#77. How the Cerebellum May Adjust the Gains of Reflexes [Neuroscience]

 

NE

Red, theory; black, fact

The cerebellum is a part of the brain involved in ensuring accuracy in the rate, range, and force of movements and is well known for its regular matrix-like structure and the many theories it has spawned. I myself spent years working on one such theory in a basement, without much to show for it. The present theory occurred to me decades later on the way home from a conference on brain-mind relationships at which many stimulating posters were presented.

Background about the cerebellum

The sensory inputs to the cerebellum are the mossy fibers, which drive the granule cells of the cerebellar cortex, whose axons are the parallel fibers. The spatial arrangement of the parallel fibers suggests a bundle of raw spaghetti or the bristles of a paint brush. These synapse on Purkinje cells at synapses that are probably plastic and thus capable of storing information. The Purkinje cells are the output cells of the cerebellar cortex. Thus, the synaptic inputs to these cells are a kind of watershed at which stimulus data becomes response data. The granule-cell axons are T-shaped: one arm of the T goes medial (toward the midplane of the body) and the other arm goes lateral (the opposite). Both arms are called parallel fibers. Parallel fibers are noteworthy for not being myelinated; the progress of nerve impulses through them is steady and not by jumps. The parallel fibers thus resemble a tapped delay line, and Desmond and Moore seem to have [paywall] proposed this in 1988.

The space-time graph of one granule-cell impulse entering the parallel-fiber array is thus V-shaped, and the omnibus graph is a lattice, or trellis, of intersecting Vs.

The cerebellar cortex is also innervated by climbing fibers, which are the axons of neurons in the inferior olive of the brainstem. These carry motion error signals and play a teacher role, teaching the Purkinje cells to avoid the error in future. Many error signals over time install specifications for physical performances in the cerebellar cortex. The inferior olivary neurons are all electrically connected by gap junctions, which allows rhythmic waves of excitation to roll through the entire structure. The climbing fibers only fire on the crests of these waves. Thus, the spacetime view of the cortical activity features climbing fiber impulses that cluster into diagonal bands. I am not sure what this adds up to, but what would be cute?

A space-time theory

Cute would be to have the climbing fiber diagonals parallel to half of the parallel-fiber diagonals and partly coinciding with the half with the same slope. Two distinct motor programs could therefore be stored in the same cortex depending on the direction of travel of the olivary waves. This makes sense, because each action you make has to be undone later, but not necessarily at the same speed or force. The same region of cortex might therefore store an action and it’s recovery.

The delay-line theory, revisited

As the parallel-fiber impulses roll along, they pass various Purkinje cells in order. If the response of a given Purkinje cell to the parallel-fiber action potential is either to fire or not fire one action potential, then the timing of delivery of inhibition to the deep cerebellar neurons could be controlled very precisely by the delay-line effect. (The Purkinje cells are inhibitory.) The output of the cerebellum comes from relatively small structures called the deep cerebellar nuclei, and there is a great convergence of Purkinje-cell axons on them, which are individually connected by powerful multiple synapses. If the inhibition serves to curtail a burst of action potentials triggered by a mossy-fiber collateral, then the number of action potentials in the burst could be accurately controlled. Therefore, the gain of a single-impulse reflex loop passing through the deep cerebellar nucleus could be accurately controlled. Accuracy in gains would plausibly be observed as accuracy in the rate, range, and force of movements, thus explaining how the cerebellum contributes to the control of movement. (Accuracy in the ranges of ballistic motions may depend on the accuracy of a ratio of gains in the reflexes ending in agonist vs. antagonist muscles.)

