#70. 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 on 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 (pur-kin-gee) 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 therefore steady and not by jumps. The parallel fibers thus resemble a tapped delay line, and Desmond and Moore 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 all 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 in the deep-nucleus neuron 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-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 neuromodulator 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.

Role of other motor structures

The Laplace transform was previously considered in this blog to be a neural code, and its output is a complex number giving both gain and phase information. To convert a Laplace transform stored as poles (points where gain goes to infinity) in the cerebral cortex into actionable time-domain motor instructions, the eigenfunctions corresponding to the poles, which may be implemented by damped spinal rhythm generators, must be combined with gains and phases. If the gains are stored in the cerebellum as postulated above, where do the phases come from? The most likely source appears to be the basal ganglia. These structures are here postulated to comprise a vast array of delay elements along the lines of 555 timer chips. However, a delay is not a phase unless it is scaled to the period of an oscillation. This implies that each oscillation frequency maps in the basal ganglia to an array of time delays, of which none are longer than the period. These time delays would be applied individually to each cycle of an oscillation. Such an operation would be simplified if each cycle of the oscillation were represented schematically by one action potential.

Photo by Robina Weermeijer on Unsplash

#69. Role of Personalities in the Human Swarm Intelligence [population]

PO

Red, theory; black, fact

Each of the Big Five personality traits may be 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 may 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).

Social novelties may 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.

The governing neuromodulators of personality may be as follows:

• Acetylcholine-Openness
• Noradrenalin-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.”

* A possible anti-invasion adaptation and predictable from geography. The sociological term for the corresponding failure mode may be siege mentality.

#68. A Tripartite Genetic Code [genetics]

GE

Red, theory; black, fact

The filamentous alga Cladophora.

There are three genetic codes, not one. Conventional thinking holds 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

In the context of a growing embryo, control of the orientation of mitosis is arguably at the origin of organ and body morphology. For example, all cell division 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. 

The nucleus is tethered by cytoskeletal elements such as lamin, nesprin, actin, and tubulin to focal adhesions on the cell membrane, non-rotatably, so that all angle information can be referred to the previous mitotic orientation.

Observational Support 

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

A third genetic code would be 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 (lncRNA), 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 enzyme analogous to a helicase. 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 predicted, 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.

Why Three Codes?

The issue driving the evolution of the two additional genetic codes may be parsimony in coding (advantageously fewer and shorter protein-coding genes).

Disclaimer 

This next paragraph was written for researchers, not for patients or those at risk for cancer who may be seeking a cure outside the medical mainstream. 

Cancer Research May Be Held Back by the One-Code View

Mutations in the proposed cytoskeletal genome could be at the origin of cancer. Cancer cells will proliferate in a culture dish past the point of confluence, unlike healthy cells. If the cytoskeleton is required to sense confluence, as seems likely, a defective cytoskeleton incapable of performing this function could lead directly to uncontrolled growth and thus cancer. It is not clear how the immune system could detect a mutation like this, since no amino acid sequence is affected. Possibly, a special evolved system or reflex exists that telegraphs such mutations to the cell surface where the immune system has a chance of detecting them. The clustering of antigens on the cell surface is already known to enhance immunogenicity, so this hypothetical system may output a clustering signal on the cell surface that talks to the cytoskeletons of circulating immune-system cells. Alternatively, the immune-system cells may directly interrogate the body cells’ ability to detect confluence. For these ideas to apply to blood-borne cells such as leukocytes, the failure event would have to happen during maturation in the bone marrow while the cell is still part of a solid tissue.

YAP1 protein, which promotes cell proliferation when localized to the nucleus, may be gated through the nuclear pores by some kind of operculum attached to the lamin component of the nuclear envelope. The operculum would move down from the pore, thus unblocking it, when a region of nuclear membrane flattens in response to a localized loss of tensile forces in the cytoskeleton. The flattening causes a local excess of lamin area, which leads to buckling and delamination, which is coupled to operculum movement. A mutation that makes the operculum leaky to YAP1 when closed could lead to cancer. This mutation could be in an lncRNA that scaffolds key components of the nuclear membrane’s supporting proteins. A more subtle mechanism would be for the buckling and delamination to happen on a molecular scale and lead to a uniform regional increase in the porosity of the lamin layer, which would gate YAP1 permeation.

Loss of tissue adjacent to the cell would cause a loss of cytoskeletal tension on the nucleus not only on that side of the nucleus, but also on the side opposite. If these two slack regions directly dictate centriole placement on the next round of mitosis, then the new cell will automatically be placed to fill in the tissue hole. (This may constitute an important mechanism of wound healing and suggests a link between morphology and carcinogenesis.)

Evolutionary Considerations 

The multicellular morphology code was postulated to arise from precise control of the orientation of the plane of mitotic division. It now seems likely that this control will be implemented via bespoke cytoskeletal elements, since complex single-cell morphology and its genetic code probably preceded complex multicellular morphology in evolution. 

Mechanism of Multicellular Morphology Readout

These bespoke elements might be inserted into a cytoskeletal apparatus surrounding the nucleus that has commonalities with devices such as gimbals and armillary spheres. The centrioles are likely to be key components of this apparatus. Each centriole may create a hoop of microtubules encircling the nucleus, and the two hoops would be at right angles, like the centrioles themselves when parked outside the nucleus between cell divisions. During mitosis, in-plane revolution of one of the hoops through 180 degrees would be responsible for separating the centrioles. After this, both centrioles must be on this same hoop. Alternatively, the centrioles may move by synthesis at the new locations followed by disassembly of the old centrioles. Each hoop then forms a circular track for adjusting azimuth and elevation, respectively, relative to anchor points left over from the previous round of mitosis. The bespoke elements would lie along these tracks and function as variable-length shims. The remainder of the apparatus would translate these lengths into angles. The inner hoop would pass through two protein eyelets connected to the outer hoop and the outer hoop would pass through an eyelet connected to the anchor. The shims would fix the along-track distances between an inner eyelet and the outer eyelet and between an inner eyelet and a centriole (Fig. 1).

Figure 1. A hypothetical cytoskeletal apparatus for orienting mitosis; C, centrioles; zigzag, shims; dotted, a nuclear diameter; double line, anchor to cell membrane; EL, elevation; AZ, azimuth 

Top picture credit: Cladophora flavescens, Phycologia Britannica, William Henry Harvey, 1851.

#67. Extended Theory of Mind [evolution]

EV

Red, theory; black, fact

Where is human evolution going at the moment? That is a good question. Let’s 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? It 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 state." 

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.

There may be something higher than theory of mind, which not everyone possesses at this time, that could be called "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.