Hierarchical Brain

Neuromodulation

Neuromodulation is the process by which chemicals, mostly emitted from neurons, but some from glia and some specific places outside the brain, can affect the action of many synapses and neurons in the brain, and can therefore change the behaviour of many neurons. The chemicals involved are many of the same neurotransmitters that are used at chemical synapses, but neuromodulation can affect many synapses on many neurons over a wide area that is remote from the source in many different ways.

Neuromodulation is part of level 1 in my seven-level hierarchical model because it is a low-level function that involves the other components of level 1, neurons, synapses, glia and neurotransmitters. However, at a higher level of description, neuromodulation has an emergent effect on the connections between symbol schemas, which means that there are implications for many high-level features including attention, feelings, sleep and consciousness. So some of the descriptions on this page should ideally be in level 6 of my hierarchy, but I have left them here as a convenience.

(This website does not cover the subject of neuromodulation as a therapy, which aims to artificially change the activity of neurons. This should only be carried out under expert medical supervision because it could make irreversible changes to the processing of the brain. The effects could be similar to those caused by taking psychoactive drugs.)

Overview

• Neuromodulation can be described within the brain as mass action at a distance, where the action is the changing of the behaviour of neurons and synapses.
  • It has also been called heterosynaptic plasticity, meaning changes to the behaviour of a synapse caused by the cells other than the two neurons involved in the synapse, but the more general definition of neuromodulation includes changes to neurons at places other than synapses as well as changes to the behaviour of glial cells.
  • Modulation is an apt suffix to describe what these chemicals do because they change the already-existing actions of neurons and synapses.
    • However, the verb “to modulate” in everyday English usually means to dampen down or decrease something, whereas the presence of neuromodulators may quite often increase the activity of synapses or neurons.
  • The actions of neuromodulation can affect almost the whole brain, and its effects are very varied ranging from short-term changes to synapses that last a few milliseconds, to medium-term changes to the properties of neurons and synapses that can last seconds to minutes, to long-term changes to the structure of networks that can last a lifetime^{1, 2}.
    • Short-term changes can be when the neuromodulator matches the chemical that affects ion channels at a synapse, so changing the activity of that synapse.
    • Medium-term changes can be when the neuromodulator matches the chemicals accepted by G-protein-coupled receptors (GPCRs) at synapses (see GPCR - neurotransmitters), which can go on to affect ion channels and other membrane proteins, and so change future synapse functionality.
    • Long-term changes to circuits come about because of changes to the strengths or reliabilities of synapse connections, and changes to mRNA synthesis which can then cause long-term changes to behaviours³.
    • Any of these changes can vary from moment to moment and they can also interact with each other, so the overall effects are very dynamic.
    • It is thought that neuromodulation varies more between species than other brain changes vary between species, which is presumably because changes via neuromodulation can evolve more quickly that permanent structural changes to the brain⁴.
  • What this all means is that, when investigating the workings of the brain, looking at physical connections between neurons is not sufficient to establish the communication paths; neuromodulation must also be taken into account because it can create invisible non-physical connections⁵.
• Most of the contents of this page are not required to be understood for an understanding of the rest of the hierarchy of levels of description of the workings of the human brain that are described on these web pages.
  • When looked at from a functional point of view, neuromodulation is exactly the same as a neuron having many extra axons that have synapses onto multiple remote neurons.
  • This is how my modelling of the brain using simplified ABCD model neurons can include neuromodulation.
  • There are some additional complications, such as the fact that glia cells can be involved in the production of neuromodulatory chemicals⁷, and also that neuromodulators can come from organs outside the brain, or even from outside the body (e.g. alcohol or anaesthetics) but these can also be modelled as if they were just additional events that could have been initiated within the brain.
• The mechanisms of neuromodulation can be relatively easily explained given a general understanding of the way that synapses and neurotransmitters work.
  • Molecules of neuromodulators diffuse through the cerebrospinal fluid, the body of liquid that surrounds all cells in the brain, so can potentially reach all neurons and glial cells.
  • Since all neurons have synapses, the behaviour of all neurons can potentially be affected by neuromodulation.
  • Neuromodulators are, as a general rule, those neurotransmitter chemicals that are small molecules, including neuropeptides. However, nearly all neurotransmitters can have neuromodulatory effects.
  • Whether a particular synapse or neuron is affected by a particular neuromodulator and what effect it has is solely dependent on the types of receptors in the neuron and, in particular, the receptors at the synapse.
  • The types of receptors found on a particular neuron are generally specific to the type of neuron⁸.
• Some of the main neuromodulators that have effects on only some specific functions or some specific types of neurons have been categorised into systems.
  • All the neurons that have synapses that react to a particular neurotransmitter are grouped together into one of these systems.
  • The two main neuromodulators that have an effect on almost all areas of the brain are not included in these categories. These are glutamate, the most common excitatory neurotransmitter, and GABA, the most common inhibitory neurotransmitter.
• The accepted view is that neuromodulation is an important component of communication within all parts of the brain, at all times. For example, it is required for sleep, mood, body homeostasis (regulation), learning, attention and consciousness.
  • Despite this, until quite recently some neuroscience textbooks have tended to concentrate on the neuron-to-neuron communication via synapses and skip over the much more variable influence of neuromodulators^{9, 10},
  • Similarly, many models of the brain have not included the flexibility of neuromodulation.

