The Neuronal Membrane At Rest Alec JotteThe Neuronal Membrane At Rest

Introduction Action Potential – the nerve impulse. The special type of signal that is carried by neurons. Excitable Membrane – membranes of cells capable of generating and conducting action potentials

(neurons and muscle cells) Resting Membrane Potential – in a resting neuron, the cytosol along the inside surface of the

membrane has a negative electrical charge when compared to the outside. Action potential is simply a brief reversal of this condition.

The Cast of Chemicals Ion – electrically charged atoms who are responsible for the resting and action potentials. They are

dissolved in the water that is the primary ingredient of the fluid inside (cytosol) and surrounding (extracellular fluid) the neuron.

Cation – a positively charged ion. For cellular neurophysiology; Na+, K+, Ca2+ Anion – a negatively charged ion; Cl- Phospholipid bilayer – hydrophilic heads interact with the water outside/inside the cell, hydrophobic

tails create a layer between the phosphate heads. Effectively isolates the cytosol of the neuron from the extracellular fluid

Peptide Bond – bonds that connect amino acids this forms the primary structure of the protein. o Proteins are important in distinguishing the neuronal cell: enzymes catalyze chemical

reaction, cytoskeleton gives the special shape, and receptors are sensitive to neurotransmitters all these are proteins.

o Primary structure – order of amino acids. Secondary structure – shape of chain (alpha helix). Tertiary structure – 3 dimensional shape changes (bends, folds). Quaternary structure – when differen polypeptide chains bond together to form a larger molecule.

Polypeptide – proteins made of a single chain of amino acids Ion Channel – channels made of proteins, usually 4-6 that exist throughout the membrane. Ion Selectivity – certain channels only allow certain ions through. Potassium channels are selectively

permeable to K+, calcium channels to Ca2+, etc. Gating – the ability of channels to open or close based on changes in their environment. Ion Pump – proteins in the membrane that use energy from ATP breakdown to transport certain ions

across the membrane and concentration gradient.

The Movement of Ions Diffusion – net movement of ions from region of high concentration to regions of low concentration Concentration Gradient – a difference in concentration. Ions will flow down a concentration gradient

when diffusing Electrical Current (I) – the movement of electrical charge, represented by the symbol I and measure in

units called amperes (amps) Electrical Potential (Voltage, V) – the force exerted on a charged particle. It reflects the difference in

charge between the anode and cathode. Measured in volts. (anode) -6 6(cathode) the voltage is 12 Electrical Conductance – the relative ability of an electrical charge to migrate from one point to

another. Measured in siemens (S) and represented by symbol g. Dependent on the number of particles available to carry electrical charge and the ease with which those particles can travel through space.

Electrical Resistance – the relative inability of an electrical charge to migrate. Represented by R and measured in Ohms. R = 1/g

Ohm’s Law – relationships between potential (V), conductance(g), and the amount of current (I). o I = gV

There will be no current if electrical potential, or conductance is 0. Likewise, even if the conductance and potential are great, if there is no current, nothing will happen.

Driving an ion across the membrane electrically, therefore, requires that (1) the membrane has channels permeable to that ion and (2) there is an electrical potential difference across the membrane.

The Ionic Basis of the Resting Membrane Potential Membrane Potential – the voltage across the neuronal membrane at any moment, represented by the

symbol Vm

o The resting potential of a typical neuron is -65mVo Very sensitive to changes in [K+]0 because the membrane is primarily permeable to K+

Microelectrode – a thing glass tube with an extremely fine tip that penetrates the membrane of a neuron with minimal damage; used to measure Vm

Ionic Equilibrium Potential (Equilibrium Potential, EION) – the electrical potential difference that exactly balances an ionic concentration gradient, ie, not net flow of ions occurs because electrical pull = push due to concentration gradient

o How? K+ has a way stronger concentration on the inside compared to the outside. Although the inside is electrically neutral, and so is the outside (because the ratio of + to – is equal), the concentrations of the ions differ greatly. Now, if a K+ channel were to open, the K+ would rush out of the cell, down the concentration gradient. Eventually, a positive charge starts to build on the outside of the cell membrane, discouraging K+ from leaving the cells through the channels (because it is positively charged on the other side). Eventually the rate of pulling K+ in due the electrical imbalance = rate of diffusion of K+ to the outside of the membrane, and the resting potential is established.

o Key Four Points

*Large changes in membrane potential are caused by miniscule changes in ionic concentrations.

*The net difference in electrical charge occurs at the inside and outside surfaces of the membrane. The large majority of the cytosol remains electrically neutral, just the part right outside the membrane is upset by the electrical imbalance.

*Ions are driven across the membrane at a rate proportional to the difference between the membrane potential (at a given point in time) and the equilibrium potential (the set voltage that equals the ionic concentration gradient, allowing no ions to flow)

*If the concentration difference across the membrane is known for an ion, an equilibrium potential can be calculated for that ion. Ie, if the equilibrium potential will be positive or negative (if the inside of the cell is slightly negative, then the equilibrium potential will be negative).

Ionic Driving Force – The difference between the real membrane potential and the equilibrium potential (Vm – EION) for a particular ion

Nernst Equation – method of calculating the exact value of an equilibrium potential.o EION = (2.303) ((RT)/(zF)) (log ([ion]0/[ion]i))

EION = ionic equilibrium potential R = gas constant T = absolute temperature Z = charge of the ion F = Faraday’s constant Log = base 10 logarithm [ion]0 = ionic concentration outside the cell [ion]i = ionic concentration inside the cell

Sodium-Potassium Pump – enzyme that breaks down ATP in the presence of internal Na+. The energy released by this exchanges internal Na+ for external K+. This ensures that K+ is concentrated on the inside of the neuron, and Na+, on the outside. Estimated that this uses 70% of all ATP used by the brain.

Ion Concentration Outside (in mM)

Concentration Inside (in mM)

RatioOut : In

EION

(at 37 C)K+ 5 100 1 : 20 -80 mVNa+ 150 15 10 : 1 62 mVCa2+ 2 0.0002 10,000 : 1 123 mVCl- 150 13 11.5 : 1 -65 mV

Calcium Pump – an enzyme that actively transports Ca2+ out of the cytosol across the membrane. Goldman Equation – a mathematical formula that takes into consideration the relative permeability of

the membrane to different ions, and can be used to calculate the resting membrane potential. Depolarization – a change in membrane potential from the normal resting value (-65mV) to a less

negative value is called a depolarization of the membrane. Increasing extracellular potassium depolarizes neurons. Ie, if [K+] outside the neuron were to be 20, the resting potential would drop to -17mV

Blood-Brain Barrier – a specialization of the walls of brain capillaries that limits the movement of potassium (and other blood borne substances, such as lead) into the extracellular fluid of the brain

o Glia, especially astrocytes, also help control extracellular K+ levels when concentrations rise. Glia will pull K+ into the membrane via potassium pumps causing the glia to depolarize instead of the neurons

o However, muscle cells don’t have a blood barrier and so increases in [K+] in the blood can still have major consequences.

