#59. Neuromodulators as Peril Specialists [neuroscience, evolution]

NE   EV

Red: theory; black, fact

Solanum dulcamara, a plant with anticholinesterase activity.

“Life is difficulty.” -The Buddha Gautama

My PhD thesis was about a neuromodulator (acetylcholine) acting on mammalian brain. It was tough to decapitate so many rats; I never got used to it.

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.

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

#11. Revised Motor Scheme [neuroscience]

NE

Red, theory; black, fact

How skilled behavior may be generated on the assumption that it is acquired by an experimentation-like process.

A revised version of the motor control theory presented in the last post 

The revision was necessitated by the fact that there is no logical reason why a motor command cannot go to both sides of the body at once to produce a mid line-symmetrical movement. The prediction is that mid-line-symmetrical movements are acquired one side at a time whenever the controlling corticofugal pathway allows the two sides to move independently.

#10. The Two–test-tube Experiment: Part II [neuroscience]

NE

Red, theory; black, fact

This is how the brain would have to work if fragments of skilled behaviors are randomly stored in memory on the left or right side, reflecting the possibility that the two hemispheres play experiment versus control, respectively, during learning.

The Significance of Hemispheric Asymmetry 

The experimenting-brain theory predicts zero hard-wired asymmetries between the hemispheres. However, the accepted theory of hemispheric dominance postulates that this arrangement allows us to do two things at once, one task with the left hemisphere and the other task with the right. The accepted theory is basically a parsimony argument. However, this argument predicts huge differences between the hemispheres, not the subtle ones actually found.

Hard-wired hemispheric dominance may be an imperfection of symmetry in the framework of the experimenting brain caused by the human brain being still in the process of evolving, in light of the hypothesis that brain-expanding mutations individually produce small and asymmetric expansions. Our left-hemispheric speech apparatus is the most asymmetric part of our brain and these ideas predict that we are due for another mutation that will expand the right side, thereby matching up the two sides, resulting in an improvement in the efficiency of operant conditioning of speech behaviour.

These ideas also explain why speech defects such as lisping and stuttering are so common and slow to resolve, even in children, who are supposed to be geniuses at speech acquisition.

Motor Control in an Experimenting Brain

The illustration shows the theory of motor control I was driven to by the implications of the theory of the dichotomously experimenting brain already outlined. It shows how hemispheric dominance can be reversed independently of the side of the body that should perform the movement specified by the applicable rule of conduct in the controlling hemisphere. The triangular device is a summer that converges the motor outputs of both hemispheres into a common output stream that is subsequently gated into the appropriate side of the body. This arrangement cannot create contention because at any given time, only one hemisphere is active. Anatomically, and from stroke studies, it certainly appears that the outputs of the hemispheres must be crossed, with the left hemisphere only controlling the right body and vice-versa.

In healthy individuals, either hemisphere may control either side of the body, and the laterality of control may switch freely and rapidly during skilled performance so as to always use the best rule of conduct at any given time, regardless of the hemisphere in which it was originally created during REM sleep.

Laterality Control Mechanism

The first bit would be calculated and stored in the basal ganglia. It would be output from the reticular substantia nigra (SNr) and gate sensory input to thalamus to favour one hemisphere or the other, by means of actions at the reticular thalamus and intermediate grey of the superior colliculus. The second bit would be stored in the cerebellar hemispheres and gate motor output to one side of the body or the other, at the red nucleus. Conceivably, the two parts of the red nucleus, the parvocellular and the magnocellular, correspond to the adder and switch, respectively, that are shown in the illustration.

Role of the Corpus Callosum

Under these assumptions, the corpus callosum is needed only to distribute priming signals from the motor/premotor cortices to activate the rule that will be next to fire, without regard for which side that rule happens to be on. The callosum would never be required to carry signals forward from sensory to motor areas. I see that as the time-critical step, and it would never depend on getting signals through the corpus callosum, which is considered to be a signaling bottleneck.