Examples

• The most obvious evidence for the effect of neuromodulation that we can all easily be aware of is the action of certain well-known chemicals that humans commonly drink, eat, inject, smoke, or otherwise ingest. We know that the effects can be dramatic and affect the whole brain.
  • Drugs including nicotine, caffeine, alcohol and the various general anaesthetics all act as neuromodulators because they are either the same as, or have similar chemical structures to, chemicals that are produced in the brain and used as neuromodulators, so they have the same effects.
  • Any of these chemicals, in any significant quantity, will therefore affect and possibly disrupt the normal functioning of the brain.
• Another well-known effect of neuromodulation is when pain or discomfort is able to be ignored or at least experienced far less by people in a highly stressful situation, for example, on the battlefield, in a fight, or perhaps just when speaking in front of an audience.
  • This has been described as stress-induced analgesia⁶, and is a form of hypoalgesia.
  • The reason for this is that neuropeptides including enkephalin, which are opioids produced in the brain, are released as neuromodulators in response to the stressful (fight-or-flight) situation.
  • These chemicals temporarily inhibit pain sensation by activating opioid receptors that are on the presynaptic terminals of neurons involved with pain perception. This diminishes the amount of neurotransmitter released by these neurons, hence the perception of pain is less⁶.
  • These opioid receptors are a type of G protein-coupled receptor (see neurotransmitter reception) that produce proteins that can have relatively long-term effects on neurotransmission, which is how the effect can last for some time.
  • This is exactly the same reason why opioid drugs are pain killers and can last for a reasonable time.
  • There has been recent reporting of pain reduction caused by swearing particularly in those who do not swear frequently. The assumed reason for this working is that swearing activates the same types of stress and fight-or-flight hormones as stressful situations, due to their tightly-bound connections to those situations.
• Another common use of neuromodulation is to control learning¹¹.
  • The brain has to have a way of controlling which inputs cause changes to networks and which do not, and then also, of those inputs that do cause changes, how permanent those changes should be.
  • This selection process is what we call attention, and influences from many directions govern how far up the hierarchical tree of afferent processing an input gets, and therefore what changes are made to symbol schemas and efferent connections.
  • These influences clearly affect individual connections, but there are mor general circumstances when it is important that things are remembered, and the brain has evolved a shortcut way to make sure that this is done as efficiently as possible.
  • That shortcut is to distribute a neuromodulator that acts on many neurons in a number of different areas and basically sends a message to say “what is happening now is important, so it needs to be remembered”.
  • This happens at times of serious threat (the same as with fight-or-flight discussed above), but can also happen when there is a strong reward or motivation.