*The electrical potential difference across the membrane can be thought of as a battery whose charge is maintained by the work of the ion pumps.

Chapter 4: The Action Potential Alec Jotte

Properties of the Action Potential Rising Phase – first part of the action potential. Rapid depolarization of the membrane Overshoot – the part of the action potential where the inside of the neuron is positively charged with

respect to the outside Falling Phase –the part of the action potential including rapid repolarization until the membrane is

actually more negative than the resting potential Undershoot (After-Hyperpolarization) – the part of the action potential where the membrane is more

negative than the resting potential Threshold – the critical level of depolarization that must be crossed in order to trigger an action

potential. Action potentials are caused by depolarization of the membrane beyond the threshold.o What triggers this? Depends on the type of neuron. Those right against the skin open Na+

channels when the membranes are stretched (such as thumbtack man). In interneurons, certain neurotransmitters trigger the opening of those Na+ channels. Action potentials are like a camera – you push down until you cross the threshold, then *click.*

Absolute Refractory Period – once one action potential is initiated, it is impossible to initiate another for about 1 milisecond. This period of time is the absolute refractory period.

Relative Refractory Period – it can be relatively difficult to initiate another action potential for several milliseconds after the end of the absolute refractory period. This is the relative refractory period, and during this time, the amount of current required to depolarize the neuron to action potential is higher than normal.

The Action Potential, in Reality Key Terms

o Voltage Clamp – key device in determining the transient rises in number of open sodium or potassium channels

o Voltage-gated Sodium Channel – a protein that forms a pore in the membrane and is highly selective to Na+ ions. The pore is opened and closed by changes in the electrical potential of the membrane.

When the membrane is depolarized to threshold, the molecule (it’s a protein that’s actually just one really long polypeptide) twists into a shape that allows Na+ to enter the cell through the pore. The pore has a “filter” that is sized perfectly for Na+. K+ is too large to fit through. Ions must be attached to a “chaperone” water molecule

These channels (1) open with little delay, (2) stay open for about 1 msec and then close (inactive), and (3) cannot be opened again by depolarization until the membrane potential returns to a negative value near threshold

o Channelopathy – a human genetic disease casued by alterations in the structure and function of ion channels

o Tetrodotoxin (TXX) – toxin in a puffer fish that selectively blocks the Na+ channelso Voltage-gated Potassium Channel – potassium channels that open about 1msec after

depolarization. Content

o Depolarization of the cell during the action potential is caused by the influx of sodium ions across the membrane, and repolarization is caused by the efflux of potassium ions.

o So once threshold is met, Na+ channels fly open, and sodium desperately wants to get inside because Vm = -65mV, and sodium’s Equilibrium Potential is +62mV. So the drive on the Na+ ions to get into the cell is very high. So Na+ enters the cell, this is the rising phase. Then, once you hit a certain point, the sodium channels close. Potassium channels are still open however, and so K+ flows out of the cell, trying to make its way back to its equilibrium potential, -80mV. In the meantime, sodium-potassium pumps are pumping Na+ out of the cell, and K+ back in.

The rising phase is explained by inward sodium current, and the falling phase is explained by an outward potassium current.

The action potential therefore is caused by the movement of ions through channels that are gated based on changes in the membrane potential.

The rising phase was indeed caused by a transient increase in gNa (the electrical conductance proportional to the number of sodium channels open), and the falling phase was caused by a transient increase in gK

Ok, so what?o Threshold – membrane potential at which enough voltage-gated sodium channels open, so

that the membrane is more permeable to sodium than to potassium.o Rising Phase – Na+ ions rush into the cell through the open sodium channels, because the

inside of the membrane has a negative electrical potential (ie, there is a large driving force on the Na+ ions)

o Overshoot – the relative permeability of the membrane greatly favors sodium, and so the membrane potential goes to a value close to the equilibrium potential of sodium (ENa) which is greater than 0 mV.

o Falling Phase – first, the voltage-gated sodium channels shut. Second, the voltage-gated potassium channels finally open. There’s a great driving force on K+ ions when the membrane is strongly depolarized, and so K+ rushes out of the cell through the open channels, causing the membrane potential to be negative again.

o Undershoot – because the potassium channels from the falling phase are still open, the membrane is more permeable to potassium than usual. This causes a hyper-polarization in which the membrane voltage is more negative than the resting potential, until the potassium channels close again.

o Absolute Refractory Period – sodium channels inactivate when the membrane is depolarized. They cant be activated again, and therefore another action potential cant occur, until the membrane potential goes sufficiently negative to deactivate the channels.

o Relative Refractory Period – the membrane potential stays hyperpolarized until the voltage-gated potassium channels close, and so until that happens, more current is required to bring the membrane potential to threshold.

o **Meanwhile, sodium potassium pumps are working to reinstate the gradients by pushing Na+ out of the cell and K+ back into the cell

Action Potential Conductioin

o The movement of the signal is a lot like the lighting of a fuse. Once section of the membrane is depolarized and then will depolarize the segment right next to it over and over until it reaches the axon terminal. The signal can travel in either direction, but cant turn back on itself

o Action potential conduction velocity increases with increasing axonal diameter. Imagine a hose: water will flow through it. But if it’s narrow with holes in the side, the water will choose to go out of the hose. Same deal with action potential.

o Fortunately, vertebrates have another way to increase action potential velocity: myelin sheaths. The sheaths are composed of many layers of membrane provided by glial support cells (Schwann in the peripheral nervous system and oligodendroglia in the CNS). Myelin is like wrapping tape around the leaky hose – it forces the Na+ current to move down the axon instead of out. Breaks in the insulation (Nodes of Ranvier) occur so that ions can cross the membrane to generate action potentials.

o Saltatory Conduction: propagation of the action potential along myelinated axons; it basically “skips” from node to node because the myelin prevents the current from leaving, and so it can only leave or enter through those nodes.

Action Potentials, Axons, and Dendrites The membranes of dendrites and neuronal cell bodies don’t generate sodium-dependent action

potentials because they have very few voltage-gated sodium channels. Spike-Initiation Zone – the zone of the axon where the specialized gated ion channels exist – basically

the part of the neuron capable of initiating its own action potential. Usually the axon hillock, but in sensory neurons it occurs near the sensory nerve endings

Synaptic Transmission 9/1/15 5:25 PM

Introduction Synaptic transmission – the process of information transfer at a synapse Electrical synapse – electrical current flowing from one neuron to the next. This type of synapse is

common in the mammalian brain Chemical synapse – chemical neurotransmitters transfer information from one neuron to another at the

synapse. Comprise the majority of synapses in the brain.

