the Reflex: 1. **may be the mechanism by which we dampen input from our own voices** 2. Adapts the ear to continuous sound at high intensities -> loud responses would otherwise saturate the response of receptors -> increase the range we hear? 3. Suppresses low frequencies more than high frequencies, so high-frequency sounds are easier to hear than low-frequency -> why we can hear speech more easily in a noisy environment than without this reflex Basilar Membrane (fluid-filled spaces on each side) Between the scala vestibuli and scala tympani (when closed off from the scala media) Endolymph inside of the scala media Perilymph inside of the scala vestibuli and the scala tympani Base: stiff, more narrow HIGH frequency sounds processed here Apex: floppy, wider LOW frequency sounds processed here (tonotopy) Physiology of Cochlea: - Inward motion at the oval window: perilymph in the scala vestibuli is displaced, round window bulges out -> causes a wave to flow through the basilar membrane to certain locations - With a more intense stimulus the basilar membrane vibrates more and has greater amplitude vibrations which results in greater depolarization or hyperpolarization of hair cells and more action potential firing - Movement of the basilar membrane makes the stereocilia lean in different directions (opening or closing mechanically-gated K+ channels with reference to direction of the kinocilia) Sounds with too Low Frequency (pass through helicotrema)-> can’t be encoded/ mapped on the basilar membrane Organ of Corti (outer/inner hair cells, ganglion leaving the organ) Hair Cells Aren’t Neurons! Don’t Fire Action Potentials! Inner hair cells are bathed in endolymph whereas outer hair cells are found in perilymph Inner cells are less abundant but receive most input from spiral ganglion cells (90%) Outer hair cells: stereocilia are in tectorial membrane, but inner hair cells aren’t -> just in endolymph Spiral Ganglion neurons project their axons via the auditory vestibular nerve to the A1 (auditory cortex) Between basilar membrane and reticular lamina-> stereocilia extend above lamina into endolymph or the tectorial membrane. Properties of endolymph: 1. High K+ in endolymph means there is no gradient of K+ across cell membrane -> it doesn't wanna leave the cell -> equilibrium potential = 0 mV. 2. Large endocochlear potential tends to drive K+ from outside endolymph to inside hair cells, creating an inward current and a receptor potential -> if it was all perilymph, there would be no electrical potential, no ion movement -> it is all electrical, not concentration based. Inner Hair Cell Activity (bending away/toward kinocilium, ion channel, no AP) Transduction!!! Move as a unit, bend only at the base! Scenario #1: move towards kinocilium: Depolarization: Tip links pull harder / have more tension, causing the channels to open K+ rushes into cell (endocochlear potential of +140 mV), causing Voltage-gated Ca2+ channels to open  Ca2+ rushes in, glutamate released onto spinal nerve Scenario #2: move away from kinocilium: Tip links slacken / have less tension, causing the channels to close No K+ influx so cell hyperpolarizes Outer Hair Cell Activity (function, motor protein) Cochlear Amplifiers!! Low intensity sounds are amplified due to outer hair cells’ motor proteins (prestin) Causes the basilar membrane to move MORE Movement of stereocilia up and down -> triggered by receptor potential! If the frequency of a sound is 2000 Hz, the outer hair cells vibrate at that frequency. Efferent fibers that project away from the main brain stem toward the cochlea synapse into outer hair cells and release acetylcholine which changes the shape of the outer hair cells and affect the responses of inner hair cells Amplify the displacement of the basilar membrane to enhance transduction Otoacoustic emissions: caused by cochlear amplifiers, can be spontaneous or evoked! Evoked = normal, spontaneous sometimes due to cochlear damage How is Intensity Encoded in the Nervous System? Firing rates and number of active neurons! Greater rate: the basilar membrane vibrates with greater amplitude, so the hair cells membrane potential is more depolarized or hyperpolarized, so nerve fibers that synapse with hair cells fire GREATER RATE More active neurons: More intense stimuli produce movements over a greater distance, leading to MORE HAIR CELLS ACTIVATED Characteristic frequency: spiral ganglion neurons are are most responsive to a particular frequency of sound How is Frequency Encoded in the Nervous System? Tonotopy, location of activity in A1, frequency of AP in axons from cochlea, phase locking & volley coding Lower Frequencies: Phase-Locking and Volley Coding (up to 5kHz) (timing) Phase-Locking: Firing of a cell consistently at the same phase of a sound wave ○ Can be used to measure sound frequency ○ Individual cells don’t necessarily respond to every single peak of sound wave with an