Neuroscience, the scientific study of central and peripheral nervous systems in biological organisms, aims to explain behavior in terms of the activities of the brain. It explores how the activity of millions of individual nerve cells produce behavior, consciousness and the mental processes by which we perceive, act, learn, and remember. Individual subdisciplines may focus on the structure, function, evolutionary history, development, genetics, biochemistry, physiology, pharmacology, and pathology of the brain.
The nervous system has a unique position in the causation of behaviour. Under selective pressure to generate adaptive behaviour, it is subject to costs related to the amount of energy that it consumes - and in this function nervous structures carry a high metabolic demand. A human brain, although accounting for only around 2% of body weight, requires 20% of the body’s oxygen. Half of the energy drives the pumps that exchange sodium and potassium ions across cell membranes and keep the brain's batteries charged. Providing a signalling framework of such magnitude and capability requires strong selection for mechanisms that provide maximized signal to noise ratios at minimized cost. The ionic mechanisms that underlie the electrical properties of neurons, the resting membrane potential and the action potential, offer an exquisitely optimized solution.
Neurons are able to conduct and process signals that involve small changes in electrical voltage generated across the neuronal membrane. At rest, the inside of the neuron is negative relative to the cell surround - the resting membrane potential. Individual signals are integrated across different regions of the neuron and throughout sets of neuronal networks in order to determine each unit's response and output. A special type of such voltage changes features a rapid spike in voltage resulting from changes in ion conductances - the action potential. Such signals are predominantly transmitted along axonal lines where neurons interact with other cellular entities over greater distances.
Electrical Properties of Neurons
Three primary mechanisms are responsible for the electrical properties of neurons at rest and during the signalling process.
- An uneven distribution of ions exists across the cell membrane. The outside features an excess of Na+ and Cl-, while the inside has more K+ and Anions-. A significant portion of the body's metabolic cost goes into maintaining this unequal distribution by constantly running a membrane pump that exchanges 3 outward moving Na+ ions with 2 inward moving K+ ions.
- The membrane features ion pores that offer unobstructed flow for K+ ions. This outward directed conductance moves positively charged potassium ions along its concentration gradient, resulting in a negatively charged inside to the neuron. As this charge gradient builds, an equilibrium will be reached when an equal number of K+ will move out of the cell along its concentration gradient as are pushed back in along its charge gradient. This state is referred to as the resting membrane potential
- The active state of the neuron is characterized by the transient opening of voltage-gated sodium channels which causes a rapid inward flow of Na+, powered by both the concentration and the charge gradient. As the inside of the neuron overshoots to a positively charged interior, sodium channels shut close, while the Na/K pump re-equilibrates the neuron to rest.
|The electric properties of the neuronal membrane can be expressed as a circuit diagram. a. Golgi-stained neuron with long axonal process. b. Circuit diagram of neuronal membrane combining membrane resistance (Rm), membrane capacitance (Cm) and internal or axial resistance (Ri). c. Decay in signal size over distance with Space Constant. d. Change along the axon in Voltage response to the injection of a single square current pulse due to membrane capacitance|
The voltage present across the cell's membrane can be measured between a reference electrode and a conducting glass capillary tube drawn out to a very fine point, and inserted into the cell. At rest the neuronal interior is negative relative to the outside at between -60 to -80mV, while most non-neuronal cells feature a potential of about -30 mV. The current is carried by ions moving across the membrane at ion conductances when specific channels allow them to pass. Ignoring its active properties, the axon can in electrical terms be viewed as an insulated cable. An electric potential is able to spread passively along any stretch of membrane. In the process its strength decays and the slope of on- and offsets becomes less steep with distance due to the passive cable properties of the membrane. The latter include resistance along its length and both a resistance and a capacitance component across it. Signals will spread fastest when longitudinal resistance is low (e.g., via increased axonal diameter) and they will spread furthest when resistance across the membrane is high (e.g., with layers of myelin for added electrical insulation).
