Thursday, September 23, 2010

9.10 Secrets of Nerve Signals to the Brain

Physician's Notebooks 9  See Homepage -

10. Signaling in the Nervous System- Update 18 April 2018
 (This chapter is best read, at your leisure, slowly in short segments and re read as needed, using Internet Wikipedia for reference. The following descending table of contents are headings in order in the chapter.

The basic mechanism of electrical excitability
Anatomy of signaling
The Origin of the Electric Potentials
The Action Potential
Neurotransmitters, Connectivity and Synapses

The basic mechanism of electrical excitability involves voltage-gated ion channels and protein structures in the outer wall of the neuron that open and close in response to an inward Sodium ion Na+ current and an oppositely outward potassium ion K+ current.
Anatomy of signaling: Consider the thought, A pretty girl is squeezing my right hand. The squeeze excites sensory pressure receptors in my hand that generate an electric potential (generator potential) and when the potential (in millivoltage) gets large enough it switches on an action potential (AP; moves the electric impulse forward) in the attached nerve fiber. 
The AP (many APs from the squeeze) passes up my right arm through a nerve fiber and goes by the right cervical #7 dorsal spinal root ganglion, and is passed into the spinal cord in a nerve fiber that runs up to a relay neuron in the upper cord. Then the signal crosses to the left side, continues to the brainstem and passes into the left thalamus.
   The thalamus works like a switchboard. The pressure-in-right-palm signal received in left thalamus is connected with Pretty Girl’s image (a transmission from the occipital lobe visual cerebral cortex) and is split up into sub-signals (eg, its emotional meaning, its body map location, the amount of pressure, its sexual message) and each sub-signal is passed to fibers that spread out to the various parts of the cerebral cortex serving the consciousness of Pretty Girl’s hand squeeze. 
In the signal of Pretty Girl's touch; it reaches consciousness in the parietal cortex, is passed to the pre frontal cortex for an action decision, is acted upon just behind the frontal motor cortex, and the signal for action is transmitted down through mid brain to activate muscle fibers in a motor program that ends up with my saying "Hey Babe, let's go to a small motel", and doing it.
 The Origin of the Electric Potentials 

The Resting Membrane Potential Results from the Separation-Blocking of Charge Across the Cell Membrane

The neuron's cell membrane has thin clouds of negative charges spread over its inside border and they attract positive charges on the outside border. At rest the extracellular (outside border) surface of the membrane has a line of these positive charges and the inner surface has a line of negative charges (Figure below). This separation of charges is maintained because the cell membrane blocks the diffusion of electrical charges, or ions. The charge separation gives rise to a difference of electric potential, or voltage, across the membrane, the membrane potential (Vm), defined as

Vm = VinVout,

where Vin is the electric potential lined up on the inside of the cell membrane and Vout is the potential on the outside.

The excess of positive ions just outside the membrane and negative ions just inside the membrane represents a small fraction of the total number of ions inside and outside the cell at rest.

Image not available.

The membrane potential of a cell at rest is called the resting membrane potential (Vr). Since by convention the potential outside the cell is defined as zero, the resting potential is equal to Vin. Its usual range is − (minus) 60 mV to −70 mV. All electric signaling involves brief changes in the resting membrane potential that are caused by electric currents across the cell membrane.

The electric current is carried by chemical ions, both positive (cations) and negative (anions). The direction of current is conventionally defined as the direction of net movement of positive charge. Thus, in an ionic solution cations, or positive charge, move in the direction of the electric current and anions move in the opposite direction. In the nerve cell at rest there is no net charge movement across the membrane. When there is a net flow of cations or anions into or out of the cell, the charge separation across the resting membrane is disturbed, altering the electric potential of the membrane. A reduction or reversal of charge separation, leading to a less negative inside membrane potential, is called depolarization because it brings the oppositely polarized charged sides of the membrane closer together as numbers (less polarized). An increase in charge separation, leading to a more negative inside membrane potential, is called hyperpolarization.

