Touch a hot pan and your hand is off it before you feel the pain. In that fraction of a second, a signal travelled from your fingertip to your spinal cord and back to your arm muscles. Nerve signals are not electricity flowing down a wire. They are waves of ions crossing the cell membrane, one small patch after another, and they travel at up to about 120 m/s. Understanding how a neuron makes that wave, and how it passes the message to the next cell with a chemical, explains reflexes, memory, anesthetics, caffeine, antidepressants and addiction. First, the overall layout of the system:
- Central nervous system (CNS): the brain and spinal cord. It integrates information and makes decisions.
- Peripheral nervous system (PNS): all nerves outside the CNS. It carries information into and out of the CNS. Its somatic division controls skeletal muscles (mostly voluntary, plus reflexes); its autonomic division controls smooth muscle, cardiac muscle and glands (involuntary).
- Sympathetic division of the autonomic system ("fight or flight"): heart rate and force increase, pupils dilate, bronchioles dilate, digestion slows as blood is diverted to muscles, the liver releases glucose, the bladder relaxes. Its neurons mostly release norepinephrine at the organs.
- Parasympathetic division ("rest and digest"): heart rate slows (via the vagus nerve), pupils constrict, bronchioles constrict, digestion is stimulated, the liver stores glucose as glycogen, the bladder contracts. Its neurons release acetylcholine at the organs. The two divisions act like a brake and an accelerator on the same organs.
- Brain regions: the cerebrum (cerebral cortex, two hemispheres joined by the corpus callosum; frontal lobe for planning and movement, parietal for touch, temporal for hearing and memory, occipital for vision); the cerebellum (coordination and balance); the thalamus (relays sensory input to the cortex); the hypothalamus (homeostasis and control of the pituitary); and the brainstem, including the medulla oblongata (breathing rate, heart rate, blood pressure) and the pons (relays signals, helps regulate breathing).
Neurons and nerve impulses
A neuron is a cell specialized to carry electrochemical signals. Dendrites are short branches that receive signals from other cells and carry them toward the cell body, which contains the nucleus and most organelles. The axon is a single long extension that carries the signal away from the cell body, starting at the axon hillock (the trigger zone). Many axons are wrapped in a myelin sheath, layers of fatty membrane made in the PNS by Schwann cells (in the CNS by oligodendrocytes). Myelin insulates the axon so ions cannot cross there. The small uninsulated gaps between Schwann cells are the nodes of Ranvier. At the far end, axon terminals (synaptic knobs) release neurotransmitter onto the next cell. In the PNS, the outer membrane of the Schwann cells (the neurilemma) forms a tube that helps a cut axon regrow; the CNS lacks this, which is one reason spinal cord injuries rarely heal. Neurons come in three functional types. Sensory (afferent) neurons carry impulses from receptors toward the CNS; interneurons (association neurons) lie entirely within the CNS, connect sensory to motor neurons and do the integrating; motor (efferent) neurons carry impulses from the CNS to effectors (muscles and glands). The simplest circuit that uses all three is the reflex arc: receptor → sensory neuron → interneuron in the spinal cord → motor neuron → effector. The response happens before the brain is informed, which saves time. (The knee-jerk reflex is even simpler: the sensory neuron synapses directly with the motor neuron.)
A neuron at rest has a voltage across its membrane of about −70 mV: the inside is negative relative to the outside. It is set up by two things. First, the sodium–potassium pump (Na⁺/K⁺-ATPase) uses one ATP to move 3 Na⁺ out and 2 K⁺ in, so Na⁺ is concentrated outside and K⁺ inside, and each cycle moves one more positive charge out than in. Second, and more importantly, the resting membrane has many open K⁺ leak channels but few open Na⁺ channels. K⁺ diffuses out down its concentration gradient, carrying positive charge with it, while large negatively charged proteins stay trapped inside. The inside becomes negative until the electrical pull back in balances the diffusion outward. A membrane held at this voltage is polarized, and it stores energy in the ion gradients like a charged battery.
| Phase | What the channels do | Result |
|---|---|---|
| Resting | K⁺ leak channels open; voltage-gated Na⁺ and K⁺ channels closed; pump running | About −70 mV |
| Stimulus and threshold | A stimulus opens some Na⁺ channels; if the membrane reaches about −55 mV (threshold), voltage-gated Na⁺ channels open in large numbers | Positive feedback: Na⁺ entry depolarizes, which opens more Na⁺ channels |
| Depolarization | Na⁺ rushes in, down its concentration and electrical gradients | Inside becomes positive, peak about +30 to +40 mV |
| Repolarization | Na⁺ channels inactivate (close and cannot reopen yet); slower voltage-gated K⁺ channels open and K⁺ flows out | Potential falls back toward −70 mV |
| Hyperpolarization | K⁺ channels are slow to close, so a little too much K⁺ leaves | Briefly about −80 to −90 mV (undershoot) |
| Return to rest | K⁺ channels close; leak channels and the pump restore the resting state | −70 mV |
- All-or-none: if threshold is reached, a full-size action potential fires; if not, nothing propagates. A stronger stimulus does not make a bigger action potential.