Types of Synapses Electrical

o Gap junction – specialized sites at which electrical synapses occur. At a gap junction, membranes of two cells are very close together – the tiny gap between them is spanned by proteins called connexins. These proteins form a channel between the two cells and ions are free to flow from one cell to the next. As a result, most are bidirectional (can go either way) unlike chemical synapses. Cells connected by these are said to be electrically coupled. Important for places where normal function requires high synchronization.

o Postsynaptic potential – when an action potential is trigger in one cell, some of the ionic current will flow through the gap junction into the next neuron. This current causes a postsynaptic potential (PSP) in that second neuron, but it usually is very small and often not enough in and of itself to trigger an action potential in the second neuron. However, one neuron will usually form many electrical synapses with other neurons, so many PSPs occurring at once could be strong enough to trigger AP

Chemical – pre and post synaptic membranes are separated by a small synaptic cleft (10 wider than the separation of a gap junction). Presynaptic side of the cleft is referred to as the presynaptic element and is usually an axon terminal. Terminal is full of synaptic vesicles.

o Secretory granule (dense-core vesicle) – large vesicles in the axon terminal containing soluable protein.

o Membrane differentiations – dense gatherings of protein on just next to (on the inside) and within the pre and post synaptic membranes are referred to as membrane differentiations

o Active zone – the actual sites of neurotransmitter release; proteins will jut into the cytoplasm of the terminal along the intracellular face of the membrane – the tiny field of pyramids

o Postsynaptic density – the protein thickly accumulated in and just under the postsynaptic membrane. These proteins convert the intercellular signal (neurotransmitters) into an intracellular signal (change in membrane potential or other chemical change)

o Neuromuscular junction – chemical synapses of motor neurons and skeletal muscle. Fast and reliable. AP in the motor neuron always causes AP in the muscle cell it innervates. Presynaptic terminal has many active zones and the synapse is just really big.

o Motor end-plate – the post-synaptic membrane of a neuromuscular junction – this is the membrane of the muscle cell. They have many shallow folds to increase surface area and therefore also the number of receptors. Allows many neurotransmitters to be realized focally onto a large surface of chemically sensitive membrane

CNS Synapseso Postsynaptic membrane is on a dendrite: axodendritic

o Postsynaptic membrane is on another axon: axoaxonico Postsynaptic membrane is on the cell body: axosomatico Dendrites form synapses with each other: dendrodendritic

Principles of Chemical Synaptic Transmission Most neurotransmitters fall into one of three categories:

o 1. Amino acids – small organic molecule (synaptic vesicles) For example: Glutamate (Glu) Gamma-amniobutyric acid (GABA) Glycine (Gly)

o 2. Amines – small organic molecule (synaptic vesicles) Acetylcholine (ACh) Dopamine (DA) Epinephrine Histamine Norepinephrine Serotonin (5-HT)

o 3. Peptides – large molecules (secretory granules) CCK Dynorphin

Glutamate (Glu), Gamma-amniobutyric acid (GABA), and Glycine (Gly) – fast chemical synaptic transmission at most CNS synapses is mediated by these amino acids.

Acetylcholine (ACh) – mediates fast synaptic transmission at all neuromuscular junctions Neurotransmitter Synthesis and Storage

o Some amino acids are very prevalent in all cells (Glu, Gly). Others, (GABA) are make only by the neurons that release them. Specific synthesizing enzymes are transported to the axon terminal where they locally and rapidly direct transmitter synthesis.

Transporter – special proteins present in the vesicle membranes who are responsible for collecting and concentrating neurotransmitters that have been synthesized in the cytosol

o Peptides – a long peptide is synthesized in the rough ER, and the golgi will split it. One of the smaller peptide fragments is the neurotransmitter. Secretory granules full of it will bud off from the golgi and are transported to the axon terminal via axoplasmic transport.

Neurotransmitter Release – triggered by the arrival of an action potential in the axon terminalo Voltage-gated calcium channel – depolarization of the terminal membrane causes these,

located in the active zones, to open. Ca2+ will flood into the cell – this is the signal that causes the neurotransmitter to be released from the synaptic vesicles

Exocytosis – the membrane of the synaptic vesicle will fuse to the presynaptic membrane at the active zone, allowing the contents of that vesicle to spill out into the synaptic cleft. Certain vesicles are already “docked” at the active zones (via interaction of their proteins), and increased Ca2+ causes proteins to alter their formation so that the membranes form a pore that allows neurotransmitter to escape into the cleft.

Peptide neurotransmitters & secretory granules aren’t located at the active sites, and so don’t get set off by every influx of Ca2+. This is why they take longer – they require more Ca2+ to travel a longer distance.

Endocytosis – method by which the vesicle membrane is recovered. The recycled vesicle is refilled with neurotransmitter and used again

Neurotransmitter Receptors and Effectorso Transmitter-gated ion channel – membrane-spanning proteins that are made of 4-5 subunits

that form a pore between them. Neurotransmitters cause a conformational change that allows them to open. Do not show the same degree of ion selectivity as do voltage gated channels.

Excitatory postsynaptic potential (EPSP) – the postsynaptic membrane depolarization caused by the presynaptic release of a neurotransmitter. This occurs when a transmitter-gated ion channel opens and Na+ flows into the cell through it (ACh-gated and glutamate-gated ion channels do this)

Inhibitory postsynaptic potential (IPSP) – the postsynaptic membrane is hyperpolarized as a result of presynaptic release of a neurotransmitter. A transmitter-gated ion channel opens and Cl- flows into the cell through it (glycine-gated or GABA gated ion channels)

o G-protein-coupled receptor – can be used by all 3 types of neurotransmitters. Results in slower, longer-lasting, and much more diverse postsynaptic actions. Metabotropic receptors. Basically can have two results – open a channel, or activate and enzyme to make secondary messangers

Steps

1. Neurotransmitter binds to receptor proteins embedded in postsynaptic membrane

2. Recpetor protein activates small G-Proteins, that are free to move along the intracellular face of the postsynaptic membrane

3. The activated G-Proteins will active “effector” proteins Effector proteins can be G-protein-gated ion channels in the

membrane or enzymes that synthesize secondary messengers.o Second messenger – diffuse away in the cytosol and

activate additional enzymes that can regular ion channel function and alter cellular metabolism.

