Human Physiology – Neurons & the Nervous System
The human nervous system consists of billions of nerve cells (or neurons)plus supporting (neuroglial) cells. Neurons are able to respond to stimuli (such as touch, sound, light, and so on), conduct impulses, and communicate with each other (and with other types of cells like muscle cells).
Neurons can respond to stimuli and conduct impulses because a membrane potential is established across the cell membrane. In other words, there is an unequal distribution of ions (charged atoms) on the two sides of a nerve cell membrane. This can be illustrated with a voltmeter:
The membranes of all nerve cells have a potential difference across them, with the cell interior negative with respect to the exterior (a). In neurons, stimuli can alter this potential difference by opening sodium channels in the membrane. For example, neurotransmitters interact specifically with sodium channels (or gates). So sodium ions flow into the cell, reducing the voltage across the membrane.
Once the potential difference reaches a threshold voltage, the reduced voltage causes hundreds of sodium gates in that region of the membrane to open briefly. Sodium ions flood into the cell, completely depolarizing the membrane (b). This opens more voltage-gated ion channels in the adjacent membrane, and so a wave of depolarization courses along the cell — the action potential.
As the action potential nears its peak, the sodium gates close, and potassium gates open, allowing ions to flow out of the cell to restore the normal potential of the membrane (c) (Gutkin and Ermentrout 2006).
Establishment of the Resting Membrane Potential
Membranes are polarized or, in other words, exhibit a RESTING MEMBRANE POTENTIAL. This means that there is an unequal distribution of ions (atoms with a positive or negative charge) on the two sides of the nerve cell membrane. This POTENTIAL generally measures about 70 millivolts (with the INSIDE of the membrane negative with respect to the outside). So, the RESTING MEMBRANE POTENTIAL is expressed as -70 mV, and the minus means that the inside is negative relative to (or compared to) the outside. It is called a RESTING potential because it occurs when a membrane is not being stimulated or conducting impulses (in other words, it’s resting).
Neuron resting potential
What factors contribute to this membrane potential?
Two ions are responsible: sodium (Na+) and potassium (K+). An unequal distribution of these two ions occurs on the two sides of a nerve cell membrane because carriers actively transport these two ions: sodium from the inside to the outside and potassium from the outside to the inside. AS A RESULT of this active transport mechanism (commonly referred to as the SODIUM – POTASSIUM PUMP), there is a higher concentration of sodium on the outside than the inside and a higher concentration of potassium on the inside than the outside (Animation: How the Sodium-Potassium Pump Works).
The Sodium-Potassium Pump
Used with permission of Gary Kaiser
OVERALL, therefore, there are lots of positively charged potassium ions just inside the membrane and lots of positively charged sodium ions PLUS some potassium ions on the outside. THIS MEANS THAT THERE ARE MORE POSITIVE CHARGES ON THE OUTSIDE THAN ON THE INSIDE. In other words, there is an unequal distribution of ions or a resting membrane potential. This potential will be maintained until the membrane is disturbed or stimulated. Then, if it’s a sufficiently strong stimulus, an action potential will occur.
Voltage sensing in a sodium ion channel. The voltage sensors in a sodium channels are charged ‘paddles’
that move through the fluid membrane interior. Voltage sensors (two of which are shown here) are linked mechanically to
the channel’s ‘gate’. Each voltage sensor has four positive charges (amino acids) (Modified slightly from Sigworth 2003).
In a cross section view of the voltage-dependent potassium channel,
two of the four paddles move up and down, opening and closing the
central pore through which potassium ions flow out of the cell, restoring the
cell’s normal negative inside, positive outside polarity.
An action potential is a very rapid change in membrane potential that occurs when a nerve cell membrane is stimulated. Specifically, the membrane potential goes from the resting potential (typically -70 mV) to some positive value (typically about +30 mV) in a very short period of time (just a few milliseconds).
The potassium channels then open, and, because there is more potassium inside the membrane than outside, positively-charged potassium ions diffuse out. As these positive ions go out, the inside of the membrane once again becomes negative with respect to the outside (Animation: Voltage-gated channels) .
Threshold stimulus & potential
- Action potentials occur only when the membrane in stimulated (depolarized) enough so that sodium channels open completely. The minimum stimulus needed to achieve an action potential is called the threshold stimulus.
- The threshold stimulus causes the membrane potential to become less negative (because a stimulus, no matter how small, causes a few sodium channels to open and allows some positively-charged sodium ions to diffuse in).