Hyperpolarizing (increasing the inside membrane negativity) responses are always passive, as are small depolarizations. However, when depolarization approaches a critical level, or threshold, the cell responds actively, suddenly with the opening of voltage-gated ion channels ("click-on" or digital effect), which produces an all-or-none action potential .

   Diagrams with text explain electric conduction - Use loupe

Upper part of the Figure: a neuron fiber shown as a cylinder with a section of the fiber membrane removed to show the relationship of the inside-fiber to the outside. The electric polarization of the fiber is due to the outer side excess of the sodium ion Na+. Note that under resting condition, the nerve fiber membrane outside is electrically positive (++++) and the inside of the membrane is negative (- - - -). It makes a pressure difference from outside to inside across the membrane of minus 70 millivolts (-70 mV, the pressure to push the negatively charged electrons into the cell). The down-and-up arrows delimit a short segment that shows reversal (depolarization) of the resting potential surface electric charges due to the Na+ channels there opening to allow the Na+ to rush inside into the low-Na+ (and more electrically negative) inside-fiber border and to reverse the polarity of the membranes in the short pointed-to segment. The outside then, temporarily, becomes --------- negative and the inside +++++ positive in the depolarized short segment. This is the depolarization that generates the action potential. 
Bottom: A single action potential (AP) graphed. (Also shown in lower graph above)
The Action Potential:

In the graph above, lower part, is a short period of time (c.6 milliseconds) of the moving AP nerve impulse. The AP graph records the wave of sudden reversal of the polarization (from -70 to +30 mV; to push sodium ions (cations, Na+) into the cell as indicated in the cylinder in upper part of the Figure. The resting potential, here minus 70 mV,  is the inactive polarized state of the fiber membrane at the zero time point on the graph. With the depolarization, the membrane potential suddenly rises to a peak of nearly +30mV. Once initiated (by physical or chemical stimulus) the nerve impulse moves forward (to your right in the upper cylinder and also in the graph) by the progressive depolarization of the fiber membrane at its wave front enhanced due to the repolarization and refractoriness to electric excitation (period of being unresponsive to any stimulation) of the membrane in its rear. This is how signals are originated and how a signal self-propagates in direction away from origin as nerve impulse. It is important in understanding the initiation of neurotransmission that the above picture (the cylinder of the nerve fiber with the pluses on the outside and minuses on the inside) is the stable, resting state of all nerve fibers and that the effect that causes depolarization destabilizes this balanced state and results in a sudden, temporary mini-explosion of energy that starts the AP on its way.
(Main text) The start and build-up of the electric signal is a "generation potential" and its sudden action to move the signal forward in the nerve fiber is the "action potential" (AP). At rest the nerve fiber is in a stable, electrically polarized state that is due to the outer side of its membrane's being positively charged and the inner side, negatively charged across the non-freely conducting membrane with an electric pressure from outside to inside of minus 70 milliVolts (-70 mV). This is the resting potential. An important feature of a nerve cell is that its inside fluid is low in sodium ion (Na+) compared to its outside, extracellular fluid. This is the stabilizing resting condition. This resting low Na+ inside the nerve fiber is very important for normal nerve function and it is maintained by the fiber membrane in its resting potential state blocking Na+ from passing from the outside into the inside fluid (which it normally would tend to do because of the great concentration difference of Na+ ion between high-Na+ outside and low-Na+ inside the cell) and by Na+ pumps that get activated by a rise in Na+ inside the nerve fiber and then start to pump the excess Na+ ion out of the nerve fiber fluid. (Like you would pump water out of your sinking rowboat) The reason why an electric signal gets generated into an action potential is the on-off  Na+ ion channel switches. These "switches" (Na+ channel protein molecules inserted in the cell membrane) are excitable points in parts of the nerve body or nerve fiber membranes or sensory bodies in the skin. These Na+ ion channels should be seen as digital click valves. They are very sensitive to stimuli (pressure, heat, chemical, electrical) that excite a nerve to initiate a signal. They are a type of valve that will open further from the rapid inflow (Here Na+). This is a positive feedback - the desired effect is boosted by the initial increasing flow. It is called all-or-none effect because once it starts it goes with explosive speed to its peak. In the resting nerve fiber state, as described with resting potential minus (-)70 mV, the ion channels are in the shut position and the fiber membrane blocks the entrance of Na+ into the inner fiber fluid. But with excitatory stimulus - as in the previous example of Pretty Girl squeezing my right palm and increased pressure on sensory nerve endings -, the initial stimulus causes the Na+ ion channels to click into a partly open state and, because of the very high concentration Na+ in the fluid just outside the membrane and the negative electrical field inside, the Na+ ions rush through the now partly open ion channels into the nerve fiber, and above a minimal threshold the increasing rapid flow of these forward rushing Na+ ions slams open the ion channel gates to maximum opening. So what had started as a small inflow of Na+ suddenly is a high inflow. This has immediate electrical effect on the fiber's electrical difference that at rest was minus (-) 70 mV, increasing it. (Lower minus number toward 0 and then increasing + number). The sudden local upping of electrically positive Na+ inside the nerve fiber reverses the electrical polarization on both sides of the nerve fiber membrane in that localized area, making the inside of the membrane positive to the outside. The segment of membrane excited by the touch has now become depolarized (reversal of the original resting ++++ on outside, ------- on inside polarization). This is very unstable and very short lasting because, as soon as the excess Na+ enters the inside-cell fluid, the cell starts pumping it back out. Also special K+ ion channels open and allow K+ to exit thus restoring the original fiber membrane polarization so that it returns to ++++++ on outside of fiber and ------- inside. If you look again the cylinder shown in the figure , you will see the short segment between the arrows which is depolarized. The state of that depolarization constantly moves toward your right - away from its original stimulus - because of the very rapid decay of the action potential electrical spike (see the figure with the spike graph) due of the Na pump and the open K+ channels on the left rapidly restoring the resting potential and making it more negative and thus refractory to new action potential. Thus, the direction of the action potential moves to the right (in the figure) up the nerve fiber away from Pretty Girl's hand squeeze of my palm. In the sensory system, the initiation and build-up of this nerve impulse action potential ("the generative depolarization") is caused by a mechanical event. (In this case the hand squeeze)