Brain Mechanism of Operant Conditioning 

Evaluation 

How would the basal ganglia identify the "best" rule of conduct in a given context? I see the dopaminergic compact substantia nigra (SNc) as the most likely place for a hemisphere-specific "goodness" value to be calculated after each rule firing, using hypothalamic servo-error signals processed through the habenula as the main input for this. The half of the SNc located in the inactive hemisphere would be shut down by inhibitory GABAergic inputs from the adjacent SNr. The dopaminergic nigrostriatal projection would permanently potentiate simultaneously-active corticostriatal inputs (carrying context information) to medium spiny neurons (MSNs) of enkephalin type via a crossed projection, and to MSNs of substance-P type via uncrossed projections. The former MSN type innervates the external globus pallius (GPe), and the latter type innervates the SNr. These latter two nuclei are inhibitory and innervate each other. 

This arrangement sets up a winner-take-all competition between GPe and SNr, with choice of the winner being exquisitely sensitive to small historical differences in dopaminergic tone between hemispheres. The "winner" is the side of the SNr that shuts down sensory input to the hemisphere on that side. The mutually inhibitory arrangement could also plausibly implement hysteresis, which means that once one hemisphere is shut down, it stays shut down without the need for an ongoing signal from the striatum to keep it shut down.

Process Control

Each time the cerebral cortex outputs a motor command, a copy would go to the subthalamic nucleus (STN) and could plausibly serve as the timing signal for a "refresh" of the hemispheric dominance decision based on the latest context information from cortex. The STN signal presumably removes the hysteresis mentioned above, very temporarily, then lets the system settle down again into possibly a new state.

Launching an Experiment 

We now need a system that decides that something is wrong, and that the time to experiment has arrived. This could plausibly be the role of the large, cholinergic interneurons of the striatum. They have a diverse array of inputs that could potentially signal trouble with the status quo, and could implement a decision to experiment simply by reversing the hemispheric dominance prevailing at the time. Presumably, they would do this by a cholinergic action on the surrounding MSNs of both types.

Coding Analogies 

Finally, there is the second main output of the basal ganglia to consider, the inner pallidal segment (GPi). This structure is well developed in primates such as humans but is rudimentary in rodents and even in the cat, a carnivore. It sends its output forward, to motor thalamus. I conjecture that its role is to organize the brain's knowledge base to resemble block-structured programs. All the instructions in a block would be simultaneously primed by this projection. The block identifier may be some hash of the corticostriatal context information. A small group of cells just outside the striatum called the claustrum seems to have the connections necessary for preparing this hash. Jump rules, that is, rules of conduct for jumping between blocks, would not output motor commands, but block identifiers, which would be maintained online by hysteresis effects in the basal ganglia.

The cortical representation of jump rules would likely be located in medial areas, such as Brodmann 23, 24, 31, and 32. Brodmann Areas 23-24 are classed as limbic system, and areas 31-32 are situated between these and neocortex. This arrangement suggests that, seen as a computer, the brain is capable of executing programs with three levels of indentation. Dynamic changes in hemispheric dominance might occur independently in neocortex, medial cortex, and limbic system.

#9. The Two–test-tube Experiment: Part I [neuroscience]

NE

Red, theory; black, fact

Your brain is like this.

The motivating challenge of this post is to explain the hemispheric organization of the human brain. That is, why we seem to have two very similar brains in our heads, the left side and the right side.

Systems that rely on the principle of trial-and-error must experiment. The genetic intelligence mentioned in previous posts would have to experiment by mutation/natural selection. The synaptic intelligence would have to experiment by operant conditioning. I propose that both these experimentation processes long ago evolved into something slick and simplified that can be compared to the two–test-tube experiment beloved of lab devils everywhere.

Remember that an experiment must have a control, because "everything is relative." Therefore, the simplest and fastest experiment in chemistry that has any generality is the two-test-tube experiment; one tube for the "intervention," and one tube for the control. Put mixture c in both tubes, and add chemical x to only the intervention tube. Run the reaction, then hold the two test tubes up to the light and compare the contents visually (Remember that ultimately, the visual system only detects contrasts.) Draw your conclusions.

