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Bio.590-8.Neurons

Integrative Physiology Ch. 8 - Neurons: Cellular and Network Properties

QuestionAnswer
Nervous system (NS) A network of trillions of nerve cells linked together in a highly organized manner to form the rapid control system of the body
Neurons The basic signaling units of the NS. “Nerve cells” that carry electrical signals rapidly and, in some cases, over long distances. They are uniquely shaped, most having long, thin extensions known as processes.
The processes that extend from neurons are usually classified as either: Dendrites or axons
Neurotransmitters The chemical signals released into the ECF by neurons in most pathways
Are all neurons linked via exchange of neurotransmitters? No, in a few pathways neurons are linked by gap junctions, allowing electrical signals to pass directly from cell to cell
Emergent properties of the nervous system Complex processes such as consciousness, intelligence, and emotion cannot be predicted from what we know about the properties of individual nerve cells
Synonyms: Action potential AP, spike, nerve impulse, conduction signal
Synonyms: Autonomic nervous system Visceral nervous system
Synonyms: Axon Nerve fiber
Synonyms: Axonal transport Axoplasmic flow
Synonyms: Axon terminal Synaptic knob, synaptic bouton, presynaptic terminal
Synonyms: Axoplasm Cytoplasm of an axon
Synonyms: Cell body Cell soma, nerves cell body
Synonyms: Cell membrane of an axon Axolemma
Synonyms: Glial cells Neuroglia, glia
Synonyms: Interneuron Association neuron
Synonyms: Rough endoplasmic ER Nissl substance, Nissl body
Synonyms: Sensory neuron Afferent neuron, afferent
The nervous system can be divided into two parts (technically 3 if you include the enteric nervous system; that will be covered in the digestive system chapter): The central nervous system (CNS) and the peripheral nervous system (PNS). Note: the PNS is AKA the visceral nervous system because it controls contraction and secretion in the various internal organs (viscera)
What does the CNS consist of? The brain and spinal cord
What does the PNS consist of? The afferent (or sensory) neurons and efferent neurons
Efferent neurons are subdivided into two groups: The somatic motor division and the autonomic division
What does the somatic motor division of efferent neurons control? Skeletal muscles
What does the autonomic division of efferent neurons control? Smooth and cardiac muscles, exocrine glands, some endocrine glands, and some types of adipose tissue
Autonomic neurons are further subdivided into two branches The sympathetic and parasympathetic branches
Enteric nervous system A third division of the nervous system. It’s a network of neurons found in the walls of the digestive tract. While frequently controlled by the autonomic division of the nervous system, it can also function autonomously as its own integrating center
Does the CNS require inputs from the PNS to function? The significant processes of the CNS do not require inputs from the PNS. E.g. a decapitated head, if somehow kept alive, will still thing, dream, etc.
The nervous system is composed primarily of two cell types: Neurons and glial cells (AKA glia or neuroglia)
The functional unit of the nervous system The neuron
Define “functional unit” The smallest structure that can carry out the functions of a system
The processes that extend outward from the cell bodies of neurons can be classified as: (include a brief description of each) Dendrites (they receive incoming signals) or axons (they carry outgoing information). Note: dendrites and axons are THE features that allow neurons to communicate
Structurally how are neurons classified? By the number of processes that originate from the cell body. They may described as pseudounipolar, bipolar, multipolar, or anaxonic
Pseudounipolar Axon and dendrites fuse during development to create one long process.
Bipolar Single axon and single dendrite
Multipolar Many dendrites and branched axons
Anaxonic Lacking an identifiable axon
Functionally how are neurons classified? Sensory (afferent) neurons, interneurons, and efferent (somatic motor and autonomic) neurons
Sensory neurons They carry information about temperature, pressure, light, and other stimuli from sensory receptors to the CNS. Some can have very long processes extending from the CNS to limbs. Others (e.g. in nose) can be smaller
Interneurons Neurons located entirely in the CNS. They often have complex branching processes allowing them to communicate with many neurons
Efferent neurons Often have enlarged regions along the axon called varicosities which store and release neurotransmitters
Nerves The long axons of afferent and/or efferent peripheral neurons are bundled together with connective tissue into cordlike fibers called nerves. These extend from the CNS to their targets.
Sensory nerves Nerves carrying afferent signals only
Motor nerves Nerves carrying efferent signals only
Mixed nerves Nerves carrying both afferent and efferent signals
Cell body (cell soma) of a neuron Resembles that of a typical cell with a nucleus and all organelles needed to direct cellular activity. The cytoskeleton extends outward into the axon/dendrites. The cell body is generally small, about 1/10 of the neuron
If the axon or dendrite is severed, which portion dies? The distal portion. The part that is still connected to the cell soma stays alive because the soma is the control center of the neuron
To say something is “innervated” by a neuron is another way of saying That something is controlled by a neuron
Mnemonic for remembering afferent/efferent axon/dendrite Ad and ex. Afferent neurons receive signals via their dendrites. Efferent neurons send signals via their axons.
Dendrites increase the _____ of a neuron Surface area
How many dendrites do cells have? The simplest neurons have only a single dendrite. At the other extreme, neurons in the brain may have multiple dendrites with incredibly complex branching.
Dendritic spines Portions of the dendrites that further expand surface area, varying from thin spikes to mushroom-shaped knobs
The primary function of dendrites in the PNS To receive incoming information and transfer to an integrating region within the neuron
The primary function of dendrites in the CNS More complex function. Dendritic spines can function as independent compartments, sending signals back and forth with other neurons in the brain. Many contain polyribosomes and can make their own proteins
What makes dendritic spines a hot area of research? They can change their shape and size in response to input from other cells. Changes in dendritic spine morphology occur in learning and memory as well as various pathologies, e.g. Alzheimer’s.