Metabotropic receptor – receptors that can trigger widespread metabolic effects *The same neurotransmitter can have different effects on different cells because of

the different postsynaptic receptor proteins. Autoreceptor – presynaptic neurotransmitter receptor proteins. Activation of these

(usually g-protein-coupled receptor proteins) usually will inhibit neurotransmitter release, or stimulate the production of more of a certain kind of neurotransmitter. This allows a presynaptic terminal to regulate itself; feedback inhibition.

Neurotransmitter Recovery and Degradationo Neurotransmitters can diffuse away from the synapse, or neurotransmitter transporter proteins

in the presynaptic membrane will suck them back in. Once inside the cytosol, they can be enzymatically destroyed or packed back up into synaptic vesicles. Glia surrounding the synapse also aid in the removal of neurotransmitters from the cleft. Enzymatic destruction can also occur at in the cleft itself.

o Removal is key – if not, some channels may no longer be sensitive to its neurotransmitter. As a result, it doesn’t work anymore. This is how many poisionous gases work.

At the neuromuscular junction, high concentrations of ACh after several seconds leads to a process called desensitization – basically the transmitter-gated channels close despite the continued presence of ACh. Usually, the destruction of ACh by AChE will prevent this, but if AChE is inhibited, the ACh receptors will become desensitized and neuromuscular transmission will fail.

Neuropharmacology – the study of the effects of drugs on the nervous system tissueo Inhibitor – one class of drug action wherein the drug inhibits the normal function of specific

proteins involved in synaptic transmission Receptor antagonist – inhibitors of neurotransmitter receptors. Bind to the receptors

and block (antagonize) the normal action of the transmitter.o Receptor agonist – a second class of drug action wherein the drug mimics the actions of the

naturally occurring neurotransmitter (eg, nicotine activates the ACh receptors in skeletal muscle)

Nicotinic ACh receptor – the ACh-gated-ion channels in muscle (this is to distinguish them from other types of ACh receptors, such as those in the heart as these are not activated by nicotine)

Principles of Synaptic Integration

Synaptic integration – the process by which multiple synaptic potentials combine within one postsynaptic neuron

The Integration of EPSPs (Excitatory Postsynaptic Potential)o Elementary unit of neurotransmitter release is the contents of a single synaptic vesicle

(usually they all have about the same number in them). EPSPs at a given synapse are quantized; they are multiples of an indivisible unit, the quantum, that reflects the number of transmitter molecules in a single synaptic vesicle and the number of postsynaptic receptors available.

o Miniature postsynaptic potential – usually just called a “mini. Amount of EPSP generated by the transmitter contents of one vesicle. Therefore, the amplitude of the postsynaptic EPSP is just an integer multiple of the mini amplitude.

o Quantal analysis – method of comparing amplitudes of minis and evoked postsynaptic potentials (caused by the released of hundred to thousands of vesicles) to determine just how many vesicles were released during normal synaptic transmission.

Example: neuromuscular junction one action potential triggers exocytosis of about 200 synaptic vesicles, causing an EPSP (change in membrane potential of the postsynaptic membrane) of 40 mV or more. At many CNS synapses however, an AP will cause the exocytosis of only a single vesicle, cause an EPSP of only a few tenths of a millivolt

o EPSP summation – the simplest form of synaptic integration in the CNS. Spatial summation – the adding together of EPSPs generated simultaneously at many

different synapses on a dendrite Temporal summation – adding together of EPSPs generated at the same synapse, if

they occur within rapid succession (~ 1-15 msec) The current entering at the sites of synaptic contact must spread down the dendrite,

through the soma, to the spike-initiation zone to be depolarized beyond threshold before an action potential can be generated. Many dendrites have many voltage-gated sodium channels, however. As a result, EPSPs flowing down would open some of these channels. This will add to the electrical current, allowing the synaptic signal to “stay alive” longer.

Length constant – the distance where depolarization is 37% of that at the origin. This is dependent on two factors

o Internal resistance – the resistance to current flowing longitudinally down the dendriteo Membrane resistance – the resistance to current flowing across the membrane

Inhibition – the difference between the postsynaptic receptors of inhibitory synapses and regular synapses is this small. Both synapses use transmitter-gated ion channels, however, inhibitors bind different neurotransmitters (GABA and glycine) and they allow different ions to pass through their channels – usually Cl -. Cl- will try to bring the membrane potential to -65mV, if it isn’t already there.

o Shunting inhibition – activation of the excitatory synapse leads to influx of positive charge. It will flow down the membrane toward the soma. At the site of the inhibitory synapse, the membrane potential is ~ -65mV. Positive current will therefore fly outward across the membrane. This synapse acts as an electrical shunt, preventing the current from flowing from dendrite to the soma. This is shunting inhibition. The actual physical basis of this is the inward movement of negatively charged chloride ions, which is equivalent to outward positive current flow.

These are especially concentrated in the soma and near the axon hillock. Modulation – synaptic activation wherein receptors do not directly evoke EPSPs or IPSPs, but instead

modifies the effectiveness of EPSPs generated by other synapses. This type of synapse does not use ion channels, but does use G-protein-coupled receptors.

o Examples Binding of the amine neurotransmitter norepinephrine (NE) to receptors. This sets

off a cascade of events. Receptros activate a g-protein which activates and effector protein -

adenylyl cyclase. This enzyme converts ATP into cAMP (secondary messanger).

cAMP triggers protein kinases to catalyze phosphorylation – the addition of phosphate groups from ATP to sites on cell proteins. This causes a conformational change in a protein, thereby changing that protein’s activity.

In some neurons, one of the phosphorylated proteins is a potassium channel in the dendritic membrane, thereby reducing K+’s conductances. This increases the dendritic membrane’s resistance and therefore increases the length constant.

Neurotransmitter Systems 9/1/15 5:25 PM

Introduction Neurotransmitter System (three classes: amino acids, amines, and peptides) – the molecule, all the

molecular machinery responsible for transmitter synthesis, vesicular packaging, reuptake and degradation, and transmitter action.

o Cholinergic – a word used to describe the cells that produce and release acetylcholine. o Noradrenergic - a word used to describe the cells that produce and release norepinephrine. o Glutamatergic - a word used to describe the synapses that produce and release glutamate.o GABAergic – a word used to describe the synapses that produce and release GABA.o Peptidergic – a word used to describe the synapses that produce and release peptides.o *These are also used to describe the various neurotransmitter systems. Ex: cholinergic system

Studying Neurotransmitter Systems What defines a neurotransmitter?

o 1. The molecule must be synthesized and stored in the presynaptic neuron Methods used to show this include immunocytochemistry and in situ hybridization

Immunocytochemistry: basically, inject the neurotransmitter molecule into the bloodstream – this produces an immune response. Antibodies form, and they bind tightly to the transmitter of interest. These antibodies are removed and chemically tagged, then applied to a section of brain tissue. They will color just those cells that contain the transmitter candidate. This method can also be used to tag the synthesizing enzymes for transmitter candidates. If it is found that both and enzyme and transmitter candidate are contained in the same neuron – or axon terminal – then it can help show that the molecules satisfies this first requirement.

