Exam 3 Add-on: up to 10 possible bonus points 1. Neurons use electrical and chemical signaling to pass information along specific routes (circuits) in the CNS and PNS. Within an individual neuron, most information flow is unidirectional, proceeding from the dendrites to the cell body, then to the initial segment of the axon (trigger zone), and finally to the synaptic end bulb. Describe the processes, molecule-types, and specific ions that support this unidirectional flow of information in the neuron. Start with the neuron at rest and explain what happens when it is stimulated by neurotransmitter at its dendrites. (Complete in 2-3 paragraphs). Try to use all of the following terms in your response: PROCESSES: resting membrane potential; graded potential; depolarization; hyperpolarization; summation; action potential MOLECULE TYPES: lipids; leak channels; Na+/K+ ATPase; ligand-gated channels; voltage-gated channels IONS: organic anions (inside the neuron); Cl-; Na+; K+ A neuron’s dendrites and cell body can be bombarded with thousands of depolarizing and hyperpolarizing graded potentials, all of which are summed Action potentials are regenerative – they do not decay or dissipate with time and distance from source Ensures ‘one-way’ communication down the axon to the axon terminal Overview of an Action Potential Resting Phase • Em = -70 mV • All voltage-gated Na+ and K+ channels are closed at resting potential Depolarizing Phase • Em = -55 mV • Na+ channels open, buildup of positive charges – Membrane is depolarized • AP goes, membrane potential reaches +30 mV Repolarizing Phase • Em = +30 mV • Na+ channels inactivate • K+ channels open. • Membrane starts to repolarize Repolarizing Phase continues • Em = -95 mV • K+ outflow continues • Na+ channels still inactivated • Membrane repolarizes After-hyperpolarizing phase • Em = -95 mV • K+ outflow continues; channels eventually close • Membrane potential returns to -70 mV Refractory Period Absolute refractory period Relative refractory period 16 Action Potentials Propagate from the Trigger Zone to Axon Terminals 17 Refractory period ensures one-way propagation 18 Action Potentials are All-Or-None phenomena 19 If APs are All-Or-None, how do they encode stimulus intensity? 20 Stimulus Strength and AP Frequency Code Copyright 2010 John Wiley & Sons, Inc. 21 What are the factors that influence speed of AP conduction? ◼ ◼ ◼ Temperature Diameter of axon: larger diameter → faster conduction Myalination vs. non-myalination Copyright 2010 John Wiley & Sons, Inc. 22 Continuous conduction Unmyelinated fibers ❑ step-by-step depolarization of each portion of the length of the axon 23 Saltatory conduction Myelinated fibers ❑ Depolarization at nodes of Ranvier ❑ high density of voltage-gated Na+ channels 24 Encoding of stimulus intensities Frequency of action potentials Sensory neuron activation – more receptors activated leads to more neurons being activated 25 Synapse – site of interaction between 2 neurons or between a neuron and an effector cell Pre-synaptic neuron sends signal Skeletal muscle Post-synaptic neuron receives signal 26 2 Types of synapses ❑ electrical ◼ ◼ ❑ ionic current spreads to next cell through gap junctions faster, two-way transmission & capable of synchronizing groups of neurons chemical ◼ one-way information transfer from a presynaptic neuron to a postsynaptic neuron 27 Chemical Synapses 1 Nerve impulse Presynaptic neuron 2 Ca2+ Ca2+ Voltage-gated Ca 2+ channel Synaptic end bulb Cytoplasm Synaptic vesicles Synaptic cleft Postsynaptic neuron 28 Chemical Synapses 1 Nerve impulse 2 Ca2+ Ca2+ Voltage-gated Ca 2+ channel Synaptic end bulb Cytoplasm Synaptic vesicles Synaptic cleft Ca2+ 3 29 Chemical Synapses 1 Nerve impulse 2 Ca2+ Ca2+ Voltage-gated Ca 2+ channel Synaptic end bulb Cytoplasm Synaptic vesicles Synaptic cleft Ca2+ 3 Neurotransmitter receptor Neurotransmitter Na+ 4 5 Ligand-gated channel closed 6 Postsynaptic potential Ligand-gated channel open 7 Nerve impulse 30 Excitatory and Inhibitory Postsynaptic Potentials ◼ The effect of a neurotransmitter can be either excitatory or inhibitory ❑ a depolarizing postsynaptic potential is called an EPSP ◼ ◼ ❑ it results from the opening of ligand-gated Na+ channels the postsynaptic cell is more likely to reach threshold an inhibitory postsynaptic potential is called an IPSP ◼ ◼ ◼ it results from the opening of ligand-gated Cl– or K+ channels it causes the postsynaptic cell to become hyperpolarized the postsynaptic cell is less likely to reach threshold 31 Summation 32 Removal of Neurotransmitter ◼ Diffusion out of the