Most neurons have how many axons? Only one
Axon hillock The region of the cell body where the axon originates
Axon collateral A branch off of the main axon. They can either branch out for more communication or feed back onto the soma to provide modulation of cell firing.
Axon terminal The swelling at the end of an axon is called an axon terminal. An axon terminal contained mitochondria and membrane-bound vesicles filled with neurocrine molecules
The primary function of an axon Transmit outgoing electrical signals from the integrating center of the neuron to the end of the axon. At the distal end of the axon, the electrical signal is usually translated into a chemical message by secretion of chemicals
Types of chemicals secreted by axons Neurotransmitters, neuromodulators, and neurohormones
Where do neurons that secrete neurotransmitters usually terminate? Near their target cells which are usually other neurons, muscles, or glands
Synapse The region where an axon terminal meets its target cell. It includes the presynaptic axon terminal, the postsynaptic dendrite, and the synaptic cleft
Presynaptic cell The neuron that delivers the signal to the synapse
Postsynaptic cell The neuron that receives the signal from the presynaptic cell
Synaptic cleft The narrow space between the two cells (the presynaptic and postsynaptic cells)
Axonal transport The process by which proteins synthesized in the soma are transported to the axon or axon terminal. This has to occur because axons lack ER and ribosomes to make their own proteins
Slow axonal transport Moves material by axoplasmic (cytoplasmic) flow from the cell body to the axon terminal. Material moves at a rate of .2-2.5 mm/day, which means the material transported are not consumed rapidly by the cell
Fast axonal transport Uses motor proteins on stationary microtubules that walk material to and from the axons. Material is moved at rates of 400 mm/day in this fashion.
Direction of fast axonal transport and material carried Two directions: either forward (anterograde) transport carrying synaptic and secretory vesicles, or backward (retrograde) transport carrying old cellular components from the axon terminal to the cell body for recycling
Glial cells They outnumber neurons 50-1. As opposed to previous views, glial cells’ functions are more than just physical support. But it is true that they do not participate directly in the transmission of electrical signals over long distances
Types of glial cells in the CNS and PNS CNS: oligodendrocytes, microglia, astrocytes, and ependymal cells. PNS: Schwann cells and satellite cells
Structural support provided by glial cells Neural tissue secretes very little extracellular matrix, and glial cells provide structural stability to neurons by wrapping around them
Schwann cells and oligodendrocytes Schwann cells in the PNS and oligodendrocytes in the CNS support and insulate axons by forming myelin.
Myelin A substance composed of multiple concentric layers of phospholipid membrane. In addition to providing support, the myelin acts as insulation around axons and speeds up their signal transmission
What is the process by which myelin is formed? Glial cells will wrap around an axon, squeezing out the glial cytoplasm so that each wrap becomes two phospholipid membrane layers. Gap junctions connect the layers together and nutrients can flow through.
Difference between Schwann cells and oligodendrocytes The number of axons they wrap around. One oligodendrocyte will form myelin around portions of several axons. One Schwann cell will only associate with one axon, thus one axon will have many different Schwann cells
Nodes of Ranvier (AKA myelin sheath gaps) Gaps left between the myelin-insulated areas of axons. At each node a small portion of axon maintains contact and communication with the ECF.
Satellite cell A nonmyelinating Schwann cell. They form supportive capsules around nerve cell bodies located in ganglia
Ganglion A cluster of nerve cell bodies found outside the CNS. Ganglia appear as knots or swellings along a nerve.
The analog of PNS ganglia in the CNS Nuclei (singular: nucleus)
How do glial cells help maintain neurons and guide them during repair and development? They secrete glial-derived growth and neurotrophic factors
Astrocytes Highly branched glial cells that may make up to half the cells in the brain – they come in many subtypes and have many roles. They communicate with each other via gap junctions. Their processes may exchange chemical with neurons
Functions of astrocytes Exchange chemicals at synapses; provide neurons with substrates for ATP production; maintain CNS homeostasis by taking up K+ and water; and they surround blood vessels forming the blood-brain barrier
Microglia Specialized immune cells that reside permanently in the CNS. When activated they remove damaged cells and foreign invaders.
How can microglia be bad? Activated microglia sometimes release damaging reactive oxygen species (ROS) that form free radicals. The resultant oxidative stress caused by ROS is believed to contribute to neurodegenerative diseases such as ALS
Ependymal cells Specialized cells that secrete a selectively permeable epithelial layer, the ependyma, which separates the fluid compartments of the CNS. The ependyma is one source neural stem cells
Neural stem cells Immature cells that can differentiate into neurons and glial cells.
Note: levels of cell potency Unipotent (e.g., adult stem cells, differentiate into one cell); oligopotent (a few cell types of a particular line); multipotent (multiple cell types of a particular line); pluripotent (many different cell types); totipotent (any cell type)
Neural stem cells Remnants of neural stem cells that remain undifferentiated even after an adult reside along with the ependymal cells in the subependymal layer. They’ve also been found in the hippocampus
Why are nerve and muscle cells characterized as “excitable tissues”? Due to their ability to propagate electrical signals over long distances rapidly in response to a stimulus
Two factors that influence membrane potential Concentration gradients of ions across the cell membrane and membrane permeability to those ions
Nernst equation The equation which describes the membrane potential that a single ion would produce if the membrane were permeable only to that one ion. For any one ion, this membrane potential is known as the equilibrium potential of the ion
REVIEW NERNST EQUATION IN CLASS AND ON PAPER IF NEEDED REVIEW NERNST EQUATION IN CLASS AND ON PAPER IF NEEDED
Goldman-Hodgkin-Katz (GHK) equation Used to calculate the resting membrane potential that results from the contribution of all ions that can cross the membrane. Note: this means if the membrane is not permeable to an ion, it’s not included.