Details of my proposals

• Neuromodulation can be described as acting differently at different levels of description.
  • At a low level of detail, the action of many different neuromodulators on millions of neurons and trillions of synapses in the brain is extremely complex and very rapidly changing, and it would be extremely difficult to make sense of it.
  • However, at a higher level of detail, it is clear from the examples above that the concentration of certain common neuromodulators can cause high-level changes in the brain - e.g. mood, sleep, the ability to remember and learn, actions to take and so on.
    • At first sight, this seems like a puzzle - how does any individual neuron “know” what receptors it should have and therefore which neuromodulators it should respond to?
    • The answer is clearly that it doesn’t, all neurons of a particular type potentially respond to the same neuromodulators and therefore have the same receptors.
    • An important factor is that chemicals in the cerebrospinal fluid diffuse quickly so their effect will only be relevant if the concentration of molecules is high enough, which depends on the numbers released and the distances involved.
    • In many ways, this is similar to the decision made inside a neuron at the start of the axon as to whether or not to fire an action potential; it is often described as a summation, but it is in fact simply dependent on the concentration of ions, which in turn depends on the number of ion molecules arriving and the distance they have to travel.
  • At the lowest level, neuromodulation only makes any significant different to a neuron or a synapse if that neuron or synapse is activated.
  • At the higher level, neuromodulation only makes any significant different to a symbol schema’s connections to other symbol schemas if the symbol schema in question is activated.
• So within my hierarchical levels of description described on this website we should examine how neuromodulation works at the level of symbol schemas (which should be discussed in level 6 of my hierarchy).
  • The three examples given above can all be examined at the level of symbol schemas.
    • The effects of the various drugs can be described at the level of neurons and synapses, but they clearly can cause a large scale disruption to connections between symbol schemas. In particular, drugs that act as anaesthetics (including alcohol in sufficient quantity) can almost completely disrupt the efferent connections from the self symbol schema that are required for attention and therefore consciousness.
    • Similarly, hypoalgesia (not feeling pain) can be described as above in terms of the effects of particular neurotransmitters on certain synapses, but can also be described as the dampening of signals from symbol schemas that represent pain to the self symbol schema.
    • The modulation of attention, that affects learning, must be a lowering of the strength of the inhibitory influence of one symbol schema over another, so that attention can be paid to one thing for longer than normal, without distractions. In other words, the ability to concentrate on one subject would be enhanced by a drop in inhibition.
    • Sleep must include (among other things) a drop in strength of efferent connections from my self symbol schema towards sensory areas, so that I became much less conscious of external stimuli.
• Neuromodulation is obviously a slower process than transmission of signals via neurons, so it is mostly used to change states that do not have to happen very quickly.
  • This includes alertness, sleepiness, attention etc., none of which need to happen within milliseconds.
  • However, it is also used for some states that do need to happen quite quickly such as emotional states of high alert.

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References For information on references, see structure of this website - references