A neuron is at rest when it has not been activated for some time. At that state it exhibits a negatively charged inside relative to the surrounding environment. The Resting Potential emerges from an unequal distribution of ions across the cell's membrane. An excess of K+ and of various Anions- exists on the inside while Na+ and Cl- exist in higher concentrations on the outside. The membrane is dotted with proteins that permit the flow of ions (i.e., ion pores) or control their flow (i.e., ion channels) across it. In a cell at rest only potassium ions (K+) are able to flow freely between the two compartments. Initially we observe a net flow of positively charged potassium ions from the inside where they are more numerous to the outside where their concentration is much lower (i.e., concentration gradient). With a net flow of positively charged ions from the inside across the membrane, the inside becomes increasingly negative relative to the outside (i.e., charge gradient). This charge gradient pulls positively charged potassium ions back into the cell. The resting potential settles into an equilibrium when as many potassium ions are pushed out of the cell along their concentration gradient, as will enter the cell along the accompanying charge gradient.
This equilibrium potential for potassium can be calculated using the Nernst potential for known inside and outside concentrations of any given ion
|Nernst Potential (E) =||2.303 * RT/zF * log([ion]out/[ion]in)|
where R = the gas constant (8.3143 joules/mole-degree); T = absolute temperature in degrees Kelvin (310 degrees); z = ionic valence; F = Faraday's constant (96,487 coulombs/mole). At a room temperature of 25oC) 2.303 * RT/zF solves to 0.0578V or rounded as 58mV.
Depending on their respective inside and outside concentrations at the particular cell, different ions will produce different equilibrium potentials (reversal potentials). The ion concentrations are usually similar to those listed:
The Nernst potential for potassium thus can be simplified to the following formula
and for sodium is
The cell's resting membrane potential combines all relevant ion currents with K+ ions figuring most prominently due to their high resting conductance. In addition a small number of Na+ ions leak into the cell. The resulting resting membrane potential is thus slightly lower compared to the EK+ at around -65mV. To maintain the concentration gradient across the membrane of resting neurons, ATP continually supplies energy to the Na+/K+ ATPase (ion pump) as ions leak across the axonal membrane.
An Action potential represents a transient inward current of cations (Na+). It is generated when the graded membrane potential rises above threshold either spontaneously or because of depolarizing input. During the action potential, voltage-gated sodium channels are opened when the potential rises (i.e., depolarizes) from resting potential (-65mV) to the cells threshold (-55mV). These channels close again when the potential further rises to +10mV. As sodium ions spread to neighboring areas of axonal membrane, they depolarization adjacent patches of membrane with subsequent opening of sodium channels there. The signal then proceeds to run the entire length of the axon (i.e., the all-or-none-principle).
A Refractory period follows the action potential during which time the neuron reestablishes its normal resting potential. At the beginning of this period it is impossible for another signal to be transmitted, this is called absolute refractory phase. This is followed by the relative refractory phase where it is possible to send another signal but more exitation than normal is needed.
The Duration of an action potential is 1-2ms in Vertebrates and 1-100ms in Invertebrates. Frequency of firing ranges from <1 to about 100/sec (100 Hz). The Amplitude ranges between 70-80mV when recorded intracellularly and 5-200µV when recorded extracellularly.
Two electrically excitable cells, such as neurons or muscle cells, may be electrically coupled where an action potential in one cell moves directly into the other via arrays of gap junctions. Electrical synapses are fast but cannot be modulated. They are mostly used in neuronal circuits for escape behaviors where speed of conduction is essential. Electrical synapses (gap junctions, electrotonic junctions) allow current to flow between separate neurons when ions pass through gap junctions. Connexons (where 6 connexin proteins form a hemi-channel) are the actual pores that allow ions to flow past the two membranes. A connexon in the presynaptic membrane lines up precisely with its respective equivalent in the postsynaptic membrane, forming a continuous channel from one neuron to another. With a pore diameter of about 1.5m-9 many small molecules can pass through efficiently. Intracellular Ca2+ concentration, pH, or phosphorylation of connexins can profoundly alter the easy with which ions annd proteins may pass through the pore. As there is no synaptic delay in transmission of current from cell to another, the conduction of potential changes is considerably faster than through chemical synapses. Although electrical synapses are often bi-directional, some synapses pass current better in one direction than the other (i.e., rectifying synapse) Electrical synapses are commonly used in time-critical processes (escape behaviors), when rapid synchronization of many cells is needed (e.g., vertebrate cardiac muscle), between glial cells, or early in development.