In Situ Hybridization: a probe (strand of RNA complimentary to the mRNA that codes for a certain polypeptide/protein) is chemically labeled, and applied to a section of brain tissue. Neurons that contain the label contain the mRNA that codes for that protein or polypeptide. The probes are usually labeled by making them radioactive.

Autoradiography is used to detect radioactive probes – brain tissue is put on a special sheet of film that is sensitive to radioactive emissions.

o 2. The molecules must be released by the presynaptic axon terminal upon stimulation In some cases (mostly in the peripheral nervous system), a specific set of neurons

can be stimulated while taking samples of the fluid surrounding their synaptic targets. Then this sample can be used to see if it creates a synaptic response similar to those of intact synapses. Then the sample can be chemically analyzed to determine the structure of the active molecule (this is how ACh passed stage 2). This doesn’t work in the CNS because there are so many intertwining axons and transmitters.

In the CNS, researches have to stimulate many synapses in a brain region and then collect and measure all chemicals that are released. Use brain slices that are kept alive in vitro. Slices bathed in K+ solution, causing depolarization. Also, must be shown that the transmitter candidate is not released when Ca2+ isn’t present. Even still, its not certain that the chemicals released were from the terminals – could have been released as a secondary consequence of synaptic activation. Step 2 is the hardest to satisfy (especially in the CNS).

o 3. The molecule must evoke the same response as that produced by the release of naturally occurring neurotransmitter from the presynaptic neuron

Microionophoresis – neurotransmitter candidates are dissolved in solutions that cause them to acquire a net electrical charge. Put into a pipette, which slowly injects little bits of transmitter candidate right next to the synapse. Then a microelectrode in the postsynaptic neuron measures the effects on the membrane potential.

If this causes electrophysiological change that mimics the effects of transmitter released at the synapse (and criterion 1 and 2 are satisfied), then the molecule and transmitter are usually considered to be the same chemical.

Studying Receptorso No two neurotransmitters bind to the same receptor. However, one neurotransmitter can bind

to many different receptors. Each of the different receptors a neurotransmitter binds to is called a receptor subtype.

o Three methods are used to study the difference receptor subtypes of the various neurotransmitter systems: neuropharmacological analysis, ligand-binding methods, and molecular analysis of receptor proteins

Neuropharmacological Analysis – studying how different drugs affect the different subtypes is used: nicotine is a receptor agonist in skeletal muscle, but has no effect in the heart. Muscarine (mushroom poison) has no effect on skeletal muscle, but is an agonist (binds in the place of ACh and slows the heart to the point of death) at the cholinergic receptor subtype in the heart. Use of selective antagonists is also used (curare at ACh nicotinic receptors and atropine at ACh muscarinic receptors).

Difference drugs were used to distinguish subtypes of glutamate receptors – which mediate much of the synaptic excitation in the CNS.

AMPA Receptor, NMDA Receptor, and Kainate receptors, each named for a different chemical agonist, are three subtypes of glutatonic receptors.

Ligand-Binding Methods – technique of studying receptors using radioactively labeled ligands. Ligands are chemical compounds that bind to a specific site on a receptor. This method was used to isolate neurotransmitter receptors and determine their chemical structure. Discovered by the study of opiates.

Molecular Analysis – molecular analysis is the most recent method and has given the appreciation of the massive complexity of receptor subtype diversity.

Neurotransmitter Chemistry Most of the known neurotransmitter molecules are either (1) amino acids, (2) amines derived from

amino acids, or (3) peptides constructed from amino acids. ACh is an exception, but is made from acetyl CoA, which is a byproduct of cellular metabolism

o Dale’s Principle – The idea that a neuron has only one neurotransmitter Usually not true of peptide-containing neurons Co-Transmitter – when two or more transmitters are released from one nerve

terminal, they are called co-transmitters Cholinergic Neurons

o Acetylcholine – the neurotransmitter at the neuromuscular junction, and therefore synthesized by all the motor neurons in the spinal chord and brain stem.

o Choline Acetyltransferase (ChAT) is the enzyme that makes ACh by combining Choline (which exists in the extracellular fluid in low concentrations) and Acetyl CoA. ChAT makes ACh, then a transporter concentrates it into a vesicle.

Because the availability of choline limits how much ACh can be synthesized, the transport of choline into the neuron is said to be the rate-limiting step in ACh synthesis.

o Nicotonic ACh receptors – skeletal muscleo Muscarinic ACh receptors – cardiac muscle

Catecholaminergic Neuronso The amino acid tyrosine is the precursor for three different amine neurotransmitters that

contain a chemical structure called a catechol. These neurotransmitters are collectively called catecholamines.

Catecholamine neurotransmitters include dopamine (DA), norepinephrine (NE), and epinephrine (aka adrenaline).

Found in regions of the nervous system involved in movement, mood, attention, and visceral (non-voluntary) function

Tyrosine hydroxylase catalyzes the first step in catecholamine synthesis – converting tyrosine to a compound called dopa.

The activity of TH is rate-limiting for catecholamine synthesis. Feedback inhibition keeps TH in check.

Tyrosine Dopa Dopamine Norepinephrine Epinephrineo There are enzymes on each arrow that facilitate the

change. The actions of catecholamine neurotransmitters are terminated by the

selective uptake of the NTs back into the axon terminal via Na+ dependent transporters (no AChE equivalent for these NTs).

The catecholamines may be enzymatically destroyed by the action of monoamine oxidase (MAO), an enzyme found in the outer membrane of mitochondria.

Serotenergic Neuronso Amine neurotransmitter serotonin (5-HT) is derived from the amino acid tryptophan.

Serotonergic neurons are few in number, but play important roll in mood, emotional behavior, and sleep.

Serotonin is created similar to dopamine. Tryptophan 5-HTP 5-HT Rate-limiting factor is the availability of tryptophan in the extracellular

fluid bathing the neurons – tryptophan comes from the diet. 5-HT is removed from the cleft via a specific transporter.