1. ^ SnapShot: neuromodulation - Bucher and Marder 2013
   doi: 10.1016/j.cell.2013.09.047 downloadable here or see GoogleScholar.
   Fifth paragraph, under the heading “Neuromodulators Act in a Variety of Ways”: “Neuromodulator receptors can be found in all neuronal compartments, influencing every aspect of neuronal computation, from synaptic integration to action potential initiation and propagation to presynaptic transmitter release. The two most common types of modulator actions are through ionotropic or metabotropic (G-protein-coupled) receptors. Ionotropic receptors in extrasynaptic membrane can directly change membrane potential and input resistance and therefore affect response properties or spontaneous activity. G-protein-coupled receptors often act through second messenger systems that activate kinases that phosphorylate ligand- or voltage-gated ion channels to change their gating properties.”
2. ^ Neuromodulation of neurons and synapses - Nadim and Bucher 2014
   doi: 10.1016/j.conb.2014.05.003 downloadable here or see GoogleScholar.
   Last-but-one sentence of abstract: “...neuromodulators can exert effects at multiple timescales, from short-term adjustments of neuron and synapse function to persistent long-term regulation.”
   Second sentence of introduction: “All nervous system function, from simple reflexes to sleep, memory and higher cognitive tasks, ultimately result from the activity of neural circuits. A wide variety of substances, including small molecule transmitters, biogenic amines, neuropeptides and others can be released in modes other than classical fast synaptic transmission, and modify neural circuit output to produce extensive adaptability in behaviors. They do so by changing the properties of a circuit’s constituent neurons, their synaptic connections or the inputs to the circuit. Such functional reconfiguration of hard-wired circuits is essential for the adaptability of the nervous system.”
   Page 2 under the heading “Neuromodulation of synapses”: “Neuromodulators modify synaptic communication through a number of mechanisms which can be broadly divided into effects that target synapses directly and those that indirectly modify synaptic interactions by changing the excitability of neurons. Indirect effects include presynaptic modulation that can lead to changes in action potential shape, and postsynaptic modulation that for example increases voltage-gated inward currents to enhance EPSPs. ... Direct effects on synaptic interactions can also be divided into pre- and postsynaptic mechanisms. Presynaptically, neuromodulators often target the probability of vesicular release by modifying presynaptic Ca²⁺ influx, the size of the reserve pool, or proteins in the active zone. On the postsynaptic side, the expression and properties of transmitter receptors can be modified to change postsynaptic responses independent of neurotransmitter release. Modulation of neurotransmitter release can also occur through local feedback that alters the level of release through retrograde messengers or autoreceptors. Finally, neuromodulator release itself can be subject to modulation. For example, nitric oxide (NO) can modify modulatory actions of glutamate or serotonin (5-HT), an example of a broader category of neuromodulatory actions referred to as meta-modulation.”
   Page 7, second sentence of “Summary and conclusions”: “Synaptic modulation is not limited to changes in the strength of connections, but involves modifications of short- and long-term synaptic plasticity. Similarly, neuromodulation of intrinsic excitability is not limited to simple amplification or reduction of responsiveness to input, but can shape the nonlinear interactions between different currents to give rise to qualitatively different membrane behaviors. A single modulator can control multiple aspects of synaptic and intrinsic dynamics in a single neuron, and multiple modulators can affect these properties through converging and diverging intracellular pathways. The complexity of cell-type specific effects, their highly nonlinear dynamics, as well as the fact that multiple neuromodulators may act at the same time, presents a challenge in trying to understand consequences for circuit output. Even if much of the modulatory effects are described quantitatively in a given circuit, their functional synthesis will require new theoretical approaches and computational modeling.”
3. ^ Neuromodulation of Neuronal Circuits: Back to the Future - Marder 2012
   doi: 10.1016/j.neuron.2012.09.010 downloadable here or see GoogleScholar.
   Start of abstract: “All nervous systems are subject to neuromodulation. Neuromodulators can be delivered as local hormones, as cotransmitters in projection neurons, and through the general circulation. Because neuromodulators can transform the intrinsic firing properties of circuit neurons and alter effective synaptic strength, neuromodulatory substances reconfigure neuronal circuits, often massively altering their output.”
4. ^ Neuromodulation - Katz and Calin-Jageman - 2009 from Encyclopedia of Neuroscience volume 6, pages 497-503.
   doi: 10.1016/B978-008045046-9.01964-1.
   Summary of chapter: “Neuromodulation is the alteration of neuronal and synaptic properties by neurons or substances released by neurons. Neuromodulatory actions, which are generally mediated by G-protein-coupled receptors, affect ion channels and other membrane proteins, thereby altering the firing, synaptic release, or synaptic response properties of neurons. Neuromodulation changes how neurons act in the context of neuronal circuits, allowing anatomically defined circuits to produce multiple outputs reconfiguring networks into different functional circuits. The effects of neuromodulation are not static but, rather, produce a dynamic regulation of neuronal circuits. Changes in neuromodulation may play an important role in the evolution of species-specific behaviors.”
5. ^ Beyond the connectome: how neuromodulators shape neural circuits - Bargmann 2012
   doi: 10.1002/bies.201100185 downloadable here or see GoogleScholar.
   The abstract and introduction on page 458 says that a wiring diagram (the popular word now is a connectome) of the brain is not sufficient to allow one to know exactly what happens because the action of neuromodulators can alter the way that synapses work and therefore can change the functional connectivity.
   From the abstract: “These wiring diagrams are incomplete ... because functional connectivity is actively shaped by neuromodulators that modify neuronal dynamics, excitability, and synaptic function. Studies ... have revealed the ability of modulators and sensory context to reconfigure information processing by changing the composition and activity of functional circuits. Each ultrastructural connectivity map encodes multiple circuits, some of which are active and some of which are latent at any given time.”
6. ^ ^ Ibid. Beyond the connectome: how neuromodulators shape neural circuits