For mammalian cells what ions do we assume influence the membrane potential in resting cells? Na+, K+, and Cl-
Qualitatively explain the GHK equation Resting membrane potential is determined by the combined concentrations of the (concentration gradient * membrane permeability) for each ion
REVIEW GHK EQUATION IN CLASS AND ON PAPER IF NEEDED REVIEW GHK EQUATION IN CLASS AND ON PAPER IF NEEDED
The resting membrane potential of a cell is determined primarily by The K+ concentration gradient and the cell’s resting permeability to K+, Na+, and Cl-
Recap: What does it mean for a cell to “depolarize”? To lose its polarity (i.e., charge). In the case of a living cell which typically has a negative charge, if the negative charge decreases (e.g. as a result of incoming positively charge ions) then the polarity decreases.
Recap: What does it mean for a cell to “hyperpolarize”? That means the cell’s polarity increases. In other words, the negative charge of the cell increases (e.g. as a result of positively charge ions leaving the cell)
If the membrane potential of a cell changes profoundly, e.g. from -70 to +30, does this indicate that the concentration gradients of any ions have changed? No. Remember: a very tiny number of ions can move across the membrane and greatly influence the electrical charge. Only 1 of every 100,000 K+ ions are required to cross the membrane to alter its potential by 100mV
What’s the simplest way for a cell to change its ion permeability? By opening or closing existing channels in the membrane… Note: neurons contain a variety of gated ion channels that alternate between open and closed states, depending on the intracellular and extracellular conditions
What’s a slower method a cell uses to change its ion permeability? For a cell to insert NEW channels into the membrane or remove existing channels
Four major types of selective ion channels in the neuron Na+ channels, K+ channels, Ca^2+ channels, and Cl- channels. Note: there are other, less selective channels such as the monovalent cation channels that allow both Na+ and K+ to pass
The ease with which ions flow through a channel is called the channel’s _____. Conductance
What causes channel conductance to vary? The gating state of the channel and with the channel protein isoform
K+ leak channels These channels are major determinants of resting membrane potential and spend most of their time in an open state, unlike many other channels which open or close in response to stimuli.
Three types of channels that open or close in response to stimuli (1) mechanically gated ion channels, (2) chemically gated ion channels, and (3) voltage-gated ion channels
Mechanically gated ion channels: what types of neurons are they found in and what is their function? Found in sensory neurons and open in response to physical forces such as pressure or stretch
Chemically gated ion channels: what is their function? In most neurons they respond to a variety of ligands, such as extracellular neurotransmitters and neuromodulators or intracellular signal molecules
Voltage-gated ion channels: what role do they play? They respond to changes in the cell’s membrane potential. These changes play an important role in the initiation and conduction of electrical signals
Threshold voltage The minimum stimulus for a channel opening – it varies from one channel type to another
Channelopathies Inherited diseases caused by mutations in ion channel proteins. Because ion channels are linked to electrical activity, many channelopathies manifest themselves in disorders of excitable tissues (nerve and muscle)
Examples of channelopathies Long Q-T syndrome (caused by gene mutations in K+, Na+, or Ca^2+ channels, symptoms: arrhythmia, fainting, and sometimes sudden death); some forms of epilepsy and malignant hyperthermia; and cystic fibrosis
Channel opening to allow ion flow is called Channel activation
Is the speed of channel activation constant among the various channels? No, it varies
Example of varying channel activation rates Na+ and K+ channels of axons are both activated by cell depolarization. However, the Na+ channels open very rapidly and the K+ channels open slower. The result is an initial flow of Na+, followed later by K+
Inactivation Many channels are activated by depolarization and close during repolarization. Some channels, however, will automatically close even though the depolarization hasn’t stopped; this is called inactivation.
The study of the rates and mechanisms of the opening and closing of channels can be described as Gated channel kinetics; a branch of enzyme kinetics
Current (abbrev. I_ion) The flow of electrical charge carried by an ion.
The direction of I_ion depends on The electrochemical gradient of the ion
Which direction do each of the ions typically move? K+ usually flows out of the cell – Cl-, Na+, and Ca^2+ usually flow into the cell. Note: the net flow of these ions will either depolarize or hyperpolarize the cell, creating an electrical signal
Two basic types of electrical signals Graded potentials and action potentials
Graded potentials Variable-strength input signals (depolarizations or hyperpolarizations) that travel over short distances and lose strength as they travel through the cell. They’re used for short-distance communication.
Action potential Very brief, large depolarizations that travel for long distances through a neuron without losing strength. Their function is rapid signaling over long distances
If a depolarizing graded potential is strong enough when it reaches an integrating region within a neuron, the graded potential initiates _____ An action potential
Where do graded potentials occur? They occur in the dendrites and cell body, or less frequently, near the axon terminals.
Why use the word “graded” in graded potentials? Because their size, or *amplitude*, is directly proportional to the strength of the triggering event. A large stimulus creates a strong graded potential and a small stimulus creates a weak graded potential
When do graded potentials occur? Chemical signals from other neurons open chemically gated ion channels, allowing ions to enter or leave the neuron. Mechanical stimuli can also open some channels. Also, graded potentials can occur if channels close, e.g., K+
Local current flow The wave of depolarization that moves through the cell.
By convention, how is current measured As the net movement of positive electrical charge
The strength of the initial depolarization in a graded potential is determined by… …how much charge enters the cell -- E.g., if more Na+ channels open, more Na+ enters, and the initial amplitude is higher. The stronger the initial amplitude, the farther the graded potential can spread before dying out
Two reasons graded potentials lose strength as they move through the cytoplasm Current leak and cytoplasmic resistance
Current leak Some of the positive ions leak back across the membrane as the depolarization wave moves through the cell. The membrane in the neuron cell body is not a good insulator and has open leak channels
Cytoplasmic resistance The cytoplasm itself provides resistance to the flow of electricity, just as water creates resistance that diminishes the waves from the stone
Trigger zone If a graded potential is strong enough it will eventually reach the trigger zone. It’s the integrating center of the neuron and contains a high concentration of voltage-gated Na+ channels in its membrane.