Cells are also able to communicate chemically across a gap (i.e., synapse), which forms a directional connection from one neuron to another cell. The neurotransmitter is emitted from the terminal endings of one cell's axon onto a dendrite or body of a second cell. The arrival of a signal leads to the release of a neurotransmitter from the presynaptic terminal, diffusion across the synaptic cleft, and binding to receptors in the postsynaptic membrane. Ionotropic or metabotropic receptors are binding proteins which alter ion conductances at the postsynaptic cell membrane (e.g., increase in Na+ conductance depolarizes and is excitatory, CL- hyperpolarizes and is thus inhibitory). When excitatory, the postsynaptic cell is depolarized with an excitatory post-synaptic potential (EPSP) and an action potential is elicited if the threshold is reached; in inhibitory connections, the postsynaptic cell is hyperpolarized with an inhibitory post-synaptic potential (IPSP) and it will thus be harder for other inputs to drive the cell towards an action potential. A single input is rarely sufficient to lead to an action potential in the post-synaptic cell. Multiple EPSPs may add and reach the threshold when a series of action potentials arrive at high rate. Chemical synapses are capable of integrating a complex scenario of inputs:
Neurotransmitter refers to a compound that is released at a synapse and diffuses across the synaptic cleft to act on a receptor located on the membrane of a postsynaptic cell, which may be another neurone, a muscle cell or a specialized gland cell. A wide range of chemicals are used as neurotransmitters in the nervous system. Stored in synaptic vesicles. they are released during the arrival of an action potential and produce changes in the excitability of the postsynaptic membrane. Ca2+ influx at the axon terminus is required for synaptic release.
Neuromodulator refers to a compound that is released within a localized region of CNS, the receptor for which is not necessarily sited on an anatomically apposed postsynaptic cell. Thus a neuromodulator may affect several postsynaptic cells with specificity conferred mainly by the distribution of receptors. Main action is on second messenger systems, e.g. cAMP or inositole triphosphate, presumably affecting protein phosphorylation
Sometimes the same neurochemical may have rapid transmitter type effects, followed by longer modulatory influences. This suggests that neurotransmitter and neuromodulator effects may be most effectively classified at the receptor level. Activation of receptors on a protein structure directly incorporating an ion channel (a ionophore) are defined as neurotransmission while activation of receptors coupled indirectly to ion channels (e.g. via second messenger systems) are defined as neuromodulation.
For the signal to be passed from one neuron to the next it must have enough energy to break a point called the threshold. Once the threshold is broken the signal is transmitted. The neuron fires at the same strength every time. The strength of a signal is decided by how many different neurons are being fired and at what frequency they are being fired.
Activity in any presynaptic neuron alone is rarely sufficient to elicit an action potential in the postsynaptic neuron. Summation of synaptic inputs, however, can occur when a neuron receives multiple exitatory inputs in short order. Synaptic processing describes the ways in which the electrical events in different neurons may interact through interactions at their synapses. Synaptic inputs are mostly located on the dendritic tree of a neuron, while axonal action potentials represent the neuron's output. In order to drive a neuron the integrated influence of the electrical events generated by the synapses must be sufficient to spread through the dendrites to the soma and into the initial segment of the axon (i.e., the axon hillock, trigger zone). The latter is the site of action potential generation. Synaptic integration is thus key to understanding the contribution of individual neurons to information processing within neural networks.
In spatial summation the cell responds when activity from multiple inputs arrives at the same time. If the combined excitation brings the cell to threshold, an actionpotential is initiated. The arrival of a spike train in a presynaptic neuron may produce multiple EPSPs. If these inputs begin to build on each other, the postsynaptic cell may reach threshold and produce an action potential.
Passive membrane properties are important. Long time constants increase the chances for temporal summation. Large space constants determine the likelihood of spatial integration. The size of the postsynaptic cell counts, as a synaptic current delivered into a small neuron will produce a much greater effect than in a large postsynaptic cell.