- If the membrane potential reaches the threshold potential (generally 5 – 15 mV less negative than the resting potential), the voltage-regulated sodium channels all open. Sodium ions rapidly diffuse inward, & depolarization occurs.
- During an action potential, a second stimulus will not produce a second action potential (no matter how strong that stimulus is)
- corresponds to the period when the sodium channels are open (typically just a millisecond or less)
- Another action potential can be produced, but only if the stimulus is greater than the threshold stimulus
- corresponds to the period when the potassium channels are open (several milliseconds)
- the nerve cell membrane becomes progressively more ‘sensitive’ (easier to stimulate) as the relative refractory period proceeds. So, it takes a very strong stimulus to cause an action potential at the beginning of the relative refractory period, but only a slightly above threshold stimulus to cause an action potential near the end of the relative refractory period
The absolute refractory period places a limit on the rate at which a neuron can conduct impulses, and the relative refractory period permits variation in the rate at which a neuron conducts impulses. Such variation is important because it is one of the ways by which our nervous system recognizes differences in stimulus strength, e.g., dim light = retinal cells conduct fewer impulses per second vs. brighter light = retinal cells conduct more impulses per second.
How does the relative refractory period permit variation in rate of impulse conduction? Let’s assume that the relative refractory period of a neuron is 20 milliseconds long and, further, that the threshold stimulus for that neuron (as determined, for example, in a lab experiment with that neuron) is 0.5 volt. If that neuron is continuously stimulated at a level of 0.5 volt, then an action potential (and impulse) will be generated every 20 milliseconds (because once an action potential has been generated with a threshold stimulus [and ignoring the absolute refractory period], another action potential cannot occur until the relative refractory period is over). So, in this example, the rate of stimulation (and impulse conduction) would be 50 per second (1 sec = 1000 ms; 1000 ms divided by 20 ms = 50).
If we increase the stimulus (e.g., from 0.5 volt to 1 volt), what happens to the rate at which action potentials (and impulses) occur? Because 1 volt is an above-threshold stimulus, it means that, once an actional potential has been generated, another one will occur in less than 20 ms or, in other words, before the end of the relative refractory period. Thus, in our example, the increased stimulus will increase the rate of impulse conduction above 50 per second. Without more information, it’s not possible to calculate the exact rate. However, it’s sufficient that you understand that increasing stimulus strength will result in an increase in the rate of impulse conduction.
Impulse conduction – an impulse is simply the movement of action potentials along a nerve cell. Action potentials are localized (only affect a small area of nerve cell membrane). So, when one occurs, only a small area of membrane depolarizes (or ‘reverses’ potential). As a result, for a split second, areas of membrane adjacent to each other have opposite charges (the depolarized membrane is negative on the outside & positive on the inside, while the adjacent areas are still positive on the outside and negative on the inside). An electrical circuit (or ‘mini-circuit’) develops between these oppositely-charged areas (or, in other words, electrons flow between these areas). This ‘mini-circuit’ stimulates the adjacent area and, therefore, an action potential occurs. This process repeats itself and action potentials move down the nerve cell membrane. This ‘movement’ of action potentials is called an impulse.
- impulses typically travel along neurons at a speed of anywhere from 1 to 120 meters per second
- the speed of conduction is influenced by the presence or absence of myelin
- Neurons with myelin (or myelinated neurons) conduct impulses much faster than those without myelin.
Myelination, the process by which glial cells ensheath the axons of neurons in layers of myelin, ensures the rapid conduction of electrical impulses in the nervous system. The formation of myelin sheaths is one of the most spectacular examples of cell-cell interaction and coordination in nature. Myelin sheaths are formed by the vast membranous extensions of glial cells: Schwann cells in the peripheral nervous system (PNS) and oligodendrocytes in the central nervous system (CNS). The axon is wrapped many times (like a Swiss roll) by these sheetlike membrane extensions to form the final myelin sheath, or internode. Internodes can be as long as 1 mm and are separated from their neighbors by a short gap (the node of Ranvier) of 1 micrometer. The concentration of voltage-dependent sodium channels in the axon membrane at the node, and the high electrical resistance of the multilayered myelin sheath, ensure that action potentials jump from node to node (a process termed “saltatory conduction”) (ffrench-Constant 2004).