Amino Acidergic Neuronso Amino acids Glu, Gly, gamma-amniobutyric acid (GABA) are the neurotransmitters at most

CNS synapses.

o Glutamatergic cells therefore just have a higher concentration of Glu, because Glu exists in all cells (as it is among the 20 amino acids that compose proteins). Transporters are the big difference btween glutagatergic and nonglutamatergic cells – because this transporter can concentrate glutamate until it reaches a value of about 50mM in synaptic vesicles.

o GABA is not one of the 20 amino acids that make up proteins – it is only synthesized by the cells that need it. GABA is synthesized by glutamic acid decarboxylase (GAD) and so it’s a good marker for GABAergic cells. GABAergic neurons are the major source of synaptic inhibition in the nervous system.

o Synaptic action is terminated by the selective uptake into presynaptic treminals and glia via Na+ dependent transporters. GABA is metabolized once back inside the cell by GABA transaminase.

Other Neurotransmitter Candidates and Intercellular Messengerso ATP- Few other small molecules act as chemical messengers between neurons – such as ATP.

ATP is usually packaged in vesicles with another classic transmitter. ATP binds to purinergic receptors – some are transmitter-gated ion channels, some

are G-protein-coupled purinergic receptors.o Endocannabinoids: New discovery – small lipid molecules, called endocannabinoids – are

released from postsynaptic to presynaptic terminals. Communication in this direction is called retrograde signaling – endocannabinoids therefore are called retrograde messengers.

Bascially, repeated firing of action potentials in a postsynaptic neuron causes elevated Ca2+ which prompts synthesis of endocannabinoid molecules from membrane lipids. Unusual qualities about endocannabinoids:

They are not packaged in vesicles; instead they are manufactured rapidly and on-demand

They are small and membrane permeable; once synthesized, they diffuse rapidly across the membrane of their cell to contact neighboring cells

They bind selectively to the CB1 type o cannabinoid receptor, which is mainly located on certain presynaptic terminals.

CB1 receptors are g-protein-coupled; main effect is to reduce opening of presynaptic calcium channels.

o Nitric Oxide: NO is membrane permeable and small, suggesting it may also be a retrograde messenger. Powerful effects especially in the regulation of blood flow. It can even pass through one cell to get to another on the other side. But it does break down very rapidly.

*Should be noted that NTs aren’t specific to neurons – they can also exist in different parts of the body and have different effects in these parts.

Transmitter-Gated Channels Channels are sensitive detectors of chemicals and voltage, regulate the slow of surprisingly large

currents, and sift between various similar ions. It can be regulated by other receptor systems. Very versatile.

o Basic Structure of Transmitter-Gated Channels

ACh: five protein subunits form a pore. Two ACh must bind to the two alpha subunits, and this opens the channel. Each subunit polypeptide has 4 segments that coil into alpha helixes. These helixes are hydrophobic, and so are probably the part in the membrane. Most channels are thought to be similar in structure to the nicotinic ACh receptor described above.

Glutamate receptors are different – four subunits that form the channel.o Amino Acid-Gated Channels

Mediate most fast synaptic transmission in the CNS. These are the properties that distinguish them from one another and define their function

Pharmachology of their binding sites describes the transmitters that bind to them and how drugs impact them

Kinetics of the transmitter binding process and channel gating determine the duration of their effect

Selectivity of the ion channels determines whether they produce excitation or inhibition, and whether Ca2+ enters the cell in significant amounts

Conductance of open channels help determine the magnitude of their effects.

Glutamate-Gated Channels AMPA (named after the selective agonist) gated channels are permeable to

potassium and sodium, but not calcium. When they open, rapid and large depolarization occurs. AMPA receptors therefore mediate excitatory transmission in the CNS.

NMDA-gated channels also cause excitation by admitting sodium – differ from AMPA because (1) are permeable to Ca2+ and (2) inward current through them is voltage dependent.

1. When the channel opens, sodium and calcium flood inward 2. In order for these ions to flood in, the cell must be depolarized

already. At normal negative potential, the channels become clogged with Mg2+, in an event called magnesium block. Thus, ionic current through these channels is voltage dependent.

*Both glutamate and depolarization must coincide before the channel will pass current

GABA-Gated and Glycine-Gated Channels GABA responsible for most synaptic inhibition in the cell. Inhibition must

be tightly regulated, so this is why the GABA channels have many other sites on it for other chemicals to modulate its function. Benzodiazepine and Barbiturates are two classes of drugs that bind to the channel. When these drugs are bound to the channel at the same time as GABA, it increases the duration or frequency of channel openings, resulting in more inhibitory Cl- current, therefore stronger IPSPs.

Glycine mediates most of the rest of synaptic inhibition (not in the CNS)

G-Protein-Coupled Receptors and Effectors – Multiple subtypes of G-protein-coupled receptors in every known transmitter system.

The Basic Structure of G-Protein-Coupled Receptorso Simple variation on a common plan: single polypeptide containing 7 alpha helices.

Extracellular loops of the polypeptide bind neurotransmitters, intracellular loops bind g-proteins

o The Ubiquitous G-Proteins (Guanosine triphosphate binding protein) – about 20 types, but all have the same MO

1. Each G-Protein has 3 subunits – alpha, beta, and gamma. In resting state, GDP is bound to Ga and the whole complex floats around inner surface of the membrane

2. If this at rest protein bumps into the proper type of receptor and if that receptor has the transmitter molecule bound to it, the G-protein exhanges the GDP for a GTP (from the cytosol)

3. Activated protein splits into two parts: alpha subunit plus GTP, and beta-gamma complex. Both then move to influence various effector proteins

4. Ga is an enzyme that eventually terminates its own activity by converting GTP to GDP

5. The alpha complex and beta-gamma complex come together, restarting the cycle G-Protein-Coupled Effector Systems

o The shortcut pathway – g-protein-gated ion channels Ex: muscarinic receptors in the heart ACh receptors bind to ACh and g-protein,

then the G-protein is activated and goes and opens a K+ channel. This slows depolarization (the heart rate, in this scenario).

This pathway is faster, but localized.o Second Messenger Cascade – G-protein activates certain enzymes. These enzymes activate

other enzymes via second messengers and so on. This results in widespread effects. Activation of adenylyl cyclase will cause a rise of

cAMP this activates protein kinase A. Signal can be amplified. For example, activation of G-proteins can stimulate

phospholipase C (PLC) which splis a membrane phospholipid creating two molecules that serve as secondary messengers (Diacylglycerol, DAG and Inositol – 1, 4, 5 – triphosphate, IP3). DAG activates protein kinase C. IP3 binds to channels in organelles, causing them to dispel Ca2+. This calcium activates Calcium-Calmodulin-Deptendent Protein Kinase (CaMK), which is implicated in the molecular mechanisms of memory.

o Phosphorylation and Dephosphorylation Key downstream enzymes are usually protein kinases – proteins that transfer

phosphate from ATP in the cytosol to proteins. Phosphorylation of ion channels for example can influence the probability that they will open or close.