Now, look again at the graph and note, just following the downward repolarization the brief further downward curve, or negative hump, that quickly reverses into the straight horizontal line, the "resting potential". This is a brief period of hyperpolarization, where the reversal of the repolarization had been overdone by too much Na+ ion and K+ ion having exited out of the cell; this hyperpolarization is quickly reversed by a natural coming to equilibrium of the Na+ and K+ concentrations. During hyperpolarization there is a relative refractory period (depolarization only by higher than normal stimulation, a higher threshhold) and the activity caused by the AP current is inhibited. This inhibition prevents  instability at the start point of depolarization. It prevents reverse waves from the action potential and gives it a forward direction.
The Na+ pump is powered by a nano-size motor (reduced about one billion times from human-made size motors) conversion of chemical energy into a mechanical transporter of ions through the membrane against particle diffusion concentration gradient (In this case against a concentration gradient of more than 100 to 1 in Na+ ion outside to inside cell and K+ ion inside to outside). The metabolic drive of the pump comes from energy packets of Adenosine Triphosphate (ATP) produced from the energy transfer of oxidation of blood sugar, glucose. That is why our nervous system is highly dependent on a source of oxygen and glucose and will collapse within minutes of being deprived of oxygen (in hypoxia) or energy nutrients like glucose (in hypoglycemia).

More About the Action Potential Movement in a Nerve Fiber   The AP spike begins at the point of initial depolarization and travels forward at a rate that depends on the width of the nerve fiber and the presence of myelin-cover of the nerve fiber. (The larger the width (diameter squared) the faster the nerve impulse, and the presence of the myolin sheathe markedly speeds the impulse)
Keep focused on the importance of ions via their channels in signaling. Like digital control, the channels click close or click open, and this will set limits and direction on the signaling. I have mentioned Sodium Na+ and Potassium K+; but also Chloride Cl-, Calcium Ca++  and Magnesium, Mg++ ions play a role in electrical signaling and have their own ion channels or may block other ion channels as in the case of Mg++ blocking Na+ channels. The K+ is highly concentrated inside cells, but outside the cells in the blood plasma such a high concentration would be toxic. Calcium, Ca++ has particular importance for ion pore (channel) function so it too must stay within very strict limits inside and outside cells, which has caused worry for those who use calcium-channel blockers as medication.