action potential Volley coding: Intermediate sound frequencies are represented by the pool activity of a number of neurons each of which fire in a phase-locked manner At very low frequency, phase locking is used whereas at intermediate frequency both phase locking and tonotopy are useful and at high frequencies tonotopy must be relied on Higher Frequencies: Auditory Tonotopy (above 5 kHz) Volley-coding and phase locking is the solution to the fact that tonotopy only encodes higher frequencies Tones are represented topographically There is a “map” that extends throughout the auditory pathway How do we determine where a sound is coming from? Vertical Sound Localization (part of the ear) Combination of direct and reflected sounds off of the pinna helps tell where a sound is  The time difference between the direct pathway and the reflected pathway changes when you move vertically -> combining these two types of input help us determine where a sound is in the vertical pathway Moving your head helps too! Horizontal Sound Localization (head shadow, interaural time delay, summation in superior olive) Requires both ears more than vertical localization does! Duplex theory of sound localization: interaural time delay and interaural intensity difference combines Azimuth: horizontal angle or direction Interaural Time delay: low frequencies 20-2000 Hz The interaural time delay is the time difference between arrival at one ear and the other Binaural superior olive then computes the delay and locates the sound by summing input from axons to make EPSP or not! Sound Shadow / Interaural Intensity Difference: high frequencies (2000 Hz-20,000 Hz) Interaural arrival time is not useful for locating continuous sounds with frequencies so high that one cycle of the sound wave is smaller than the distance between your ears. To look at these songs we use interaural intensity differences between the two ears due to a shadow casted by your head. If sound comes from the right the left ear will hear a significantly lower intensity and vice versa Auditory Pathway (first area of the brain for binaural input, lesions) Spiral ganglion -> auditory nerve (cochlear nerve)-> ventral cochlear nuclei-> superior olive-> inferior colliculus -> MGN (thalamus) -> auditory cortex First area of binaural input: superior olive Lesions: (affect sound localization most!) ○ Below superior olive: lose all info from ipsilateral ear (left cochlear nuclei = lose left ear info) ○ Above superior olive: no ear deafness! There is a copy in the other superior olive Mapping of Characteristic Frequencies in A1: - Rostral & lateral: low frequencies - Caudal & medial: high frequencies - Binaural neurons in A1 as well Other Facts About the Auditory System: - Outer hair cells have no cytoskeleton - Tonotopy is preserved throughout the auditory system: cochlear nucleus, superior olive, MGN, and primary auditory cortex as well all demonstrate tonotopy.. - Intensity /loudness = the difference in density between compressed and rarefied regions in the wave - If you replaced the endolymph with perilymph, you simply wouldn’t be able to hear!! Endocochlear potential is everything. - Neurons in A1 are BROADLY TUNED!!! Have characteristic frequencies, but don’t just respond to a single frequency! Respond to MANY, just with varying degrees in the response! - Primary auditory cortex is in the temporal lobe, and there are alternating groups of cells that are excited by sound in both ears or excited by sound from one ear/inhibited from sound in the other. - Super low frequency sounds don’t even vibrate the basilar membrane, they just go through helicotrema, which is why we can’t hear them Understanding where the endocochlear potential / etc. comes from: - +80 mV: the endolymph is 80 mV more positive than the perilymph,yielding the +80 mV endocochlear potential. - +125 gradient across the stereocilia membrane: the inside of the hair cell stereocilia is about 45 mV more negative than the perilymph, yielding the +125 value for the gradient. Chapter 12 S1: Parietal Lobe 3 Categories of Somatic Sensation: 1. Exteroception -> sensing external conditions 2. Proprioception -> (inside) sensing the body’s position in space 3. Enteroception: (inside) visceral sensory system-> senses the body’s internal conditions -> not always accessible to the consciousness 3 Categories of Exteroception: mechanoreception, thermoception, nociception 2 Pathways of Exteroception Information: epicritic & proteopathic 1. Epicritic: touch / tactile / vibration (DCML pathway) 2. Proteopathic: pain, temp, & itch (spinothalamic pathway) Mechanoreceptors (4 types, RFs, fast/slow adapting, superficial/ deep) Sensitive to bending/stretching 1. Pacinian Corpuscle (fast adapting, large RF, deep, larger frequencies) 2. Meissner's Corpuscle (fast adapting, small RF, shallow, smaller frequencies) glabrous 3. Merkel’s Disk (slow adapting, small RF, shallow) glabrous 4. F