Control of the learning process

If a Purkinje cell fires too soon, the burst in the deep cerebellar nucleus neuron will be curtailed too soon, and the gain of the reflex loop will therefore be too low. The firing of the Purkinje cell will also disinhibit a spot in the inferior olive due to inhibitory feedback from the deep nucleus to the olive. I conjecture that if a movement error is subsequently detected somewhere in the brain, this results in a burst of synaptic release of some monoamine modulator into the inferior olive, which potentiates the firing of any recently-disinhibited olivary cell. On the next repetition of the faulty reflex, that olivary cell reliably fires, causing long-term depression of concurrently active parallel fiber synapses. Thus, the erroneous Purkinje cell firing is not repeated. However, if the firing of some other Purkinje cell hits the sweet spot, this success is detected somewhere in the brain and relayed via monoamine inputs to the cerebellar cortex where the signal potentiates the recently-active parallel-fiber synapse responsible, making the postsynaptic Purkinje cell more likely to fire in the same context in future. Purkinje cell firings that are too late are of lesser concern, because their effect on the deep nucleus neuron is censored by prior inhibition. Such post-optimum firings occurring early in learning will be mistaken for the optimum and thus consolidated, but these consolidations can be allowed to accumulate randomly until the optimum is hit.

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#76. Role of personalities in the human swarm intelligence [population]

PO

Red, theory; black, fact.

Précis: each of the Big Five personality traits is a dimension along which people differ in some socially important behavioral threshold. These are, respectively: openness > uptake of innovations; conscientiousness > uptake of taboos; extraversion >  committing to collectivism*; agreeableness > becoming militant; neuroticism > engaging in/submitting to persecution. The personality trait is written on the left of the ">" and the putatively impacted social threshold is on the right.

These threshold spectra enable social shifts that are noise-resistant, sensitive to triggers, and rapid. Noise resistance and sensitivity together are called good “receiver operating characteristics,” a concept often used in the scientific literature.

A metaphor that suggests itself is lighting a camp fire. The spark is first applied to the tinder. Ignition of the tinder ignites the kindling. Ignition of the kindling ignites the small sticks. Ignition of the small sticks ignites the big sticks, and everything is consumed.

Orderly fire-starting appears to require a spectrum of thresholds for ignition in the fuel, as may orderly social shifts. To further extend the metaphor, note that the fuel must be dry (i.e., situational factors must be permissive).

11-07-2022: Social novelties spread upward to higher-threshold social strata by meme propagation reinforced by emotional contagion. The emotional energy necessary for emotional contagion would come from the individual’s interaction with the novelty, which would feature a positive feedback.

17-11-2024: The governing neuromodulators of personality may be as follows (See my post, “Neuromodulators as Peril Specialists”):

Acetylcholine-Openness

Noradrenaline-Neuroticism 

Serotonin-Agreeableness 

Histamine-Conscienciousness

Dopamine-Extraversion 

Our capacities for all of the enumerated social shifts were selected in evolution and most can be assumed to be still adaptive when correctly triggered. In today’s world, shifts to persecution are probably the least likely to still be adaptive, and could be a holdover from our Homo erectus stage. Persecution leads to refugee production, and refugee production could have been the reason that guy was such a great disperser.

As the geologists say, “The present is the key to the past.”

* 01-17-2023: A possible anti-invasion adaptation and predictable from geography. The sociological term may be siege mentality.

#75. A Tripartite Genetic Code [Genetics]

GE

 Red, theory; black, fact

(Originally posted in the "Enhancers" post.) 

The filamentous alga Cladophora.

Last update: 08-19-2024

In this post, conceived while I was in a hospital, I propose that there are three genetic codes, not one. Conventional thinking says that there is just one code, which encodes the amino acid sequence of proteins into DNA. Here are the two new ones:

A morphology code for the multicellular level

08-01-2022: The interaction of semipermanent charges on chromatin, a possibility introduced in the "Enhancers" post, could structure the chromosomes into reproducible configurations within the nucleus. For instance, a chromatin segment with a net positive charge will tend to stick to a segment with a net negative charge, leading to their respective chromosomes being spot-welded at that point. An analogy from protein chemistry would be a disulfide bridge. This structuring may be followed by transmission of nuclear 3D information through the nuclear membrane to dictate the nuclear diameter along which the centrosomes separate to initiate mitosis. This, in turn, will dictate the orientation of the mitotic division plane. In the context of a growing embryo, such control of the orientation of mitosis is arguably at the origin of organ and body morphology. For example, all planes parallel will result in a filamentous organism like Cladophora. Planes free to vary in only one angle (azimuth or elevation) will produce a sheet of cells, a common element in vertebrate embryology. Programmed variation in both angles can produce a complex 3D morphology like the vertebrate skeleton. Thus we begin to see a genetic code for morphology, distinct from the classical genetic code that specifies amino acid sequences. 

<08-05-22: Possibly, each chromosome folds in a hairpin turn near the center of the nucleus and ends up occupying a specific conical solid angle. A cell generation counter or the developmental signals around the cell then activate a centrosome-maker gene in one specific chromosome and no other. This gene is then transcribed into a long noncoding RNA molecule that protrudes from a specific nuclear pore and triggers the assembly of a new centrosome just outside the nucleus at a specific azimuth and elevation. The nucleus is tethered by cytoskeletal elements such as lamin, nesprin, actin, and tubulin to focal adhesions on the the cell membrane, non-rotatably, so that all angle information can be referred to the previous mitotic orientation. The final step is dislodging the old centrosome and sweeping it into the antipodal position of the new one. This could be done by an array of microtubules growing radially out of the new centrosome but constrained to stay close to the nuclear membrane. 

Thus, there appear to be two tiers of control of mitotic orientation available: controlling which chromosome or chromosome arm produces the centrosome-maker RNA, and controlling the pattern of histone epigenetic marks in the nucleus and thus the chromatin charge pattern and thus the 3D structure into which the chromosomes assemble, and thus the mitotic angles assigned to a given chromosome.> <09-01-22: At the DNA level, the code for multicellular morphology would take the form of promoter-controlled segments that transcribe into long noncoding RNAs having a special two-domain structure: a domain that binds to a particular kind of histone-modifying enzyme and a domain that binds to a particular DNA sequence. These lncRNAs would specify, at the second tier of control, local charge changes in chromatin in a context-dependent manner.><09-14-2022: In organisms that are morphologically complex but have few chromosomes in their karyotype, such as fruit flies, the mitotic angles could be assigned to reproducible chromatin loops as well as to whole chromosomes, suggesting a 3-tiered control system.><19-08-2024: The nucleus is usually spherical or ovoid and is about ten times more rigid than the surrounding cytoplasm, features which may be related to the demands of the morphology read-out process. Consistent with this, blood is a tissue without a morphology, and the nucleated cells of the blood have nuclei that are mostly irregular and lobate. The lymphocytes found in the blood have round nuclei, however, but these cells commonly form aggregates that can be considered to possess a simple morphology.>

A morphology code for the single-cell level in cells with nuclei

<08-20-22: I further propose a third genetic code: a code for single-cell morphology, and cell morphology can be very elaborate, especially in neurons. This will probably involve storing information about cytoskeleton morphology in DNA. Neurons express especially many long noncoding RNAs, so I suggest that these transcripts can carry morphological information about cytoskeletal elements. This information could be read out by using the lncRNA as a template on which to assemble the cytoskeletal element, then removing the template by enzymic hydrolysis or by some spirane-like enzyme. Greater efficiencies could be achieved by introducing some analog of transfer RNAs. LncRNAs are already implicated in transcriptional regulation, and this might be done indirectly by an action on the protein scaffolding of the chromatin. Moreover, as you would predict from this theory, lncRNAs are abundant in cytoplasm as well as in the nucleus, and the cytoplasm contains the most conspicuous cytoskeletal structures. The template idea is similar to but goes beyond the already-established idea that lncRNAs act as scaffolds for ribonucleoprotein complexes. Since cytoskeletal elements are made from monomers of few kinds, we would expect the template to be highly repetitious, and lncRNAs are decidedly repetitious. Indeed, transposons and tandem repeats are thought to drive lncRNA evolution. See https://doi.org/10.1038/s41598-018-23334-1, in Results, subsection: "Repetitive sequences in lncRNAs," p. 4 in the PDF.>

An uncertainty principle for molecular biology?