   Page 462, under the heading “Neuromodulation in flies and mammals”, subheading “Sensory inputs are gated and modulated by internal states”: “One mechanism by which neuromodulators reconfigure circuits is to change the gain of peripheral sensory inputs. A familiar example of this kind of plasticity is stress-induced analgesia, an acute suppression of pain responses that has been characterized in rodents and to some extent in humans. During stress, enkephalin and other peptides (endogenous opioids) are released by descending brainstem circuits and peripheral cells, and temporarily inhibit pain sensation by activating G protein-coupled opioid receptors on the presynaptic terminals of primary nociceptive neurons and spinal cord resident neurons. The opioid receptors diminish synaptic neurotransmitter release by nociceptive neurons, inhibiting the perception of pain. Stress-induced analgesia is a dramatic example of the uncoupling of a sensory stimulus by a neuromodulator, and demonstrates that the principle of flexible circuit composition extends to mammals.”
7. ^ Release of neurotransmitters from glia - Fields 2010
   doi: 10.1017/s1740925x11000020 downloadable here or see GoogleScholar.
   Start of abstract: “There is no question about the fact that astrocytes and other glial cells release neurotransmitters that activate receptors on neurons, glia and vascular cells, and that calcium is an important second messenger regulating the release.”
   Second paragraph: “Should the same molecule, glutamate, for example be called a neurotransmitter when it is released from axons through membrane channels, rather than from synaptic vesicles, or released by reversal of amino acid transporters in communicating with other neurons? Or, should glutamate, when released from neurons through non-vesicular mechanisms, be referred to by some different name. Likewise, when glutamate is released from an astrocyte, should it be called a 'gliotransmitter', even when this mediates communication with neurons?”
8. ^ Hundreds of small molecules known as neuromodulators might influence how we learn - Allen Institute (an independent nonprofit bioscience research institute) 2021
   Sixth paragraph: “The proteins that recognize and react to neuromodulators, a certain kind of receptor protein, seem to be highly specific for different neuron types. That is, each kind of neuron in the brain also bears a unique neuromodulator receptor, into which a single kind of neuromodulator fits, like a key into a lock.”
9. ^ Cognitive Neuroscience: The Biology of the Mind - Gazzaniga, Ivry and Mangun, Fourth Edition 2014 Norton & Company USA
   This otherwise very useful book has sections on neurons, synapses and synaptic transmission, but in its 645 pages has no mention of neuromodulation or neuromodulators.
10. ^ Principles of Neural Science Fifth edition - Kandel et al. McGraw-Hill US 2012
    This comprehensive reference work, in its 2012/3 edition, has only four passing references to neuromodulators or neuromodulation, despite detailed chapters on synaptic transmission and neurotransmitter action. This omission is fixed in the latest sixth edition of 2021 with over 20 references.
11. ^ Livewired - David Eagleman, Canongate 2020
    Page 149 under the heading “Allowing the real estate to change”: “How does the brain know when something important has happened and that it should change its wiring accordingly? One strategy is to turn on plasticity when events in the world are correlated. That is, encode only those things that co-occur, such as seeing a cow and hearing a moo. In this way, related events become bound together in the tissue. Slow change is important here, because sometimes associations are spurious. ... For instance, you may see a cow but hear the bark of an unrelated dog. The brain would be ill-advised to permanently store every accidental co-occurance [sic], so its solution is to change sluggishly, just a little at a time. In this way, it can encode only those things that commonly coincide. Real matches distinguish themselves from noise by occuring [sic] together over and over again. But despite the wisdom of slow and steady change, extracting averages isn’t the whole story. Consider one-trial learning, in which you touch a hot stove once and learn not to do it again. Emergency mechanisms exist to make sure that life- or limb-threatening events are permanently retained. But the story of one-trial learning goes deeper than that. Think back to when you were young and your aunt taught you a new word ('This is called a pomegranate'). You didn’t need to learn this in an emergency situation, and nor did your aunt need to make the association a hundred times. She calmly told you once, and you got it. Why? Because it was salient to you. You loved your aunt, and you derived social benefit from knowing a new word and being able to ask for the fruit. This is one-trial learning not because of threat, but instead because of relevance. Inside the brain, this relevance is expressed through widely reaching systems that release chemicals called neuromodulators. By releasing with high specificity, these chemicals allow changes to occur only at specific places and times instead of all over at every moment. An especially important chemical messenger is called acetylcholine. Neurons that release acetylcholine are driven by both reward and punishment. They’re active when an animal is learning a task and needs to make changes, but not once the task is well established. The presence of acetylcholine at a particular brain area tells it to change, but it doesn’t tell it how to change. In other words, when the cholinergic neurons (those that spit out acetylcholine) are active, they simply increase plasticity in the target areas. When they’re inactive, there’s little or no plasticity.”
    End of note 20 on page 273: “Note that many neuromodulators transiently change the balance of excitation and inhibition; this had led to one hypothesis that disinhibition is one mechanism by which neuromodulation enables long-term synaptic modifications.”
    Page 152, 3rd paragraph: “Cholinergic neurons [those that release the neuromodulator acetylcholine] reach out widely across the brain, so when these neurons start chattering away, why doesn’t that turn on plasticity everywhere they reach, causing widespread neural changes? The answer is that acetylcholine’s release (and effect) is modulated by other neuromodulators. While acetylcholine turns on plasticity, other neurotransmitters (such as dopamine) are involved in the direction of change, encoding whether something was punishing or rewarding. Researchers all over the planet are still working to decipher the complex choreography of the neuromodulatory systems - but we know that collectively these chemical messengers allow reconfiguration in some areas while keeping the rest locked down.”

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