Location of synapses is important. Control of the cell's activity usually driven by excitatory synapses on dendrites. Inhibitory synapses located on the cell body are able to shut down activity. Synapses at presynaptic release sites are modulatorym controlling the amount of neurotransmitters released.
Basic familiarity with key concepts in electricity is essential in order to appreciate the neuronal mechanisms active during such integration. Ohm's law holds that the rate at which electric charges flow (i.e., Current or I) depends on the force and its direction exerted onto the charged particle (i.e., Potential, V) and the ease with which the flow can occur (i.e., Conductance, g). The latter can also be expressed as the reciprocal of the conductance, namely as the degree to which the conductor obstructs the flow of charges (i.e., Resistance, R). The flow of electricity is defined as flowing from negative to positive.
|Ohm's Law:||I = g * V|
The basic functional unit of the nervous system are neurons, i.e., cells that are specialized for processing and communicating information. Neurons have a basic structure of:
- The cell body (or soma) is the bulbous end of a neuron, containing the cell nucleus and much of the cells metabolic machinery.
- The axon carries information away from the cell body and may range in size from several microns to as long as several meters in giraffes and whales. Axons may branch into terminal buttons (designated sites of communication) at its end.
- Dendrites receive neurotransmitter secreted by the axon of other neurons.
- Synapse is a specialized junction between cells of the nervous system which permits signalling between them.
Glial cells function as support for the neurons; they produce the myelin sheath which surrounds some neurons and also form part of the blood-brain barrier. The ratio of glial cells to neurons in the nervous system is disputed. Glial cells function as support for the neurons; they produce the myelin sheath which surrounds some neurons and also form part of the blood-brain barrier.
Organization of the Mammalian Nervous System
The neurons can all be placed in one of two systems, the central nervous system or the peripheral nervous system.
Central Nervous System
The central nervous system has a fundamental role in the control of behavior. It contains the brain and the spinal cord which are both incased in bone that protects them from mechanical injury. Both the brain and spinal cord receive signals from the afferent neurons and send signals to muscles and glands through efferent neurons.
Structure and Function
The CNS consists of brain and spinal cord. The brain is split up into three major sections.
The anteriormost division of the developing vertebrate brain that contains the most complex neural network in the CNS. The telencephalon (i.e., forebrain) has two major divisions, the lower diencephalon, which contains the thalamus and the hypothalmus, and the upper telencephalon, which contains the cerebrum.
The midbrain is located between the forebrain and the hindbrain and processes sensory and motor information relaying between the forebrain and the spinal cord.
The hindbrain is a well protected central core of the brain and includes the cerebellum, reticular formation, and the brain stem. The cerebellum plays an important role in the integration of sensory perception and motor output. It utilizes constant feedback on body position to fine-tune motor movements. The brain stem contains the pons, and the medulla oblongata. The pons relays sensory information between the cerebellum and cerebrum. The medulla oblongata is the lower portion of the brainstem. It controls autonomic functions such as breathing and vomiting, and relays nerve signals between the brain and spinal cord. The reticular formation is a part of the brain which is involved in stereotypical actions, such as walking, sleeping, and lying down.
In the past only two methods of observation were available. The first was observing individuals who have received brain damage and assume that the part of the brain that was damaged controlled the behavior or sense that had changed. The second was connecting electrodes to the outside of someones head and recording the readings.
Newer methods include computed tomography (CT scan), positron emission tomography (PET scan), magnetic resonance imaging (MRI), and superconduction quantum interference devices (SQUID).
Peripheral Nervous System
Any part of the nervous system that is not part of the central nervous system is part of the peripheral nervous system. The nerves in the peripheral nervous system is split up into the autonomic and somatic. The somatic connect the central nervous system to sensory organs (such as the eye and ear) and muscles, while the autonomic connect other organs of the body, blood vessels and glands.
- Laughlin SB., de Ruyter van Steveninck RR, and JC Anderson. "The metabolic cost of neural information." Nature Neuroscience 1.1 (1998): 36-41.