09-02-2022: These ideas call into question the assumption that all biological order stems from primary amino acid sequences and that a glorified bacterial genome, if artfully regulated, can produce a human. Is there a fundamental limit on how high an amino acid residue can extend its influence in the structural hierarchy of biology? Even something as big as a ribosome appears to need help from ribosomal RNAs to keep its act together. However, perhaps the issue is coding parsimony.

Two more biological questions:

1. Does a cell in a multicellular organism run a metabolic simulation of the whole organism to help it carry out its specialized role more efficiently? Are these little guys thinking of us?

2. Is immune cycling the answer to preventing cancer? Let’s say you deliberately take a drug to suppress your immune vigilance for one month out of each year, then discontinue the drug to let it rebound. During suppression, the micro cancers run wild for a short time, thereby growing large enough for the immune function to easily detect them upon its return. They get whacked, of course, and the immune system learns something in the process, making it a more effective anti cancer system going forward. The analogy here would be a cat playing with a mouse it has caught. Since it is play, it is a learning activity; the cat is working on its game. Pre-civilization, human immune suppression would have happened regularly due to prolonged  environmental stressors, leading to cannier immune systems and lower cancer rates than we now experience.

This agrees with the impression I have that cancer is a disease of modern lifestyles. The following article may or may not be relevant: Coventry, B.J., Ashdown, M.L., Quinn, M.A. et al. CRP identifies homeostatic immune oscillations in cancer patients: a potential treatment targeting tool?. J Transl Med 7, 102 (2009).  https://doi.org/10.1186/1479-5876-7-102 

#74. Extended Theory of Mind [Evolution]

EV

Red, theory; black, fact.

Where is evolution going at the moment? Pretty good question. Let us look around, then. I am writing this in a submarine sandwich joint where one sandwich maker is serving two customers. The radio brings in a ballad by a lady vocalist at a tempo suggestive of sex. Now a DJ (Mauler or Rush) is amusing the listeners with some patter. The window shows that rush hour is over and only a few home-bound stragglers are in the street. If I crane my neck, I can see the green beacon on the new electric charging station. 

That will do for starters. Sandwich maker, pro singer, DJ, bureaucrat, electrician—I couldn’t do any of that. We are a society of specialists, and such societies feature differentiation with integration. So, how far back does this go? At most, nine millennia; about 450 generations. Time enough for evolution? Doesn’t matter; we want direction here, not distance.

Contemporary natural selection of humans will therefore reward differentiability and integratability.

Differentiability: vocational choices often begin in childhood with hobbies, and there is a certain frame of mind associated with hobbies called “flow.” I therefore suggest that we are being selected for a susceptibility to flow. 

Integratability: society is held together by our ability to coordinate with others, and the key ability here is thought to be “theory of mind,” or the ability to infer the mental states of those with whom we interact. Likewise, we are being selected for theory-of-mind ability.

I would like to suggest that there is something higher than theory of mind, which not everyone possesses at this time: extended theory of mind: inferring the mental states of those not present, and whose very existence is itself inferred. A society strong in this trait will appear to be communicating with one another through solid walls, as if by ESP. 

Who are these Chosen? Probably military generals, politicians, and the executive class. Go figure.

However, the human cranium is probably as voluminous as it can get and still allow childbirth, so the gray matter subserving the new ability will have to be included at the expense of some other, preferably obsolete ability, like accuracy in spearing game animals.

So challenge your mayor to a game of darts and see how he does. This theory is falsifiable.

Photo by Le Vu on Unsplash