#66. Neuromodulators as Peril Specialists [Neuroscience]

NE

Red: theory; black, fact.

Solanum dulcamara, a plant with anticholinesterase activity.

“Life is Difficulty”

My PhD thesis was about a neuromodulator acting on mammalian brain. It was tough to decapitate all those rats; I never got used to it. But if you can’t stand the formaldehyde, get out of the lab.

The basic theory

I conjecture that the primordial function of any type of transmitter substance acting on the g-protein-coupled cell-surface receptors or nuclear receptors of neurons was to coordinate the whole-organism response to some class of perils.

 

Complications

Glutamate, GABA, and acetylcholine are usually considered neurotransmitters, not neuromodulators, but all three have G-protein-coupled receptors in addition to ionotropic receptors and are thus both.

In thermoregulation, hypothalamic glutamate and GABA act on the body via the serotonergic raphe pallidus nucleus. The implied connection with predation (See table) would be due to the fact that animals become torpid at extremes of temperature and thus easy prey. The larger predator would have a smaller surface to volume ratio and thus slower warming and cooling after leaving its refugium to hunt. The predator thermal advantage would have been the selection pressure for thermal sensitivity in the anti-predation system, which eventually became upstream of temperature regulation effectors generally. 

The functional assignments suggested in Table 1 would mostly pertain to a very primordial brain. The implication is that any modern biological function of the neuromodulator substance other than organizing the response to a specific type of peril was elaborated out of the primordial function over long-term evolution, which can act opportunistically to confer new functions on preexisting adaptations.

An example of such elaboration is shown for dopamine in the inferred social role. A pre-adaptation for this role split may have been breast-feeding.

Table 1.

Peril	Substance	Failure mode
Extremes of heat and cold	glutamate and GABA	?
Predator	serotonin	depression
Parasite	histamine	phobia
Rival conspecific	noradrenaline	paranoia
Social isolation Starvation	dopamine dopamine	autism (-), ADHD (+) addiction
Non-reproduction	testosterone and estrogen	overpopulation
Change per se	acetylcholine	positive symptoms of schizophrenia

Food poisoning, Substance P

<10-30-2020: human failure modes added.>

Complex instincts

A network of neuromodulator interactions exists, which may serve to implement the more complex innate behaviors such as migration, nest building, and care of the young. The chemically information-rich peptide neuromodulators such as oxytocin, orexin, and cholecystokinin may organize the fine details of such behaviors.

Mosaic model

Thus, all human-characteristic behaviors will be made of the same primordial behavioral components, but in different combinations and sub serving different functions. For example, there seems to be at least a bit of the male-female interaction mixed into all our fraught dyadic interactions of whatever biological purpose; if operant learning helps to shape the behavior, you can be sure that dopamine is involved; the perception of any existential threat will call up serotonin, and so on.

Notes on serotonin

07-06-2020: The assignment of serotonin to the organization of anti-predation defenses may require some explaining because this chemical is usually thought of as some kind of happy juice due to evidence from SSRI-type drugs that elevating its concentration in the brain can often produce a mood elevation in clinically depressed patients. I propose that the anti-predation defenses organized by serotonin have a short-term part and a long-term part (called phasic and tonic, respectively, when referring to individual neurons). One predator emergency would trigger only the short-term part, organized by a single burst of serotonin release in the brain and spinal cord. (Four of the eight serotonin-releasing brain nuclei innervate the spinal cord, where our fastest reflexes are organized, which we need to escape from lunging predators.) Multiple predator emergencies happening within too short a time would induce the long-term part. Paradoxically, this part would be organized by a long-term reduction in the release of serotonin to below its normally non-zero baseline level, probably due to upregulation of the inhibitory 1B serotonin autoreceptors on the serotonergic presynaptic terminals. Depressed mood would ensue, which we know involves little physical activity. This can now be interpreted as the patient moving slowly or not at all to escape the notice of the local predator—the sloth strategy. SSRIs increase the long-term serotonin levels in the brain, thereby suppressing the long-term anti-predation adaptations, thereby producing a mood elevation—while increasing rates of all-causes premature death in patients by 33%! (See: The Mortality and Myocardial Effects of Antidepressants Are Moderated by Preexisting Cardiovascular Disease: A Meta-Analysis. Maslej MM, Bolker BM, Russell MJ, et al. Psychother Psychosom. 2017;86:268-282.) Apparently, the present environment contains real existential threats for some people (dominance contests leading to social hierarchies?) equivalent to the presence of a predator, and depression can be read as a withdrawing from the fray that confers a net survival benefit.

Other neuromodulators will also show desensitization phenomena, notably dopamine, where this can lead to addiction or, in the social aspect, ADHD or hedonic adaptation.

The modal-brain theory 

03-27-24: Neuromodulators are here postulated to shift the brain between the default mode in which reproduction occurs to one of six peril-addressing functional states or modes. Shifts between modes are postulated to be all-or-nothing. Variations in personality and the causes of mental illnesses would inhere in variations in the lifetimes of the modal states. Some of the complexity of sleep states may stem from the presence of multiple waking functional modes requiring distinct maintenance processes during sleep.

Schizophrenia may be a combination disorder with comorbid solitariness-enhancing disregulation related to dopamine and rigidity-loss disregulation related to acetylcholine, simultaneously caused by an aversive social positive feedback. Loss of sociality would remove social controls on behavioral variability, thus synergizing with runaway rigidity loss controlled by acetylcholine. See my post #61,“Stress and Schizophrenia.”