synaptic cleft ❑ ◼ Enzymatic degradation ❑ ◼ Acetylcholinesterase (AChE) Reuptake by neurons ❑ ◼ move down concentration gradient Receptor-mediated endocytosis Uptake by neuroglia ❑ Neurotransmitter transporters 33 Damage and repair of neurons ❑ CNS ◼ ◼ ◼ ◼ Extremely little to no repair in the brain and spinal cord Injury to the brain and spinal cord is usually permanent Scar tissue is a barrier to regeneration Structure of myelin sheath/oligodendrocytes 34 Repair within the PNS ◼ Damage to dendrites or axons 35 Ch 12: Introduction to the Nervous System ◼ Sensory function: to sense changes in the internal and external environment through sensory receptors. ❑ Sensory neurons ◼ Integrative function: to analyze the sensory information, store some aspects, and make decisions regarding appropriate behaviors. ❑ Interneurons ◼ Motor function: to respond to stimuli by initiating action. ❑ Motor neurons 1 Nervous System Divisions: CNS and PNS ◼ Central nervous system (CNS) ❑ consists of the brain and spinal cord ◼ Peripheral nervous system (PNS) ❑ ❑ consists of cranial and spinal nerves that contain both sensory and motor fibers connects CNS to muscles, glands & all sensory receptors 2 Organization of the Nervous System Copyright 2010 John Wiley & Sons, Inc. 3 Cells of the nervous system 4 Structure of a Motor Neuron Cell body Axon Dendrites Axon terminal Synaptic end bulb 5 Detail of the Cell Body Initial segment Axon hillock (trigger zone) Dendrites Nucleus Nissl bodies 6 Functional Classification of Neurons A. Sensory neurons are afferent neurons. The information is carried from the PNS into the CNS DENDRITES AXON Myelin sheath CELL BODY AXON TERMINAL 7 Some afferent neurons have modified dendrites Dendrite (corpuscle of touch) 8 Functional Classification of Neurons B. Motor neurons are called efferent neurons. The information is carried away from the CNS 9 Functional Classification of Neurons C. Interneurons are in the CNS, integrate sensory information and elicit a motor response Interneuron Sensory neuron Motor neuron 10 Neuroglia of the CNS Covering around brain Microglial cell Oligodendrocyte Myelin sheath Neuron Blood capillary Astrocytes Neurons Ventricle Ependymal cell 11 Schwann Cells: Neuroglia of the PNS Myelinated axon Unmyelinated axons axons Schwann cell Schwann cell Neurolemma axon Myelin sheath 12 Formation of Myelin Sheaths Nucleus Cytoplasm Axon Myelin sheath 13 Multiple Sclerosis – disease of the CNS 14 Two types of neuronal tissue: gray and white matter ◼ White matter – primarily myelinated axons ◼ Gray matter – neuronal cell bodies, dendrites, unmyelinated axons, axon terminals, neuroglia. ❑ Nissl bodies cause gray color. 15 Neuron Communication ◼ Neurons are electrically excitable ❑ ◼ Changes in voltage alters function Two basic features allow communication ❑ ❑ Presence of ion channels – flow of ions is electrical current in a biological system Resting membrane potential – electrical potential difference (voltage) across the plasma membrane 16 The resting potential is a small build-up of charges on either side of the neuronal cell membrane Copyright 2010 John Wiley & Sons, Inc. 17 The resting potential is generated by three features of neuronal cell biology Copyright 2010 John Wiley & Sons, Inc. 18 Resting potential exists over the entire surface of a neuron – input occurs at dendrites/cell body Cell body Axon Dendrites Axon terminal Synaptic end bulb 19 Input is mediated by ligand-gated channels Copyright 2010 John Wiley & Sons, Inc. 20 Input is mediated by mechanically-gated channels Copyright 2010 John Wiley & Sons, Inc. 21 Ion flow through gated channels alters the resting potential, causing graded potentials Copyright 2010 John Wiley & Sons, Inc. 22 Ion flow through gated channels alters the resting potential, causing graded potentials Copyright 2010 John Wiley & Sons, Inc. 23 Graded Potentials ◼ Hyperpolarizing or depolarizing ◼ Localized changes in membrane potential (opening of channels) ❑ ◼ Ligand-gated and mechanically gated channels They can generate an action potential 24 Stimulus strength Membrane potential in millivolts (mV) Graded potentials vary in amplitude (size) Resting membrane potential Stimulus 3 Stimulus 2 Stimulus 1 Time in milliseconds (msec) 25 Neuron Communication ◼ Two types of electric signals ❑ ❑ graded potentials that are local membrane changes only action potentials that can travel long distances graded potential action potential 26 Summation of graded potentials can generate an action potential (AP) • 2 stimuli occur close together in time means larger depolarizing potential. 