Enzymes called protein phosphatases rapidly remove these phosphate groups. Phosphatases dephosphorylate proteins.

o Function of Signal Cascades

Why? They are slow and complex compared to transmitter-gated ion channels, but signal amplification. The use of small messengers such as cAMP also allows signaling over a distance. Finally, signal cascades can generate long-lasting chemical changes in cells, which may form the basis for memory.

Divergence and Convergence in Neurotransmitter Systems One neurotransmitter can activate more than one subtype of receptor, and cause more than one

postsynaptic response – this is called divergence. This can occur at any point along the cascade. Neurotransmitters can also exhibit convergence, in which many NTs and receptors can converge to

affect the same effector systems. Neurons integrate divergent and convergent signaling in a complex map of chemical effects.

The Structure of the Nervous System Alec Jotte

Gross Organization of the Mammalian Nervous System Two divisions: Central Nervous System (CNS) and Peripheral Nervous System (PNS) Anatomical References

o Rostral or Anterior: towards the noseo Caudal or Posterior: towards the tailo Dorsal: pointing upo Ventral: pointing down

Bilateral Symmetry: right and left sides are mirrors of each other – this is the case for most of the nervous system

o Midline: invisible line running down the middle of the nervous systemo Medial: structures closer to the midlineo Lateral: structures farther away from the midlineo Two structures on the same side of the midline are ipsilateral to each othero Two structures on opposite sides of the midline are contralateral to each other

A slice of brain is called a section. To slice is to section.o Anatomical Planes of Section

Midsagittal Plane: belly button to nose direction. Sagittal plane. Right/left halves Horizontal Plane: parallel to the ground. Dorsal/ventral parts Coronal Plane: perpendicular to the ground. Anterior/postier parts

The Central Nervous Systemo CNS consists of the brain and spinal cord. Three parts are common to all mammals: cerebrum,

cerebellum, and the brain stem.

The Cerebrum: the rostral-most and largest part of the brain. Clearly split down the middle into two cerebral hemispheres by the sagittal fissure. Right hemisphere controls left body and left hemisphere controls right body.

The Cerebellum: lies behind the cerebrum (“little brain”). Responsible for movement control. Left side controls left side and right side controls right side.

The Brain Stem: the stalk from which the cerebrum/cerebellum sprout – relays information from spinal cord cerebrum/cerebellum and vice versa. Also the site where vital function are regulated.

Spinal Cord: major receptor of information from the skin, joints, and muscles of the body to the brain, and vice versa. Spinal cord communicates to body via spinal nerves – part of the peripheral nervous system.

Spinal nerves attach between vertebrate, and each one attaches by means of two branches – dorsal root (brings information in) and ventral root (carries information out).

The Peripheral Nervous Systemo PNS consists of the nervous system other than the brain and spinal cord

PNS has two divisions – the somatic PNS and visceral PNS.o The Somatic PNS – spinal nerves that innervate skin, joints, and the muscles that are under

voluntary control. Somatic motor axons (PNS) derive from motor neurons in the spinal cord (CNS) and carry info via the ventral roots.

Somatic sensory axons – collect info from skin, joint, muscles – enter spinal cord via dorsal roots. The cell bodies of these neurons lie just outside the spinal cord and are called dorsal root ganglia.

o The Visceral PNS (aka Autonomic Nervous System or ANS) – consists of neurons that innervate internal organs, blood vessels, and glands. Bring info about visceral function to the CNS, such as pressure and O2 content of blood in arteries.

o Afferent (“carry to”) vs efferent (“carry from”) neurons. Relative terms. Afferent means carrying information towards, efferent means carrying information away from.

Cranial Nerves – 12 pairs that arise from the brain stem and innervate (mostly) the head. Some are a part of the CNS, others the somatic PNS, others the visceral PNS.

The Meninges – the CNS doesn’t come in direct contact with the overlaying bone – it is protected by 3 membrane layers called the meninges.

o Dura mater (“tough mother”) – outermost covering that forms a touch, inelastic bag that surrounds the brain and spinal cord.

o Arachnoid membrane – lies just underneath the dura mater. If blood vessels passing through the dura rupture, blood can collect here and form a subdural hematoma. This can cause pressure that disrupts the actions of the CNS.

o Pia mater (“gentle mother”) – thin membrane that adheres closely to the surface of the brain. The Pia is separated from the arachnoid membrane by a subarachnoid space filled with fluid called cerebrospinal fluid (CSF).

The Ventricular Systemo The fluid filled caverns and canals inside the brain constitute the ventricular system. This

fluid is CSF.

o CSF is produce by a special tissue called the choroid plexus, in the ventricles of the cerebral hemispheres.

Imaging the Living Brain

o Computed Tomography (CT Scan) – an x-ray source is rotated around the head within the plane of the desired cross section. It develops an image of the brain.

o Magnetic Resonance Imaging (MRI) – slowly replacing CT scans because it yields a much more detailed map of the brain than does CT, and with more flexibility. Has to do with how hydrogen in the head reacts to a strong magnetic force

o Fuctional Brain Imagine – 2 methods Positron emission tomography (PET Scan) and functional magnetic resonance

imaging (fMRI) – basically detect changes in blood flow to show which parts of the brain are active under different circumstances

Understanding CNS Function Through Development Terms that you need to know

o Collections of Neurons Gray matter – generic term for collection of neuronal cell bodies in the CNS Cortex – any collection of neurons that form a thin sheet, typically at the brain’s

surface. Nucleus – clearly distinguishable mass of neurons, usually deep in the brain Substantia – a group of related neurons deep within the brain less strict and

distinct than nuclei (substantia is neurons responsible for voluntary movement, nucleus is neurons responsible for voluntary movement of the eye)

Locus – a small, well-defined group of cells Ganglion – a collection of neurons in the PNS.

Exception, basal ganglia which lie deep in the cerebrum and control movement

o Collections of Axons Nerve – bundle of axons in the PNS. Only one collection of CNS axons is called a

nerve – this is the optic nerve. White matter – a generic term for a collection of CNS axons Tract – collection of CNS having a common site of origin and common destination Bundle – collection of axons that run together but do not necessarily have the same

origin and destination Capsule – a collection of axons that connect the cerebrum with the brain stem

Commissure – any collection of axons that connect one side of the brain to the other Lemniscus – A tract that meanders through the brain like a ribbon

Formation of the Neural Tubeo Embryo begins as a flat disk with three distinct layers of cells – endoderm, mesoderm, and

ectoderm. Endoderm gives rise to linins of many internal organs (viscera) Mesoderm gives rise to the bones of the skeleton and the muscles Ectoderm gives rise to the nervous system and the skin

o Ectoderm – the neural plate. The brain consists of a flat sheet of cells. Groove forms in the neural plate that runs rostral to caudal – neural groove. The walls of the groove are called neural folds. These will fuse and form the neural

tube. This process is called neurulation. *The entire CNS develops from the walls of the neural tube.