Where is the trigger zone located? In efferent neurons and interneurons, it is the portion including the axon hillock and the very first part of the axon (the *initial segment*). In sensory neurons, it’s adjacent to the receptor, where the dendrites join the axon.
Ions typically involved in graded potentials Na+, Cl-, Ca^2+
Excitatory vs. inhibitory graded potentials Because depolarization makes a neuron more likely to fire an action potential, depolarizing graded potentials are considered excitatory. Conversely, hyperpolarizing graded potentials are inhibitory
Subthreshold graded potential A graded potential that is below the threshold by the time it reaches the trigger zone. Note: the initial stimulus may exceed the threshold, but as it travels along the neuron it dissipates below it by the time it reaches the trigger zone
Suprathreshold graded potential A graded potential that—while it still dissipates as it travels through the neuron—still exceeds the threshold potential by the time it reaches the trigger point
Excitability The ability of a neuron to respond rapidly to a stimulus and fire an action potential
Action potentials are AKA Spikes
Do action potentials diminish in strength as they move down a neuron? Unlike graded potentials they do not
Why are action potentials called all-or-none phenomena? Because they occur as a maximal depolarization (of about 100mV) only if the stimulus reaches the threshold. Otherwise they won’t occur at all.
An action potential measured at the distal end of an axon is identical to… … the action potential that started at the trigger zone
How do action potentials of PNS neurons differ from those of CNS neurons? The PNS is simple: action potentials require two types of channels (voltage-gated Na+ and K+) plus some leak channels to reach action potential. The CNS neurons are more complex showing different electrical behavior
What type of “different” electrical behavior is exhibited by CNS neurons that make their action potentials more complex? They fire in different patterns, sometimes not even requiring an initial stimulus. Some are *tonically active*: firing regular trains of action potentials, or they can be *bursting*: burst of action potential between resting periods
How are CNS neurons able to be so unpredictable and complex? The different firing patterns are created by ion channel variants that differ in their activation and inactivation voltages, kinetics, and sensitivity to neuromodulators.
Action potential steps in a PNS neuron: (1) The neuron is at its resting membrane potential of -70 mV
Action potential steps in a PNS neuron: (2) A graded potential begins to reach the trigger zone and depolarization results
Action potential steps in a PNS neuron: (3) The membrane depolarizes to threshold. Voltage-gated Na+ channels open, and Na+ flows in. K+ channels also begin to open, but slowly.
Action potential steps in a PNS neuron: (4) The cell is rapidly depolarized by the influx of Na+. So much that the polarity of the cell is reversed (represented by an overshoot on the graph) as the membrane potential is positive (+)
Action potential steps in a PNS neuron: (5) Na+ continue to enter the cell even though it’s positive because of its concentration gradient (equilibrium isn’t reached until +60 mV). However, Na+ influx stops because Na+ channels close at about +30 mV. K+ channels open
Action potential steps in a PNS neuron: (6) When K+ channels open, there is a K+ efflux out into the ECF
Action potential steps in a PNS neuron: (7) As K+ leave the cell, the cell eventually repolarizes to -70 mV, but K+ continues to leave, hyperpolarizing it a bit, approaching -90 mV. This is called the undershoot on the graph.
Action potential steps in a PNS neuron: (8) K+ channels now close and some of the K+ leaking stops. Na+ leaks in a bit, bringing the cell back up to its resting membrane potential of -70 mV.
Influx vs. efflux Words describing the Na+ influx into the cell and K+ efflux out of the cell during the action potential
How does the Na+ channel close during depolarization when the Na+ channel is initially opened due to depolarization? Shouldn’t a positive feedback loop ensue? The Na+ channel has two components: activation and inactivation gates. Upon depolarization the activation gate opens and the inactivation gate closes, but with a slight delay after activation
How are the activation and inactivation gates oriented on the channel protein? The activation gate is a “lever” within the passageway of the channel protein. The inactivation gate resembles a “ball-and-chain” on the cytoplasmic side of the channel protein.
Refractory period Once an action potential has begun, a second action potential cannot be triggered for about 2 msec, no matter how large the stimulus.
Absolute refractory period The 2 msec representing the time required for the Na+ channel gates to reset to their resting positions. Thus, action potentials cannot overlap and cannot travel backward
Relative refractory period Follows the absolute refractory period. A second action potential is inhibited but not impossible. A stronger-than-normal graded potential is required and any action potentials that fire will have smaller amplitude than normal?
The cause of the relative refractory period Not all of the Na+ channels are in their original positions yet. Those that aren’t, require more energy for activation. Also K+ channels are still open so the efflux of K+ will offset the influx of Na+, decreasing the action potential’s depolarization
NOTE: FOCUS ON ABSOLUTE AND REFRACTORY PERIODS DURING LECTURE BECAUSE IT’S TRICKY. AFTERWARDS, REVISE FLASH CARDS IF NECESSARY NOTE: FOCUS ON ABSOLUTE AND REFRACTORY PERIODS DURING LECTURE BECAUSE IT’S TRICKY. AFTERWARDS, REVISE FLASH CARDS IF NECESSARY
If all action potentials in a neuron are the same, how does the neuron transmit information about the strength and duration of the stimulus that started the action potential? Not by means of the amplitude but via the FREQUENCY of action potentials (#action potentials/sec)
Does a single graded potential trigger a single action potential? No; even a small graded potential that is above the threshold triggers a burst of action potentials. Hence, as the strength of graded potentials increase, the frequency of action potentials increase
The amount of neurotransmitter released from an axon terminal is directly related to… (exception?) …the total number of action potentials that arrive at the terminal per unit time. The exception is during sustained activity, neurotransmitter release may decrease because the axon cannot replenish its neurotransmitter supply
How many Na+ and K+ ions cross the membrane during an action potential? Not many. Remember: the amount of ions that must cross the membrane to depolarize/repolarize/hyperpolarize the membrane is very low.
