Neuromodulation · Grey Matter

Neuromodulation is the slow adjustment of how neurons and synapses respond, made by transmitters that change excitability, release probability and plasticity across a whole region, and it is how the brain switches one fixed set of circuits between states such as alert, drowsy, curious or stressed.

Neuromodulation. Neuromodulation is the slow adjustment of how neurons and synapses respond, made by transmitters that change excitability, release probability and plasticity across a whole region, and it is how the brain switches one fixed set of circuits between states such as alert, drowsy, curious or stressed.

The classic neuromodulators are dopamine, noradrenaline, serotonin, acetylcholine and histamine, each made by a small nucleus whose axons spread over large territories, plus neuropeptides and endocannabinoids. They act almost entirely through metabotropic receptors, often outside synapses. They work on the machinery the fast signals use: they open or close potassium channels, change the probability of release, alter how dendrites integrate and set whether a coincidence will become a lasting change.

Fast transmission carries content, modulation sets context. Glutamate and GABA say what the input is and where; modulators decide how strongly the circuit should respond to it and whether to remember it.

The same circuit can produce different outputs. Studies of small invertebrate circuits showed that neuromodulators reconfigure one fixed wiring diagram into several distinct rhythms, a principle that carries over to the cortex.

It moves the operating point. By shifting excitability, neuromodulators move the excitation-inhibition balance, which is how arousal, sleep loss and stress can change a network's tendency to synchronise.

Neuromodulators change the rules of a circuit while leaving its wiring alone.

That makes a brain with fixed connections able to behave like several different machines, one per state.

Questions: What makes a neuromodulator different from a fast transmitter like glutamate? Glutamate and GABA act through ion channels at a specific synapse for milliseconds, so they carry the content of a signal: which cell, when, and with what sign. Neuromodulators such as dopamine, noradrenaline, serotonin and acetylcholine come from small nuclei with widely branching axons, are often released outside synapses, and act mostly through G protein-coupled receptors for seconds to minutes. They change how strongly neurons respond, how likely synapses are to release, and whether coincident activity will be stored. The same molecule can be both (acetylcholine is a fast transmitter at muscle and a modulator in the cortex), so the distinction is about the receptor and the wiring, more than the chemical. What does a burst of dopamine signal? Recordings in monkeys showed that midbrain dopamine neurons burst when a reward arrives unexpectedly, stay at their baseline rate when a fully predicted reward arrives, and pause when a predicted reward fails to come. As the animal learns that a cue predicts the reward, the burst moves from the reward to the cue. This is the reward prediction error of reinforcement-learning theory, the difference between what happened and what was expected, as Schultz, Dayan and Montague pointed out in 1997. Broadcast to the striatum and frontal cortex, the signal tells recently active synapses whether the outcome was better or worse than predicted, so it acts as a teaching signal more than a pleasure signal. What does acetylcholine from the basal forebrain do to the cortex? Cholinergic neurons of the nucleus basalis and nearby basal forebrain project across the cortex and are most active in attentive waking and in REM sleep. Their acetylcholine makes cortical neurons more excitable and, in many studies, boosts responses carried by incoming sensory pathways relative to activity from recurrent connections within the cortex. One account is that this tilts the cortex toward taking in new information and encoding it, rather than recalling what it already holds. Loss of these neurons early in Alzheimer's disease is one reason cholinesterase inhibitors give a modest benefit there. Where does the brain's serotonin come from, and how does it reach so many regions? Nearly all of it comes from the raphe nuclei, clusters of neurons along the midline of the brainstem; the upper ones (the dorsal and median raphe) project to the forebrain and the lower ones to the spinal cord. Like the noradrenaline and dopamine systems, a small population of cells sends highly branched axons that release serotonin over wide territories, often outside classical synapses. Serotonin then acts through more than a dozen receptor types, almost all metabotropic, so the same release can excite some cells and inhibit others. This layout makes serotonin a modulator of state (mood, sleep, appetite, the response to stress) more than a carrier of specific messages.