27 An AP is an all-or-nothing electrical signal ◼ A sequence of rapidly occurring events ❑ depolarizing phase ❑ repolarizing phase ◼ Voltage-gated Na+ and K+ channels open in sequence ◼ If a stimulus reaches threshold, the AP is always the same. ❑ A stronger stimulus will not cause a larger impulse. 28 ◼ Action potential ◼ Read the section in your textbook about action potentials ◼ Visit khanacademy.org and watch the video on electrotonic potentials and action potentials ❑ Khan academy terminology: electrotonic potential = graded potential 29 Neuronal  Excitability  and  Communication  (Chapter  12)   BIOL212,  S.  Raft   What is an electrochemical gradient? For our purposes, we can define ions as charged particles (atoms) that exist in a solvent (water). Ions can have either a positive or negative charge. Ions in a solvent are free to move as long as there are no barriers (insulators or other physical obstructions). Movement or flow of ions in biological systems is like the flow of electrons along a copper wire in an electrical device: both are examples of current. Unobstructed, ions of a particular type – say sodium ions (Na+) - will generally move from a region of high Na+ concentration to a region of low Na+ concentration, and will continue to do so until the Na+ concentration is uniform throughout the region of interest; this is called movement down a concentration or chemical gradient (let’s stick with the term chemical gradient here). Unobstructed, ions will also move in such a way as to maximize their distance from ions of like charge and minimize their distance from ions of opposite charge (likes repel; opposites attract); this will continue until the solution is net neutral in charge. This is called movement down an electrical gradient. When many types of ions co-exist in a single system (as is always the case in biology) we must put these two concepts together. We say that - without input of energy into a system – ions always move down their electrochemical gradient. This involves net movement of a particular ion until its chemical and electrical gradients are at equilibrium, when the force of a chemical gradient is exactly balanced by the force of an electrical gradient. Unusual things can happen when chemical and electrical gradients interact before reaching equilibrium. For example, if a concentration gradient of potassium ions (K+) is very steep and an electrical gradient (in the opposite direction) is very small, we might see net movement of K+ ions toward a region of positive charge! In this case, the concentration gradient overwhelms the force of the electrical gradient, and the movement of K+ toward the more positive region will continue until the two forces (electrical and chemical) balance one another exactly. What is a resting potential? Both extracellular (interstitial) and intracellular (cytosol) fluids contain a complex mixture of ions and are net neutral in charge (see Fig. 12.11a and 12.12 in your textbook). Furthermore, extracellular and intracellular fluids always have different compositions of ions. This is because: 1) cells have many active (energy-dependent) mechanisms for controlling the types of ions present in the cytoplasm; and 2) the cell membrane (lipid bilayer) is a barrier to movement of ions (it is a good electrical insulator). But the cell membrane is not a perfect insulator and ions of opposite charge can attract one another across the lipid bilayer even though their movement is obstructed by it. This results in a small buildup of opposite charges on either side of the cell membrane. In neurons at rest (not stimulated by input) this small buildup of opposite charges on either side of the cell membrane is called the resting potential. It is called the resting potential because a small voltage is established   1   Neuronal  Excitability  and  Communication  (Chapter  12)   BIOL212,  S.  Raft   across the cell membrane and voltage is a form of potential energy. In most neurons the resting potential is around -70 mV (millivolts); negative voltage indicates that the charge at the inner (cytoplasmic) side of the membrane is negative relative to the outer (extracellular) side of the membrane. We can think of the resting potential as a ground state on which the code for neural communication is built. How is the resting potential generated? Neuron cytoplasm has high concentrations of potassium (K+) cations (positive ions) and organic anions (negative ions). By ‘organic’, we mean that much of the negative charge in the cytosol is due to negative charges on phosphate groups (e.g., on