How does the cell restore Na+ and K+ in the cell as the concentration gradients inevitably (but slowly) depart from homeostasis? With sodium-potassium pumps (Na+-K+-ATPase), using ATP to exchange Na+ that enters the cell for K+ that leaked out of it.
Does the sodium-potassium pump have to restore balance after every action potential? This exchange doesn’t have to happen before the next action potential because the concentration gradient wasn’t significantly altered by the action potential. A neuron without a sodium-potassium pump may still operate for a while
Conduction of an action potential The high speed movement of an action potential along the axon is called conduction of the action potential
Why do action potentials not lose strength over distances the way graded potentials do? Because in action potentials the flow of electrical energy is a process that constantly replenishes lost energy. I.e. the action potential that reaches the axon terminal is the action potential that started at the trigger zone
Action potential movement down an axon: (1) A graded potential above the threshold reaches the trigger zone
Action potential movement down an axon: (2) The depolarization opens voltage-gated Na+ channels, Na+ enters the axon, and the initial segment of the axon depolarizes.
Action potential movement down an axon: (3) Positive charge from the depolarized trigger zone spreads to the adjacent sections of membrane, repelled by the Na+ that entered the cytoplasm and attracted by the negative charge of the resting membrane potential
Action potential movement down an axon: (4) Conduction takes place as the positive charge flows across the axon toward the terminal. As the positive charges enter the more distal portion of the membrane, the membrane depolarizes and opens more Na+ channels
Action potential movement down an axon: (5) The refractory period prevents backward conduction. Loss of K+ repolarizes the membrane. As the signal moves forward toward the axon terminal, it maintains its strength as more ions are pumped into the axon
What happens to current flow backward from the trigger zone into the cell body? By interacting with voltage-gated ion channels in the cell body they play a part in influencing and modifying the next signals that reach the cell
Two key physical parameters influence the speed of action potentials: (1) the diameter of the axon (larger = faster), and (2) the resistance of the axon membrane to ion leakage out of the cell (more leak-resistant = faster)
How does a larger diameter equate to faster conduction? Like a large pipe wherein a larger diameter means a smaller fraction of fluid is coming into contact with the walls = less friction exerted, in large axons a smaller fraction of charge experiences resistance from the membrane
Compare a giant squid axon with a mammalian axon Giant squid axons can be very large, up to 1 mm in diameter, whereas mammalian axons are very small: 200 mammal axons can fit in a giant squid’s. Conduction speed is still the same because mammals use myelin sheaths
How do myelin sheaths change conduction of action potentials? They prevent ions of leaking out of the axons which increases the speed of conduction. The resultant influx of Na+ ions as the action potential proceeds down the axon occurs only in the nodes of Ranvier, where the membrane meets ECF
Saltatory conduction On myelinated axons there is a high concentration of sodium channel proteins in the nodes of Ranvier which reinforce the depolarization. The apparent jump of action potential from node to node is called saltatory conduction
Multiple sclerosis A demyelinating disease characterized by a variety of symptoms including muscle weakness, difficulty walking, loss of vision, etc.
What happens if Na+ channels are inhibited (e.g. by a neurotoxin or local anesthetic) in a neuron? Then the Na+ channels can’t open and won’t be able to produce an action potential with the capability to travel down the axon.
What happens if K+ levels of the blood are too high? An increase in blood K+ concentration, *hyperkalemia*, shifts the resting membrane potential closer to threshold, causing cells to fire action potentials in response to smaller graded potentials
What happens if K+ levels of the blood are too low? If blood K+ concentration falls too low, known as *hypokalemia*, the resting membrane potential of the cell hyperpolarizes, moving farther from the threshold. Thus graded potentials normally able to trigger action potentials wont
Symptoms of hypokalemia Muscle weakness due to the fact that neurons that control skeletal muscles are not firing normally
The logic behind Gatorade and similar sport drinks To replenish ions such as Na+ and K+ to prevent hyponatremia (low Na+) and hypokalemia due to loss of ions in sweat. If just water is consumed it might result in too dilute ionic solutions in the blood
Two parts of a synapse The (1) axon terminal of the presynaptic cell and the (2) membrane of the postsynaptic cell
Are postsynaptic cells always neurons? No, not always. Postsynaptic cells can be neurons or non-neuronal cells
If neuron-to-neuron synapses, where are the axons situated? Typically they’re next to either the dendrites or the cell bodies of the postsynaptic neurons
How many synapses might a single neuron have? A moderate number is 10,000. Some neurons in the CNS will have in excess of 150,000 synapses on their dendrites!! Note: An adult has an average of 100 – 500 trillion synapses. Way more than stars in our galaxy
Synapses are classified as _____ or _____ Electrical; chemical
Electrical synapses Pass an electric signal, or current, directly from the cytoplasm of one cell to another through gap junctions.
Which directions can electrical currents flow through electrical synapses In both directions in MOST synapses. But in some, current can only flow in one direction; those are known as *rectifying synapses*
Where are electrical synapses found? Mainly in the neurons of the CNS. They’re also found in glial cells, in cardiac and smooth muscle cells, and in nonexcitable cells that use electrical signals, such as the pancreatic beta cell.