- Coding intensity: a stronger stimulus produces a higher frequency of action potentials, and activates more neurons. The brain reads intensity from frequency, not size.
- Refractory period: during the absolute refractory period the Na⁺ channels are inactivated, so no stimulus can trigger another action potential. During the relative refractory period (hyperpolarization) only a stronger-than-normal stimulus can. The refractory period makes the impulse travel one way along the axon and sets the maximum firing frequency.
- Propagation: Na⁺ entering one patch of membrane spreads inside the axon and depolarizes the next patch to threshold. The patch behind is refractory, so the wave moves forward only.
- Saltatory conduction: in myelinated axons, ions can only cross at the nodes of Ranvier, so the action potential "jumps" from node to node. This is much faster (up to about 120 m/s) than continuous conduction in unmyelinated axons (about 0.5–2 m/s) and uses less ATP, because fewer ions need to be pumped back. In multiple sclerosis, loss of myelin in the CNS slows or blocks conduction.
The synapse, and drugs that act on it
A synapse is the junction between an axon terminal and the next cell (another neuron, a muscle fibre or a gland). The cells do not touch: a gap of about 20 nm, the synaptic cleft, separates them. The electrical signal cannot jump the gap, so it is converted into a chemical signal. When the action potential reaches the terminal, voltage-gated Ca²⁺ channels open and calcium ions flow in. Ca²⁺ triggers vesicles filled with neurotransmitter to fuse with the membrane and release it into the cleft by exocytosis. The neurotransmitter diffuses across and binds to specific receptors on the postsynaptic membrane, opening ligand-gated ion channels. Finally the neurotransmitter is removed, either broken down by an enzyme or taken back into the presynaptic cell (reuptake), so the signal is brief and can be repeated.
- Acetylcholine (ACh) is the neurotransmitter at every synapse between motor neurons and skeletal muscle, and in the parasympathetic system. The enzyme acetylcholinesterase in the cleft breaks it into acetate and choline within milliseconds; choline is recycled to make more ACh.
- Excitatory neurotransmitters (ACh at muscle, glutamate in the brain) open Na⁺ channels and depolarize the postsynaptic membrane (an excitatory postsynaptic potential, EPSP), moving it toward threshold.
- Inhibitory neurotransmitters (GABA, glycine) open Cl⁻ or K⁺ channels and hyperpolarize the membrane (IPSP), moving it away from threshold.
- Summation: one EPSP is usually too small to reach threshold. Temporal summation adds EPSPs arriving in quick succession from one synapse; spatial summation adds EPSPs arriving at the same time from many synapses. The axon hillock fires only if the total (excitatory minus inhibitory) reaches threshold. This is how neurons "decide".
- Synapses make transmission one-way (only the terminal has vesicles; only the postsynaptic cell has receptors) and add a short synaptic delay of about 0.5 ms.
| Substance | Action at the synapse | Effect |
|---|---|---|
| SSRIs (selective serotonin reuptake inhibitors, e.g. fluoxetine) | Block the transporter that takes serotonin back into the presynaptic neuron | Serotonin stays in the cleft longer; used to treat depression and anxiety. Full benefit takes weeks, as receptors adjust. |
| Caffeine | Blocks adenosine receptors. Adenosine builds up during waking hours and normally inhibits neurons and promotes sleepiness. | Increased alertness; with regular use the brain adds adenosine receptors (tolerance), so stopping causes withdrawal headaches and fatigue |
| Nicotine | Mimics ACh at nicotinic ACh receptors; indirectly triggers dopamine release in the brain's reward pathway | Stimulation and reward; highly addictive; receptors adapt so more is needed |
| Alcohol (ethanol) | Enhances the inhibitory effect of GABA and reduces the excitatory effect of glutamate | CNS depressant: slowed reactions, impaired judgment and memory; high doses depress the breathing centre in the medulla |
| Stimulants (cocaine; amphetamines; some ADHD medications such as methylphenidate) | Block reuptake of dopamine and norepinephrine (amphetamines also push extra transmitter out) | Increased alertness and focus; misuse of the more powerful stimulants causes euphoria, raised heart rate and addiction |