ATP) and amino acid side chains. There are comparatively low concentrations of K+ and organic anions in the extracellular fluid. By contrast, extracellular fluid in the nervous system has high concentrations of Na+ cations and chloride (Cl-) anions. There are comparatively low concentrations of Na+ cations and Cl- anions in the neuron cytoplasm The origin of differences in ionic concentrations between neuronal cytoplasm and extracellular fluid is a complex topic beyond the scope of this course. However you are required to understand that these concentration differences are a pre-condition for generation of the neuron resting potential (as well as for generation of the graded potential and action potential). What you do need to know is that, given these concentration differences, three features of neuronal cell biology explain the generation of the resting potential (you should refer to Fig. 12.12 in your textbook): First, the neuronal cell membrane has so-called leak channels: these are cationselective protein pores that allow either Na+ or K+ to cross from one side of the membrane to the other. Leak channels are open all the time, and the neuron has many more K+ leak channels than Na+ leak channels. This means that at rest, the neuronal membrane is far more permeable to K+ than to Na+. Since K+ is able to leak out of the neuron (down its concentration gradient) faster than Na+ can leak in (down its concentration gradient), some extra positive charge is deposited on the outer surface of the neuronal membrane. Second, the neuronal cell membrane is completely impermeable to organic anions, the major class of negative charges in the neuronal cytoplasm. This means that a negative charge can’t ‘follow’ the leak of K+ out of the neuron. Again, this contributes to the inside of the membrane being more negative and outside being more positive. Third, the neuron has many sodium-potassium pumps in its cell membrane. The sodium-potassium pump actively (in an energy-dependent manner) and continuously exports three Na+ ions from cytoplasm to extracellular fluid while importing two K+ ions from the extracellular fluid to the neuronal cytoplasm. This unequal transfer of ions causes a net   2   Neuronal  Excitability  and  Communication  (Chapter  12)   BIOL212,  S.  Raft   charge of +1 to be sent out of the neuron each time the pump cleaves one ATP molecule (and it cleaves a lot of ATP). You must understand these three features as causing the resting potential. What causes a graded potential? All neurons receive input, either from other neurons or from the external/internal environment. External/internal sensory input is received at the dendrites or modified dendrites of a sensory neuron. Input from other neurons (to interneurons or motor neurons) is received at the dendrites or the neuronal cell body. Input may take the form of physical deformation (e.g., stretch, pressure, etc) or a chemical signal (e.g., a neurotransmitter released by another neuron). At the dendrites or cell body, physical deformation is mediated by mechanically-gated channels, while chemical signals are mediated by ligand-gated channels. Gating (opening) of either channel type in response to stimuli results in a selective (Na+ or K+ or Cl-) flow of ions through the channel and down the ion’s electrochemical gradient. In other words, there is a localized current across the neuronal cell membrane and a spatially localized alteration of the resting membrane potential. This spatially localized alteration of the resting membrane potential at the dendrites or cell body and in response to a stimulus causes graded potentials. Therefore, graded potentials are the immediate response of neurons to a stimulus. What are the characteristics of graded potentials? Up to this point, we have learned that opening of mechanically- or ligand-gated channels at the dendrites or cell body in response to stimuli causes a very brief and localized flow of current across the neuronal cell membrane. Current flow relies on differential concentrations of ions in the intracellular and extracellular fluids. The current flow has a transient and localized effect on the separation of charge at either side of the neuronal cell membrane; in other words, current flow influences the resting potential (see Fig. 12.13). If the gating of channels allows a selective flow of Na+ ions, positive charge will flow into the cell, because Na+ will flow down its chemical gradient (remember, more Na+ outside) and down its electrical gradient (Na+ will flow toward the buildup of negative charge on the inside of the