Primary advantage of electrical synapses? The rapid conduction of signals from cell to cell that synchronizes activity within a network of cells
The vast majority of synapses in the nervous system are _____ synapses Chemical
Chemical synapses Synapses in which neurotransmitters carry information from one cell to the next. The electrical signal within the presynaptic cell is converted to a chemical signal that crosses the synaptic cleft to its target
What happens when the neurotransmitter binds to a receptor on its target? The postsynaptic cell either initiates an electrical response (very rapid) or activates a second messenger pathway (a slower response)
Where does neurotransmitter synthesis take place? Either in the nerve cell body or the axon terminal
How are neurotransmitters made in the axon terminal if there are no ribosomes located there? Enzymes made in the cell body travel to the axon terminal via slow axonal transport
How neurotransmitters which are made in the cell body are transported to the axon terminals? They’re sent in vesicles by fast axonal transport
Looking at an axon terminal under an electron microscope, what would you see? Mitochondria and a lot of vesicles which contain neurotransmitters. The vesicles are docked at active zones along the membrane closest to the synaptic cleft waiting to be released. Other vesicles will act a reserve pool as well
How does the release of neurotransmitters into the synaptic cleft take place? By exocytosis
Roughly, how do neurotoxins such as tetanus and botulinum work? They exert their action by inhibiting specific proteins of the cell’s exocytotic apparatus
The vesicles near the synapse in the axon terminal of the presynaptic neuron which contain neurotransmitters can be known as Synaptic vesicles
Information transfer at the synapse: step (1) An action potential depolarizes the axon terminal
Information transfer at the synapse: step (2) The depolarization opens voltage-gated Ca^2+ channels and Ca^2+ enters the cell
Information transfer at the synapse: step (3) Calcium entry triggers exocytosis of synaptic vesicle contents. Note: calcium ions are more concentrated in the ECF so they diffuse into the cell. They bind to regulatory proteins that initiate exocytosis
Information transfer at the synapse: step (4) Neurotransmitter diffuses across the synaptic cleft and binds with the receptors on the postsynaptic cell
Information transfer at the synapse: step (5) Neurotransmitter binding initiates a response in the postsynaptic cell
Classic model of exocytosis: How is the increase in surface area by the constant fusing of the synaptic vesicles with the axon terminal membrane offset? The increase in membrane surface area is countered by endocytotic recycling of the vesicles at regions away from the active sites.
Kiss-and-run pathway of exocytosis Instead of the classic model, synaptic vesicles fuse with the membrane at a complex called the *fusion pore* where a small channel is opened just enough for neurotransmitters to flow through, then the vesicle pulls back to the pool
What are the neurocrine signal molecules that neurons release from their axon terminals? Neurotransmitters, neuromodulators, or neurohormones. Neurotransmitters and neuromodulators act as paracrine signals, with targets close to the neuron. Neurohormones, conversely, are secreted into the body and distributed throughout
Where do neurotransmitters and neuromodulators act? Generally neurotransmitters act at a synapse and elicit a rapid response. Neuromodulators act at both synaptic and non-synaptic sites and are slower acting. Some neurotransmitters and neuromodulators act as autocrine signals
Seven classes of neurocrines according to their structure (1) acetylcholine, (2) amines, (3) amino acids, (4) peptides, (5) purines, (6) gases, and (7) lipids
Which neurocrines does the CNS release? Many different neurocrines, including all of those within the major classes (excluding the gases) as well as numerous peptides that can act as neurocrines
Which neurocrines does the PNS release? The PNS only secretes three major neurocrines: acetylcholine (neurotransmitter), norepinephrine (neurotransmitter), and epinephrine (neurohormone)
(1) Acetylcholine (ACh) A chemical class by itself – it’s synthesized by acetyl CoA and choline. The synthesis from these two precursors is a simple enzymatic reaction that occurs in the axon terminal.
Choline A small molecule found in membrane phospholipids
Neurons that secrete ACh are known as _____ neurons Cholinergic
(2) Amines Derived from single amino acids: dopamine, norepinephrine, and epinephrine are all derived from tyrosine; serotonin is derived from tryptophan; and histamine is made from histadine
Dopamine, norepinephrine, and epinephrine function as neurohormones when secreted from _____ The adrenal medulla
Neurons that secrete norepinephrine are called _____ neurons Adrenergic AND, more properly known as, noradrenergic. Note: adrenergic is used as convention, but remember that they should really be called noradrenergic because they secrete NOREPINEPHRINE.
Why do we use the term “adrenergic”? Adrenaline is the British name for epinephrine. Early researchers thought epinephrine was secreted, when in fact it is norepinephrine
(3) Amino acids At least four amino acids function as neurotransmitters in the CNS: glutamate, aspartate, gamma-aminobutyric acid (GABA), and glycine
Brief description of the function of amino acid neurotransmitter: glutamate The primary excitatory neurotransmitter of the CNS. Note: their receptors are called glutaminergic receptors
Brief description of the function of amino acid neurotransmitter: aspartate Serves the same function as glutamate (excitatory neurotransmitter) but in selected regions of the brain
Brief description of the function of amino acid neurotransmitter: GABA Gamma-aminobutyric acid is the main inhibitory neurotransmitter in the brain
Brief description of the function of amino acid neurotransmitter: glycine The primary inhibitory neurotransmitter of the spinal cord. It also potentiates the excitatory effects of glutamate at one type of glutamate receptor
(4) Peptides Numerous peptides are secreted in the nervous system including: substance P, the opioid peptides, and peptides that function as both neurohormones and neurotransmitters (3 of them, they’re listed on another FC)
Peptide neurotransmitters: substance P A peptide neurotransmitter involved in some pain pathways
Peptide neurotransmitters: opioid peptides Enkephalins and endorphins, they mediate pain relief, i.e. “*analgesia*”.
Peptide neurotransmitters: those that function as both neurohormones and neurotransmitters Cholecystokinin (CCK), vasopressin, and atrial natriuretic peptide
Are peptide neurotransmitters secreted by themselves? Actually many peptide neurotransmitters are cosecreted with other neurotransmitters
(5) Purines Adenosine, adenosine monophosphate (AMP), and adenosine triphosphate (ATP), collectively known as purines, can all act as neurotransmitters.