Neurotransmitters, Connectivity and Synapses
Signaling in the nervous system is not just an electric signal in a wire. The analogy to the wire is the neuron's axon and dendrites, the ultimate nerve fibers. A single axon carries the signal away from the neuron cell body and connects via the synapse with a dendrite of a relay neuron. Typical neurons have 1 axon for sending a signal and many dendrites for receiving signals.
Furthermore, signaling, which on superficial discussion may appear a smooth, seamless on-off electric signal.
 Neural signaling at the start of the chapter was described in its ion membrane passage aspect, and much signaling uses that mode of transmission. However, at the synapse, where the initial signal is relayed across the synapse to the next fiber, a chemical mode of transmission is used that is refereed to as neurotransmission. And the chemicals are neurotransmitters. 
The neurotransmitters are chemicals of varied types; from biogenic amines like epinephrine and dopamine, to peptide fragments from amino acids, to even gas transmitters like nitrous oxide (NO) and carbon monoxide (CO) as well as opioids and cannabanoid transmitters.
The Synapse is the connection point and space where a nerve fiber (often an axon) will pass on its signal to its connecting nerve fiber (often a dendrite) or to a neuron body or to an action cell like a muscle or gland. One way, just referred to, of passing the signal, most frequent in higher animals, is by a neurotransmitter, a chemical molecule that is released at the transmitting fiber (presynaptic) end, traverses the synaptic space and attaches to a receptor on the receiving fiber or nerve body (post synaptic) and this attachment generates a new action potential that passes on or inhibits the signal. Another way is a direct electrical connection called gap junction, exactly like an electrical plug in. 
An important question in understanding signaling is: Why is chemical neurotransmission via synapse favored over electrical gap junction neurotransmission (Direct electrical connection like a plug-in) in evolution of higher organisms? The answer is that the use of chemicals for neurotransmission allows for much greater flexibility of signaling than a simple on-off electrical switching system.

The NeuroTransmitter Synapse (Inspect with loupe)
Above, 2 chemical synapses – on your left for acetylcholine (ACh in muscle fiber contraction or autonomic preganglionic neuron) neurotransmitter release and on right for norepinephrine (Norepinephrine, or NE, in autonomic sympathetic post ganglionic neuron) release that is used in the sympathetic fight or flight autonomic nervous system. Note the similarity: in that both the upper (presynaptic) neuron fiber terminations are, each, an end of a nerve fiber, and the lower (postsynaptic, receptor) is the start of the next relay nerve fiber or the receiving neuron cell surface itself. And note the space in between (the synaptic space).
Also the NeuroTransmitter (NTr) synapse can be between the end of an axon fiber and an action cell, like a muscle fiber or gland or between axon and dendrite fiber. The attachment causes a fresh depolarization and continues the electrical impulse action potential in the post synaptic fiber. (Or with an action cell such as in muscle or gland, it causes muscle fiber contraction or gland cell secretion; or it may also be inhibitory and block further transmission) Next, note the enzymatic dissolving of the ACh//receptor site bonding, (in the illustrated synapse on your left by acetylcholine esterase “AC(h)E” in the Figure dissolving the acetylcholine and allowing choline to diffuse back into the presynaptic nerve fiber and be used to make new ACh). In the NE synapse (on your right) note the “Reuptake” just at the presynaptic terminal. In the case of the NE neurotransmitter, the just-used molecules are dissolved away from the receptor site after initiating the action and either taken back into the presynaptic nerve fiber termination by reuptake or degraded by the enzyme catechol O-methyl tranferase (COMT) to inactive normetanephrine which is excreted in urine. (Inhibition of this reuptake involving serotonin, another NTr, is the way anti-depression drugs like Prozac work)
The illustrated synapse in the above figure on your left, which releases ACh, is typical of parasympathetic nervous system synapses, of preganglionic sympathetic synapses and of motor nerve/muscle fiber junctions. 
The NE (norepinephrine, above figure, your right side) synapse is typical of postganglionic sympathetic system neurons involved in fight or flight stress reactions. There are many families of neurotransmitters eg, Norepinephrine, Serotonin, Dopamine family).  It should also be mentioned that some synapses are purely electrical but relatively rare in humans.