The two hemispheres of the brain may be like the two test tubes. Moreover, the two copies of a given chromosome in a diploid cell may also be like the two test tubes. In both systems, which is which may vary randomly from experiment to experiment to simplify control. The hemisphere that is dominant for a particular action is the last one that produced an improved result when control passed to it from the other. The allele that is dominant is the last one that produced an improved result when it got control from the other. Chromosomes and hemispheres will mutually inhibit to produce winner-take-all dynamics in which at any given time only one is exposed to selection, but it is fully exposed. 

These flip-flops do not necessarily involve the whole system, but may be happening independently in each sub-region of a hemisphere or chromosome (e.g., Brodmann areas, alleles). Some objective function, expressing the goodness of the organism's overall adaptation, must be recalculated after each flip-flop, and additional flip flopping suppressed if an improvement is found when the new value is compared to a copy of the old value held in memory. In case of a worsening of the objective function, you quickly flip back to the allele or hemisphere that formerly had control, then suppress further flip flopping for awhile, as before. 

The foregoing implies multiple sub-functions, and these ideas will not be compelling unless I specify a brain structure that could plausibly carry out each sub-function. For example, the process of comparing values of the objective function achieved by left and right hemispheres in the same context could be mediated by the nigrostriatal projection, which has a crossed component as well as an uncrossed component. More on this in the next post.

#5. Why We Dream [neuroscience]

NE

Red, theory; black, fact

The Conjunction of Jupiter and Venus

We Dream Because We Learn

Operant conditioning is the learning process at the root of all voluntary behaviour. The process was discovered in lab animals such as pigeons by B.F. Skinner in the 1950s and can briefly be stated as "If the ends are achieved, the means will be repeated." (Gandhi said something similar about revolutionary governments.)

Learning in the Produce Isle

Operant conditioning is just trial-and-error, like evolution itself, only faster. Notice how it must begin: with trying moves randomly--behavioral mutations. However, the process is not really random like a DNA mutation.  Clearly, common sense plays a role in getting the self-sticky polyethylene bag open for the first time, but any STEM-educated person will want to know just what this "common sense" is and how you would program it. Ideally, you want the  creativity and genius of pure randomness, AND the assurance of not doing anything crazy or even lethal just because some random-move generator suggested it. You vet those suggestions.

How Dreams Help Learning

That, in a nutshell, is dreaming: vetting random moves against our accumulated better judgment to see if they are safe--stocking the brain with pre-vetted random moves for use the next day when we are stuck. This is why the emotions associated with dreaming are more often unpleasant than pleasant: there are more ways to go wrong than to go right. The vetting is best done in advance (e.g., while we sleep) because there's no time in the heat of the action the next day, and trial-and-error with certified-safe "random" moves is already time-consuming without having to do the vetting on the spot as well.  

A Possible Neurobiological Mechanism

Dreams are loosely associated with brain electrical events called "PGO waves," which begin with a burst of action potentials ("nerve impulses") in a few small brainstem neuron clusters, then spread to the visual thalamus, then to the primary visual cortex. I theorize that each PGO wave creates a new random move that is installed by default in memory in cerebral cortex, and is then tested in the inner theatre of dreaming to see what the consequences would be. In the event of a disaster foreseen, the move would be scrubbed from memory, or better yet, added as a "don't do" to the store of accumulated wisdom. Repeat all night.

If memory is organized like an AI knowledge base, then each random move would actually be a connection from a randomly-selected but known stimulus to a randomly-selected but known response, amounting to adding a novel if-then rule to the knowledge base.

Support For a Requirement for Vetting 

In "Evolution in Four Dimensions" [1st ed.] Jablonka and Lamb make the point that epigenetic, cultural, and symbolic processes can come up with something much better than purely random mutations: variation that has been subjected to a variety of screening processes.

An Observation and an Exegesis

Oddly, my nightmares happen just after a turn of good fortune for me. However, in our evolutionary past, my kind of good fortune may have meant bad fortune for someone else, and that someone else will now be highly motivated to kill me in my sleep. Unless I have a nightmare and thus sleep poorly or with comforting others. The dream that warned the Wise Men not to return to Herod may have been just such a nightmare, which they were wise enough to interpret correctly. The content was probably not an angelic vision, but more like Ezekiel's valley of dry bones vision in reverse.