What receptors do purines bind to? They bind to purinergic receptors in the CNS and on other excitable tissues such as the heart
(6) Gases Nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S) can serve as neurotransmitters
NO as a neurotransmitter NO is synthesized by oxygen and the amino acid arginine. As a neurotransmitter it diffuses freely into a target rather than binding to a receptor. Once inside, NO binds to receptors. Has a very short half-life.
Do only neurons release NO? No, other types of cells may release NO to serve as a paracrine signal
(7) Lipids Lipid neurocrines for example include eicosanoids, including those that are endogenous ligands for cannabinoid receptors (known as endocannabinoids)
Where are cannabinoid receptors found? CB_1 cannabinoid receptor is found in the brain; CB_2 cannabinoid receptor is found on immune cells
From where is the name “cannabinoid” receptor derived? They were named for one of their EXOGENOUS ligands, delta^9-tetrahydrocannabinoid (THC), which comes from the plant Cannabis sativa, more commonly known as marijuana. It can bind to CB_1 and CB_2 receptors
All neurotransmitters except _____ bind to one or more receptor types Nitric oxide
How might one neurotransmitter have different effects on different neurons? Each receptor to which a particular neurotransmitter can bind may have multiple subtypes, allowing one neurotransmitter to have different effects in different tissues.
How are the multiple receptor subtypes distinguished? By a combination of letter and number subscripts. E.g., serotonin (5-HT) has at least 20 receptor subtypes that have been identified, including 5-HT_1A and 5-HT_4
The two membrane receptor categories that neurotransmitter receptors fall into Ligand-gated ion channels and G protein-coupled receptors (GPCR)
Ionotropic receptors Receptors that alter ion channel function
Metabotropic receptors Receptors that work through second messenger systems. Note: Some Metabotropic GPCRs regulate the opening or closing of ion channels
Two advances that have greatly simplified the study of neurotransmitters (1) the genes for many receptor subtypes have been cloned, allowing researchers to create mutant receptors and study their properties; and (2) many agonists and antagonists have been synthesized that mimic them
Two main subtypes of cholinergic receptors Nicotinic (named because nicotine is an agonist) and muscarinic (for which muscarine, a compound found in some fungi, is an agonist
Cholinergic nicotinic receptors Found in skeletal muscle, autonomic PNS, and CNS. They’re monovalent cation channels through which both Na+ and K+ can pass. Na+ entry exceeds K+ exit, ergo the net positive charge depolarizes the cell to fire action potentials
Cholinergic muscarinic receptors They come in five subtypes. They’re all coupled to G proteins and are linked to second messenger systems. The tissue response to activation of a muscarinic receptor varies with the subtype. They occur in the CNS and autonomic PNS
Adrenergic receptors Divided into two classes: alpha and beta, with multiple subtypes of each. They’re all linked to G proteins that initiate second messengers
What’s the difference between the two classes of adrenergic receptors? They work through different second messenger pathways
Glutaminergic receptors The action of glutamate at a particular synapse depends on which of its receptor types are on the target: the (1) metabotropic glutaminergic receptor, or the (2) ionotropic glutaminergic receptor
Metabotropic glutaminergic receptor Glutamate receptors that work through GPCR
Ionotropic glutaminergic receptors (1) NMDA, named for the glutamate agonist N-methyl-D-aspartate, and (2) AMPA receptors, named for their agonist alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid
AMPA receptors Ligand-gated monovalent cation channels similar to nicotinic acetylcholine channels. Glutamate binding opens the channel, and the cell depolarizes due to the Na+ influx
NMDA receptors They’re unusual. Why? (1) they’re cation channels that let Na+, K+, and Ca^2+ to pass; (2) channel opening required both glutamate binding AND change in membrane potential
How are NMDA receptors opened? Mg^2+ is normally blocking the entrance, so even when the gate is opened after glutamate binds to it, ions can’t flow past Mg+. Once membrane potential changes, Mg^2+ dislodges, and ions can flow through
Review: synthesis and recycling of acetylcholine at a synapse (1) ACh is made from acetyl-CoA and choline. (2) In the synaptic cleft, ACh that didn’t bind to receptors are broken down by acetylcholinesterase to choline/acetate. (3) Choline is recycled back into the axon terminal
Myasthenia Gravis Autoimmune disease in which the body attacks cholinergic receptors. Severe muscle weakness ensues
Fast synaptic potential Neurotransmitter binds to receptor-channel on postsynaptic cell, ions flow in from ECF, the resulting change in membrane potential is called a fast synaptic potential because it begins quickly and lasts only a few milliseconds
Excitatory postsynaptic potential (EPSP) If the synaptic potential is depolarizing, it is called an EPSP because it makes the cell more likely to fire an action potential.
Inhibitory postsynaptic potential (IPSP) If the synaptic potential is hyperpolarizing, it’s called an IPSP because hyperpolarization moves the membrane potential farther from threshold and makes the cell less likely to fire an action potential
Slow synaptic potentials Neurotransmitters bind to GPCR’s linked to second-messenger systems. The second messenger may act from the cytoplasmic side of the cell to open/close ion channels, whereas fast synaptic potentials always open them
Is the response of slow synaptic potentials the same as fast synaptic potentials? No, the response lasts longer, usually seconds to minutes
Are slow postsynaptic responses limited to altering the open state of ion channels? No, second-messenger systems may also modify existing cell proteins or regulate the production of new proteins. This type of slow response has been linked to the growth and development of neurons and to memory
Unbound neurotransmitters much be cleared out of the synaptic cleft very quickly. What are the three ways through which this is accomplished? (1) They’re returned to the axon terminal or sent into nearby glial cells; (2) Enzymes inactivate them (e.g., acetylcholinesterase); and (3) unbound neurotransmitters simply diffuse out of the synaptic cleft
What happens to unbound norepinephrine in the synaptic cleft? They’re actively transported back into the axon terminal where they’re either (1) repackaged into vesicles, or (2) broken down by intracellular enzymes such as monoamine oxidase (MAO) found in mitochondria
Note: MAO inhibitors Used for the treatment of depression. It inhibits MAO which decreases the breakdown of monoamine neurotransmitters such as serotonin, epinephrine, melatonin, etc.
