Action potentials
Nerve cells become active when action potentials (also called nerve signals or nerve impulses) are generated. At rest, neurons have a negative polarity (ie, the inside of the cell is negative compared with the outside of the cell). The resting membrane potential is kept in a dynamic equilibrium by the active separation of ions via specific membrane pumps, such that sodium kept out of the cell and potassium kept in. The action potentials are all-or-none events that are triggered at a specific threshold value of the membrane potential of the nerve cell. At this point, membrane channels for sodium, which are closed at rest, open, allowing a massive self-sustaining entry of sodium ions (Na+) into the cell. This intracellular flooding of positive ions results in a quick loss and reversal of the negative electrical polarity (ie the inside of the cell becomes positive compared with the outside). This is quickly followed by the opening of channels for potassium ions (K+), leading to a massive exit of potassium ions from inside the neuron, thereby restoring the negative polarity of the membrane potential. After an action potential, the neuron becomes hyperpolarised and unexcitable for a short period (refractory period).
Sodium ions enter the cell during the depolarisation phase and potassium ions leave the cell during the repolarisation phase and refractory period.
From: https://en.wikipedia.org/wiki/Action_potential
When the negative resting membrane potential loses some of its polarity (usually via the entry of sodium or calcium ions via their respective channels), it depolarises. This means it becomes more excitable and can more easily reach the threshold to initiate an action potential. Conversely, if the resting membrane potential becomes more negative (usually due to potassium channels allowing more potassium to leave the cell), it hyperpolarises, and becomes less excitable.
Once started, action potentials propagate along the nerve fibre in a non-decremental manner, something like a burning fuse. Propagation speeds (‘conduction velocities‘) range from a few cm/s to almost 100m/s. The refractory period prevents action potentials from propagating backwards along the same nerve fibre.
Neural activity normally consists of regular or irregular patterns of firing of that can occur at frequencies up to 100Hz. Neurons can sustain several thousand action potentials before a significant change in concentration of sodium and potassium ions in the cell becomes critical. The restoration of the separation of sodium and potassium ions requires energy. The energy required for this pumping process comes from the splitting of ATP to ADP. The enzyme that acts as a pump transporting the sodium and potassium ions back after the action potential is thus called ‘Na-K-ATPase‘.
From: https://en.wikipedia.org/wiki/Sodium–potassium_pump
The physical bases of the neural signals have been revealed by the Nobel Laureates Alan Hodgkin and Sir Andrew Huxley1, who in the middle of last century described neural activity as equivalent electrical circuits and developed differential equations relating the electrical features to the concentrations of certain ions.
From: https://en.wikipedia.org/wiki/Membrane_potential
Action potential initiation
The process of initiating action potentials differs between sensory neurons on one hand and interneurons and motor neurons on the other.
In sensory neurons, action potentials are initiated at their peripheral nerve endings. The molecular basis of sensitivity to specific environmental stimuli varies with different sensory modalities. However, in most cases, it is due to the presence of special protein molecules on the surface of neurons and, in some cases, of cells associated with them. These receptor molecules respond to certain physical events by changing their molecular conformation which leads to the generation of an action potential. For example, specific molecular receptors detect changes in temperature, mechanical deformation, light, or the chemical composition of liquids or gasses.
In humans, the main sensory modalities for external events (‘exteroceptors‘) are olfaction (chemicals in the air), taste (chemicals in the oral cavity), touch (mechanical events on the surface of the body), hearing (air-borne vibrations) and vision (electromagnetic waves). We are aware of the position of limbs (‘proprioceptors‘) and the position of the head associated with the sense of balance (vestibular system) via specialised mechanical sensors.
In addition, different classes of sensory neurons (nociceptors, from nocere = to harm) are sensitive to chemical substances released by damaged tissues caused by trauma, extreme heat or cold, infection, tumours, irritants or toxic substances. These neurons are involved in escape responses and pain sensation.
The sensitivity to external stimuli for each sensory modality is limited to a narrow range of each physical variable. For example, in humans, light is detected within a restricted range of electromagnetic wavelengths from violet to red: the visible spectrum. These wavelengths include light reflected from the large variety of chemicals commonly present on the surface of the earth such as plants and their fruits, other animals, and geological features of the earth itself. Although humans do not detect ultraviolet or infrared wavelengths of the electromagnetic spectrum in sunlight, other species do. For example, snakes detect infrared wavelengths that identify warm-bodied animals so they can hunt at night.
From: https://en.wikipedia.org/wiki/Electromagnetic_spectrum
Neurotransmission and action potential generation
Interneurons and motor neurons are activated by the process of neurotransmission which is mostly a chemically mediated process.
When an action potential reaches to the end of the nerve fibre, the presynaptic ending triggers the release of minute amounts of chemical substances, called neurotransmitters. These chemicals, usually released from specialised storage vesicles (synaptic vesicles), cross the very narrow gap between neurons, called the synapse, and act on special proteins, neurotransmitter receptors, located on the postsynaptic membrane either on the dendrites or on the cell body of the target neuron. When they bind transmitter molecules, receptors change the excitability of the postsynaptic neuron in different ways.
From: https://en.wikipedia.org/wiki/Activity-dependent_plasticity
From: https://en.wikipedia.org/wiki/Neurotransmission
Neurotransmitters that depolarise a localised patch of the membrane of the postsynaptic neurons produce excitatory postsynaptic potentials, shifting the membrane closer to the threshold for initiating action potentials. Conversely, neurotransmitters that increase the polarity of a localised patch of the postsynaptic membrane (hyperpolarising it) generate inhibitory postsynaptic potentials that render the postsynaptic neuron less excitable.