As neural tube forms, some neural ectoderm tissue is pinched off, and ends up just next to the neural tube on either side. This is the neural crest, *and all cells with cell bodies in the PNS derive from the neural crest

o Mesoderm – develops bulges on either side of the neural tube called somites. From these, the entire vertebrate and related skeletal muscles will develop. The nerves that innervate these skeletal muscles are therefore called somatic motor neurons

Three Primary Brain Vesicleso The first step in brain differentiation is the development of three swellings called primary

vesicles at the rostral end of the neural tube. The entire brain comes from the three primary

vesicles of the neural tube. Prosencephalon (forebrain) – rostral most vesicle Mesencephalon (midbrain) – just caudal to the prosencephalon

Rhombencephalon (hindbrain) – caudal to the mesencephalon Differentiation of the Forebrain

o Secondary vesicles sprout off both ends of the prosencephalon. These are the optic vesicles and the telencephalic vesicles. The unpaired middle section that remains is called the diencephalon.

o The optic vesicles grow and fold in to eventually form the optic nerves and retinas in the adult

o Differentiation of the Telecephalon and Diencephalon

The telencephalic vesicles together form the telencephalon. Another pair of vesicles sprout off the ventral surfaces of the cerebral hemispheres, giving rise to the olfactory bulbs.

The fluid filled spaces within the cerebral hemispheres are called the lateral ventricles, and the space at the center of the diencephalon is called the third ventricle.

Two types of gray matter form in the telencephalon: Cerebral cortex and the basal telencephalon

Two types of gray matter form in the diencephalon: Thalamus and the hypothalamus

Three Major White Matter Systems in the Forebrain Cortical White Matter – contains all the axons that run to and from the

neurons in the cerebral cortex Corpus Callosum – axons that connect the two hemispheres Internal Capsule – axons that links the cortex with the brain stem,

particularly the thalamuso Forebrain Structure-Function Relationships

Somatic sensation relays in the thalamus en route to the cortex Information is carried back and forth from either hemisphere via the corpus callosum Damage to basal ganglia disrupts voluntary movement ability Hypothalmus – performs many primitive unctions. Controls the ANS.

Increases/decreases heart rate, controls fight or flight, etc. Key in motivating animals to find food, drink, and sex in response to their needs.

Differentiation of the Midbraino The dorsal surface becomes the tectum and the floor becomes the tegmentum. The CSF-

filled space in between the two is a tight narrow channel called the cerebral aqueduct and connects the third ventricle of the diencephalon to the fourth ventricle.

o Mid-Brain Structure-Function Relationships

Serves as a conduit for info passing from spinal cord to forebrain and vice versa. It also helps control sensory systems and movement. The corticospinal tract courses through the midbrain, and damage on one side produces a loss of voluntary control of movement on the opposite side of the body.

The tectum differentiates into two sections Superior colliculus – receives direct input from the eye. Controls

eye movement Inferior colliculus – receives direct input from the ears. Important

relay station for auditory info en route to the thalamus Differentiation of the Hindbrain

o Three Important Structures in Two Categoriees Metencephalon (Rostral half of hindbrain)

The Cerebellum The Pons

Myelencephalon (caudal half of hindbrain) The Medulla

Medullary pyramids – bundles of axons headed towards the spinal cord

o The CSF filled tube becomes the fourth ventricle.o Hindbrain Structure-Function Relationships

Processing sensory info, control of voluntary movement, and regulation of ANS. Cerebellum receives massive input from spinal cord and pons. Pons relay info from

the cerebral cortex. Spinal cord relays info from the body. Pons are critical – sort and relay info from the cerebral cortex to the cerebellum. When the medulla joins the spinal cord, each pyramidal tract crosses the midline,

forming the pyramidial decussation. Medulla also has neurons that perform sensory and motor functions –

auditory nerves synapse in the medulla, touch and taste the same. Differentiation of the Spinal Cord

o As tissue expands in the walls of the caudal neural tube, the cavity constricts and forms the tiny CFS-filled spinal canal.

o Spinal gray matter forms a butterfly shape dorsal horn and ventral horn with an intermediate zone in the middle.

o Spinal Cord Structure-Function Relationships

Dorsal horn cells receive sensory inputs from dorsal root fibers Ventral horn cells project axons into the ventral roots that innervate muscles Intermediate zone cells are interneurons that shape motor outputs based on sensory

inputs. Dorsal column carries sensory info to the brain. Lateral column has axons in the corticospinal tract (pyramidal tract) that

communicate voluntary movement signals. Neurons of spinal cord begin analysis of sensory info, play a role in coordinating

movements, and work simple reflexes (jerking foot off of thumbtack) Putting the Pieces Together

o The diencephalon surrounds the third ventricleo The midbrain surrounds the cerebral aqueducto The cerebellum, pons, and medulla surround the fourth ventricleo The grooves on the human brain are called sulci and the bumps are called gyri. These allow

increased surface area (i.e., more neurons, as the gray matter is only a thin sheet) without increasing the volume too much.

o The cerebral cortex is partitioned Temporal Lobe is on the sides just under the temples Frontal Lobe is just under the frontal bone of the forehead Parietal Lobe just caudal to the central sulcus which separates the frontal lobe from

the parietal lobe Occipital Lobe caudal to the parietal lobe at the very back of the cerebrum

A Guide to the Cerebral Cortex Types of Cerebral Cortex

o Cell bodies of cortical neurons are parallel to the surface of the brain. Layer of neurons closest to the surface is separated from the pia mater by a zone that lacks neurons called molecular layer, or layer 1. At least 1 cell layer contains pyramidal cells that emit large dendrites called apical dendrites, that extend into layer I, where they form multiple branches.

o Hippocampus – has only a single cell layer. Section of cortex that is between the lateral ventricle and the midline. The olfactory cortex is connected to this, and has 2 cell layers.

o There is one more cortex, called the neocortex – the neocortex is found only in mammals. Areas of Neocortex

o Broadmann constructed a cytoarchitectural map of the neocortex. Each cortical area performs different functions.

Neocortical Evolution and Structure-Function Relationshipso Primordial neocortex consisted mainly of three types of cortex

The size of the neocortex has changed drastically. Also, the number of areas that are “unassigned” in the human brain are much greater than in other animals.