Divergence Communication between neurons is not always a one-to-one event. Frequently a single presynaptic neuron branches, and its collaterals synapse on multiple target neurons. This pattern is known as divergence.
Convergence When a group of presynaptic neurons provide input to a smaller number of postsynaptic neurons, the pattern is known as convergence
Magnitude of synapses a cell can have A combination of convergence and divergence can allow a single neuron to have synapses from as many as 10,000 presynaptic neurons.
Example of a type of neuron that is normally highly branched Purkinje neurons of the CNS
Synaptic plasticity Modulation of activity at synapses. Modulation may enhance activity at the synapse (facilitation or potentiation), or it may decrease activity (inhibition or depression). Changes can be short or long term.
When two or more presynaptic neurons converge on the dendrites or cell body of a single postsynaptic cell, the response of the postsynaptic cell is determined by… …the summed input from the presynaptic neurons
What will happen if a large number of presynaptic neurons send subthreshold EPSP’ to the cell body or dendrites of a single postsynaptic neuron? They might all sum up at the trigger zone to equal a suprathreshold graded potential that will elicit an action potential
Spatial summation The initiation of an action potential from several nearly simultaneous graded potentials is an example of spatial summation (“special” referring to the fact that the graded potentials originate at different locations, i.e. “spaces”)
Postsynaptic inhibition May occur when a presynaptic neuron releases and inhibitory neurotransmitter onto a postsynaptic cell and alters its response. E.g., an IPSP can counteract two EPSP’s to cause the sum to be a subthreshold potential
Temporal summation When a single presynaptic neuron sends multiple graded potentials through another neuron, if they’re sent close enough to each other in time they may overlap and sum to create a larger graded potential
Postsynaptic integration The combination of temporal and spatial summations of all ESPS’s and ISPS’s will determine whether an action potential is initiated
Presynaptic modulation When a modulatory neuron (inhibitory or excitatory) terminates on or close to an axon terminal of a presynaptic cell, its EPSP or IPSP can alter the action potential reaching the terminal and create presynaptic modulation
Presynaptic inhibition If activity in the modulatory neuron decreases neurotransmitter release, the modulation is called presynaptic inhibition
Presynaptic facilitation Modulatory input increases neurotransmitter release by the presynaptic cell
_____ modulation provides a more precise means of control than _____ modulation. Why? Presynaptic; postsynaptic. Why? In postsynaptic modulation, all target cells of the postsynaptic neuron are altered.
Other than postsynaptic and presynaptic modulation, how else can synaptic activity become modulated? By changing the responsiveness of the target cell to neurotransmitter. E.g., by changing the identity, affinity, or number of neurotransmitter receptors.
How does a neuron change the responsiveness of a target cell to a neurotransmitter? Neuromodulators can act through second messenger systems to influence the synthesis of enzymes, membrane transporters, and receptors
Long-term potentiation (LTP) and long-term depression (LTD) Processes in which activity at a synapse brings about sustained changes in the quality or quantity of synaptic connections.
A key element in long-term changes in the CNS is… …the amino acid glutamate, the main excitatory neurotransmitter in the CNS
Long-term potentiation Glutamate is released. Net Na+ entry through AMPA depolarizes cell. Mg^2+ is ejected from NMDA and Ca*2+ flows in. Cell becomes more sensitive to glutamate via up-regulation. Paracrine signals enhance glu release
Long-term depression In the face of continued neurotransmitter release by presynaptic neuron, the postsynaptic neuron withdraws AMPA receptors (endocytosis) and inserts different subunits into AMPA receptors, changing flow
How does something as complex as the human brain develop to be so organized? Chemical signals used by the developing embryo, ranging from factors that control differentiation of stem cells to those that direct an elongating axon to its target
Growth cones The axons of embryonic nerve cells send out special tips called growth cones that extend through the extracellular compartment until they find their target cell by “sniffing” out their chemical scent.
What kinds of signals do growth cones depend on to find their targets? Growth factors, molecules in the extracellular matrix, and membrane proteins on the growth cones and on cells along the path; e.g., integrins on the growth cone membrane bind to laminins, protein fibers in the matrix.
The survival of neurons depends on _____ Neurotrophic factors secreted by neurons and glial cells. They’re proteins that are responsible for the growth and survival of developing and mature neurons
What happens if a synapse isn’t being used? That is, no neurotransmitters are being secreted? The synapse will disappear. “Use it or lose it”. Note: this is why children deprived of sensory input will experience delayed development. This is also why adults are urged to keep learning and socializing
If the cell body of a neuron dies during injury then… …the entire neuron dies.
If the cell body survives, but the axon is severed during injury… Describe the process …most of the cell still survives. Membrane seals up the wound. Chemical factors produced by Schwann cells near the injury site move by retrograde transport to the cell body, telling it that injury has occurred
What happens to the distal end of the axon that has been severed in the injury? The myelin unravels itself and the remaining fragments are cleared away by scavenger microglia or phagocytes that ingest and digest the debris
If regeneration does occur, describe the process Schwann cells of the damaged neuron secrete certain neurotrophic factors that keep the cell body alive and stimulate regrowth of the axon. The regrowth behaves similar to a growth cone, following a series of signals.
What usually occurs after injury, regeneration? Unfortunately regeneration is rare, especially in the CNS. CNS glial cells will seal off and scar the damaged region, and CNS cells secrete factors that will inhibit axon regrowth.
Action potential velocity 200 m/sec on average
Gray matter AKA neuropil
Gray vs. white matter White matter = myelinated
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