Hierarchical Brain

An explanation of the human brain

First published 1st February 2024. This is version 1.5 published 2nd March 2024.
Three pages are not yet published: sleep, memory and an index.
Copyright © 2024 Email info@hierarchicalbrain.com

Warning - the conclusions of this website may be disturbing for some people without a stable mental disposition or with a religious conviction.


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.)

Contents of this page
Overview - a high level description of neuromodulation.
Examples - some well-known examples of neuromodulation.
Details - details of my proposals on neuromodulation.
References - references and footnotes.



Details of my proposals

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.”

Page last uploaded Wed Feb 14 08:51:35 2024 MST