I have not here mentioned one of the, if not the, most important quality of neurotransmitters: they are either excitatory (enhance an effect) or inhibitory (slow, decrease or reverse an effect). This is a huge advantage of chemical over purely electrical synapses which lack the quality of switching between excitation and inhibition. As we shall see in discussion of the effects of nerve signals coming out of major brain structures - like the cerebellum, basal ganglia, cerebral cortex, each structure is dominated by either excitatory (Cerebellum) or inhibitory (Basal ganglia) output. Often, combinations of the 2 effects are the key to input-output effects, eg, an inhibitory input to a set of neurons that has an inhibitory output, disinhibits the output and has an effect of excitation. The major excitatory neurotransmitter in the CNS is glutamic acid (glutamate) from one of the natural human amino acids (cf. Monosodium glutamate flavoring for foods). The major inhibitory neurotransmitter is gamma amino butyric acid (GABA) an unusual amino acid that is not necessary in protein nutrition and that is produced as an offshoot of a carbohydrate cycle. The so-called aminergic neurotransmitters - epinephrine, norepinephrine, serotonin, and dopamine - are usually excitatory, but dopamine, which is involved in many nervous diseases particularly Parkinsonism, may be inhibitory depending on what receptor it attaches to.
The mechanisms by which  the neurotransmitters effect the change that starts the neurotransmission or other transmission of nerve impulse to muscle or gland do not end with the transmitters alone. The mechanisms involve the opening ionic channels and/or effecting changes in energy production like ATP to ADP and GTP to GDP that effect the release of neurotransmitters from the synaptic sites and then the release of transmitter vesicles and finally the interaction of transmitter and receptor site post synaptically.

The action potential (AP) which starts a nerve signal forward toward its destination (in sensory nerve from periphery to brain; in motor nerve from brain to muscle) has been discussed in its simplest form - a very brief single electrical blip on a moving graph record. But, depending on the neuron and the function of the signal, the signal may have many forms. For example it may start a train of of AP electrical blips of various frequencies (in tonically active neurons, TANs); these are important when speed of signaling response is needed because the actual resting state becomes a constant series of rapid blips, eg, 50 per second, and the signal may be a reduction of frequency. This is known as frequency coding.  
   Or the AP can be produced as spontaneous bursts of several blips, when low thresh-hold excitability is important. Or other forms that get involved with neuronal plasticity and learning process as in memory.

I want to end up with signaling in the brain. Once again, although it may seem like it, it is not simply the same as flipping an electric switch from off to on and having current flow. A signal in the brain such as the specific thought "Yes!", meaning OK to somebody's query, starts with you being stimulated by hearing and understanding the query and continues with you responding by starting an action potential (AP) to decide to make your muscles of oral expression say "OK" and then the AP passes down to the muscles of the Larynx (voice box) to neuromuscular junction synapses where neurotransmitter is released after being packaged in vesicles, passes across the synaptic space to the muscle fibers, stimulates the muscle fibers according to a specific code which directs the fibers to combine in motions that cause the word "OK" to be spoken and understood. The point I'm trying to make with this complicated description of what seems simple signal action is that underlying each action that our brain causes us to take is a whole series almost infinite of sub actions that can be acted upon in many different ways -excitation or inhibition or memorization or reversal of intent (you change your mind and change OK to No No) - so you should get what I mean when I say that a signal in the brain is not simply turning on a switch.

 This section may be difficult but should give the reader a starting understanding of chemical/electrical signaling in the brain, spinal cord and peripheral nerves. Careful, slow reading and re reading with access to Internet references will be effective in retaining and gaining the new knowledge which one may then gradual grow by further study and thought.

END OF CHAPTER. To read next click 9.11 Peripheral Nerves - Autonomic Sympathetic/Par...

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