resting cell membrane). This will locally (where the channels opened) alter the resting potential by making the inner surface of the cell membrane more positive relative to the outer surface (see Fig. 12.15b in your textbook). We call this a depolarizing graded potential, because it makes the voltage difference across the cell membrane less negative and therefore smaller (closer to zero voltage). We also call this an excitatory postsynaptic potential (EPSP) because (as you will soon see) the ‘firing’ of an action potential by a neuron in response to stimuli occurs when the resting potential at a trigger zone (initial segment of the axon) surpasses a threshold of about -55mV (more on this below).   3   Neuronal  Excitability  and  Communication  (Chapter  12)   BIOL212,  S.  Raft   If the gating of channels allows a selective flow of K+ ions, positive charge will flow out of the cell, because K+ will flow down its chemical gradient (remember, more K+ inside). This chemical gradient is so strong that it causes K+ ions to flow against its electrical gradient (a positive ion flows toward the positively charge outer surface of the membrane), but as I stated above, unusual things can happen in cellular electrophysiology. Outflow of K+ ions locally alters the resting potential by making the inner surface of the membrane more negative relative to the outer surface. We call this a hyperpolarizing graded potential, because it makes the voltage difference across the cell membrane more negative and therefore larger. We also call this an inhibitory postsynaptic potential (IPSP) because it can drive the resting potential at the trigger zone further away from threshold, thereby inhibiting the neuron from firing an action potential. All graded potentials, regardless of whether they are depolarizing or hyperpolarizing, share certain characteristics. First, graded potential vary in strength (hence the name graded) according to the strength of the mechanical or chemical stimulus (see Fig. 12.14 in your textbook). Second, their effects on the resting membrane potential are local. As graded potentials spread along the membrane from a point of origin, their strength and effect on the resting membrane potential decreases. In short, graded potentials decay or dissipate over time and space. How then, can graded potential have any effect on a neuron’s firing of an action potential? How does the a transient graded potential that begins at a dendrite work it’s way to the trigger zone of the axon at the other end of the neuron cell body? Graded potentials can influence neuronal firing of action potentials because most neurons are simultaneously stimulated at hundreds or even thousands of synaptic inputs. The many resulting graded potentials summate to provide a ‘weighted average’ of all the inputs to the neuron (see Fig. 12.16 in your textbook). The summated activity of so many inputs to the dendrites and cell body of the neuron can sufficiently alter the resting potential at the trigger zone so that the neuron either suppresses or fires an action potential. More stuff on resting and graded potential: At this point, I strongly recommend that you watch the following two Khan Academy videos: ‘Neuron Resting Potential Description’ ‘Neuron Graded Potential Description’ Search for them by name on the Khan Academy home page.               4   Neuronal  Excitability  and  Communication  (Chapter  12)   BIOL212,  S.  Raft   Where are we going next? Everything we’ve covered up to now has to do with the physical basis of neuronal excitability and the manner in which the neuron processes inputs to its dendrites and cell body. As mentioned above, the summated input affects resting potential at the initial segment of the axon (trigger zone), and this determines whether the stimulated neuron will pass the ‘message’ along to other neurons. It can do this by firing an action potential. Action potentials differ from graded potentials in a number of ways (see Table 12.1 in your textbook). Next time we meet, I will describe the mechanism of the action potential. Before then, I strongly recommend that you READ THE SECTION ON ACTION POTENTIALS IN YOUR TEXTBOOK and watch the following Khan Academy video: https://www.khanacademy.org/science/biology/human-biology/neuron-nervoussystem/v/electrotonic-action-potential This video compares and contrasts the graded potential and the action potential (note: here, graded potential is referred to as electrotonic potential – these are just two names for the same thing).   5   
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