The net effect of presynaptic excitatory and inhibitory inputs onto a postsynaptic neuron is a kind of biological arithmetic based on the number of inputs (called spatial summation) and the frequency of their arrival (temporal summation). If the sum of the synaptic inputs pushes the membrane of the postsynaptic neuron to its threshold, it will trigger an action potential.
Left: A single impulse from a presynaptic neuron elicits a single excitatory postsynaptic potential in a postsynaptic neuron, which is not enough to trigger an action potential.
Right: After a rapid sequence of presynaptic impulses, the excitatory postsynaptic potentials sum to reach threshold for generating an action potential.
From: https://en.wikipedia.org/wiki/Summation_(neurophysiology)
Neurotransmission from motor neurons to muscle cells in the body of mammals (neuromuscular transmission) has been extensively studied and found to be very effective with little requirement for temporal or spatial summation. Normally, every action potential of a motor neuron that reaches its neuromuscular junction triggers contraction of the muscle.
In addition to a spatial and temporal summation, more subtle processes can modulate synaptic transmission. Not only do neurons make synapses onto the dendrites and cell bodies of other neurons but also onto presynaptic nerve endings of other neurons. By inhibiting or exciting a presynaptic nerve ending, these axo-axonic synapses can modulate the strength of synaptic transmission between two neurons.
Neurotransmission can be fast (a few ms) or slow (several hundred ms) depending on the molecular mechanisms of activation of postsynaptic transmitter receptors. When activated, fast neurotransmitter receptors let specific ions to cross the membrane (via ligand-gated ion channels); such receptors can generate excitatory or inhibitory postsynaptic potentials depending on their type. Other neurotransmitter receptors (G-protein coupled receptors) are linked to multiple intracellular molecular processes which involve more chemical steps and only indirectly change the excitability of the postsynaptic neurons. Transmission via these receptors is slow, and can influence other metabolic processes.
Furthermore, nerve cells can utilise more than one active chemical substance as neurotransmitters. This process called multiple neurochemical transmission or plurichemical transmission. The number of neurotransmitter classes has grown well beyond the initial classic neurotransmitters which included acetylcholine, noradrenaline (norepinephrine), dopamine, serotonin (5-hydroxytryptamine, 5-HT), glutamate, and GABA (γ-aminobutyric acid). Neuropeptides, consisting of short chains of amino acids, act widely as slow neurotransmitters. In addition, molecules with unrelated biochemical functions, such as nitric oxide (NO) and adenosine triphosphate (ATP) can act as neurotransmitters. Plurichemical transmission usually involves a low-molecular weight classic transmitter in combination with one or more neuropeptides.
Chemical neuroanatomy
The discovery of multiple neurochemical transmission led to the idea that specific classes of neurons contain unique combinations of neurotransmitters and other neurochemicals. Indeed, our discovery several decades ago that enteric neurons contain and utilise more than one neurotransmitter, especially neuropeptides, opened a new era in neuroscience. Arising from these studies, I was involved, with a few others, in establishing the concept of plurichemical neurotransmission in the enteric neural circuits2. This concept eventually extended to all components of the nervous system including the brain3.
The idea of a ‘chemical coding‘ of neurons along with their associated ‘chemical neuroanatomy’ grew from these studies4 and is now well established5. Nevertheless, the role of multiple neurotransmitters in many neuronal circuits is not yet clear. It opens up a very large range of possible forms of neurotransmission that can operate in parallel with different time courses and with varying spatial extents, thereby modulating the excitability of postsynaptic neurons in highly specific ways.
Finally, some neurotransmitters may also act at some distance beyond the synaptic gap, a process described as volume transmission6. Yet there may be still a very high level of spatial and temporal precision in this form of transmission because of the specific locations of the transmitter receptors.
In addition to neurons, the nervous system consists of other cell types including glia (the supporting cells of the nervous system) and blood vessels, but I will not mention these unless relevant to this essay.
- AL Hodgkin & AF Huxley (1952): A quantitative description of membrane current and its application to conduction and excitation in nerve. The Journal of Physiology 117(4), 500–544. ↩︎
- JB Furness, JL Morris, IL Gibbins & M Costa (1989): Chemical Coding of Neurons and Plurichemical Transmission. Annual Review of Pharmacology and Toxicology 29, 289-306.
M Costa & SH Brookes (2008): Architecture of enteric neural circuits involved in intestinal motility. European Review for Medical and Pharmacological Sciences 12 (Suppl. 1), 3-19. ↩︎ - For example, see: O Hornykiewicz (2001): Chemical neuroanatomy of the basal ganglia — normal and in Parkinson’s disease. Journal of Chemical Neuroanatomy 22, 3-12.
NE Lazarov (2002): Comparative analysis of the chemical neuroanatomy of the mammalian trigeminal ganglion and mesencephalic trigeminal nucleus. Progress in Neurobiology 66, 19-59.
Oboti L et al. (2011): From chemical neuroanatomy to an understanding of the olfactory system. European Journal of Histochemistry 55(4) e35. ↩︎ - M Costa, JB Furness & IL Gibbins (1986): Chemical coding of enteric neurons. Progress in Brain Research 68: 217-239. ↩︎
- For example, there is a well-respected Journal of Chemical Neuroanatomy. ↩︎
- LF Agnati K et al (1995): Intercellular communication in the brain: wiring versus volume transmission. Neuroscience 69, 711-726.
Fuxe & DO Borroto-Escuela (2016): Volume transmission and receptor-receptor interactions in heteroreceptor complexes: understanding the role of new concepts for brain communication. Neural Regeneration Research 11, 1220-1223. ↩︎