Schwann cells (or oligodendrocytes) are located at regular intervals along the process (axons and, for some neurons, dendrites) & so a section of a myelinated axon would look like this:
Impulse conduction and Schwann cells
Multipolar neurons are so-named because they have many (multi-) processes that extend from the cell body: lots of dendrites plus a single axon. Functionally, these neurons are either motor (conducting impulses that will cause activity such as the contraction of muscles) or association (conducting impulses and permitting ‘communication’ between neurons within the central nervous system).
Unipolar neurons have but one process from the cell body. However, that single, very short, process splits into longer processes (a dendrite plus an axon). Unipolar neurons are sensory neurons – conducting impulses into the central nervous system.
Bipolar neurons have two processes – one axon & one dendrite. These neurons are also sensory. For example, biopolar neurons can be found in the retina of the eye.
Neuroglial, or glial, cells – general functions include:
1 – forming myelin sheaths
2 – protecting neurons (via phagocytosis)
3 – regulating the internal environment of neurons
in the central nervous system
Synapse = point of impulse transmission between neurons; impulses are transmitted from pre-synaptic neurons to post-synaptic neurons
Synapses usually occur between the axon of a pre-synaptic neuron & a dendrite or cell body of a post-synaptic neuron. At a synapse, the end of the axon is ‘swollen’ and referred to as an end bulb or synaptic knob. Within the end bulb are found lots of synaptic vesicles (which contain neurotransmitter chemicals) and mitochondria (which provide ATP to make more neurotransmitter). Between the end bulb and the dendrite (or cell body) of the post-synaptic neuron, there is a gap commonly referred to as the synaptic cleft. So, pre- and post-synaptic membranes do not actually come in contact. That means that the impulse cannot be transmitted directly. Rather, the impulse is transmitted by the release of chemicals called chemical transmitters (or neurotransmitters).
Micrograph of a synapse (Schikorski and Stevens 2001).
Post-synaptic membrane receptors
When an impulse arrives at the end bulb, the end bulb membrane becomes more permeable to calcium. Calcium diffuses into the end bulb & activates enzymes that cause the synaptic vesicles to move toward the synaptic cleft. Some vesicles fuse with the membrane and release their neurotransmitter (a good example of exocytosis). The neurotransmitter molecules diffuse across the cleft and fit into receptor sites in the postsynaptic membrane. When these sites are filled, sodium channels open & permit an inward diffusion of sodium ions. This, of course, causes the membrane potential to become less negative (or, in other words, to approach the threshold potential). If enough neurotransmitter is released, and enough sodium channels are opened, then the membrane potential will reach threshold. If so, an action potential occurs and spreads along the membrane of the post-synaptic neuron (in other words, the impulse will be transmitted). Of course, if insufficient neurotransmitter is released, the impulse will not be transmitted.
Impulse transmission – The nerve impulse (action potential) travels down the presynaptic axon towards the synapse, where it activates voltage-gated calcium channels leading to calcium influx, which triggers the simultaneous release of neurotransmitter molecules from many synaptic vesicles by fusing the membranes of the vesicles to that of the nerve terminal. The neurotransmitter molecules diffuse across the synaptic cleft, bind briefly to receptors on the postsynaptic neuron to activate them, causing physiological responses that may be excitatory or inhibitory depending on the receptor. The neurotransmitter molecules are then either quickly pumped back into the presynaptic nerve terminal via transporters, are destroyed by enzymes near the receptors (e.g. breakdown of acetylcholine by cholinesterase), or diffuse into the surrounding area.
Types of neurotransmitters:
1- Excitatory – neurotransmitters that make membrane potential less negative (via increased permeability of the membrane to sodium) &, therefore, tend to ‘excite’ or stimulate the postsynaptic membrane
2 – Inhibitory – neurotransmitters that make membrane potential more negative (via increased permeability of the membrane to potassium) &, therefore, tend to ‘inhibit’ (or make less likely) the transmission of an impulse. One example of an inhibitory neurotransmitter is gamma aminobutyric acid (GABA; shown below). Medically, GABA has been used to treat both epilepsy and hypertension. Another example of an inhibitory neurotransmitter is beta-endorphin, which results in decreased pain perception by the CNS.
Neurotransmitters (acetylcholine described starting at about 2:55)
Used by permission of John W. Kimball
1 – Temporal summation – transmission of an impulse by rapid stimulation of one or more pre-synaptic neurons
2 – Spatial summation – transmission of an impulse by simultaneous or nearly simultaneous stimulation of two or more pre-synaptic neurons
Used by permission of John W. Kimball