#44. The Denervation-supersensitivity Theory of Mental Illness [neuroscience, evolution, genetics]

NE  EV  GE    

Red, theory; black, fact

Midplane section of human brain annotated with the Brodmann areas, which are related to different functions

People contract mental illness but animals seemingly do not, or at least not outside of artificial laboratory models such as the unpredictable, mild-stress rodent model of depression. A simple theory to account for this cites the paleontological fact that the human brain has been expanding at breakneck speed over recent evolutionary time and postulates that this expansion is ongoing at the present time, and that mental illness is the price we are paying for all this brain progress.

The Evolution of the Human Brain

In other words, the mentally ill may carry the unfavorable mutations that have to be selected out during this progress. The mutation rate in certain categories of mutation affecting human brain development may be elevated in modern humans by some sort of "adaptive" hot-spot system. "Adaptive" is in scare quotes to indicate that the adaptation inheres in changes in the standard deviation of traits, not the average, and is therefore not Lamarkian.

In brain evolution, the growth changes in the various parts very probably have to be coordinated somehow. There may not be any master program doing this coordination. Rather, the human brain would comprise scores of tissue "parcels," each with its own gene to control the final size that parcel reaches in development. This is consistent with the finding of about 400 genes in humans that participate in establishing body size. All harmonious symmetry, even left-right symmetry, would have to be painstakingly created by brute-force selection, involving the early deaths of millions of asymmetrical individuals. 

Assuming that left and right sides must functionally cooperate to produce a fitness improvement, mutations affecting parcel growth must occur in linked, left-right pairs to avoid irreducible-complexity paradoxes. The crossing-over phenomenon in egg and sperm maturation may create these linked pairs of mutations, where the two mutations are identified with the two ends of the DNA segment that translocates. Since the two linked mutations are individually random, linkage per se does not eliminate asymmetry. That must be done by natural selection, as previously stated, so there is a subtlety here. Natural selection could equally well create adaptive asymmetry. The human heart and the claws of the fiddler crab are examples.

Functional Human Brain Anatomy 

Most of the evolutionary expansion of the human brain appears to be focused on association cortex, which would implement if-then rules like those making up the knowledge bases familiar from the field of artificial intelligence. The "if" part of the rule would be evaluated in post-Rolandic cortex, i.e., in temporal and parietal association cortices, and the "then" part of the rule would be created by the pre-Rolandic association cortex, i.e., the prefrontal cortex. The white matter tracts running forward in the brain would connect the "if" part with the "then" part, and the backward running white-matter tracts would carry priming signals to get other rules ready to "fire" if they are commonly used after the rule in question.

Possible Disorders of Brain Growth

Due to such tight coordination, the ideal brain will have a fixed ratio of prefrontal cortex to post-Rolandic association cortex. However, the random nature of the growth-gene bi-mutations, perhaps at mutational hot-spots, permitting human brain evolution will routinely violate this ideal ratio, leading to the creation of individuals having either too much prefrontal cortex or too much temporal/parietal cortex. In the former case, prefrontal cortex will be starved of sensory input. In the latter case, sensory association cortex will be starved of priming signals feeding back from motoric areas.

Denervation supersensitivity occurs when the normal nerve supply to a muscle is interrupted, resulting in a rapid overexpression of acetylcholine receptors on the muscle. This is an adaptation to compensate for weak nerve transmission with a re-amplification of the signal by the muscle. Analogous effects have been found in areas of the cerebral cortex deprived of their normal supply of sensory signals, so the effect seems to be general.

In cases of genetically-determined frontal-parietal/temporal imbalance, the input-starved side would develop denervation supersensitivity, making it prone to autonomous, noise-driven nervous activity.

Differential Growth-Related Brain Disorders 

If the growth excess is in sensory association cortex, this autonomous activity will manifest as hallucinations, resulting in schizophrenia. If the growth excess is in the prefrontal cortex, however, the result of the autonomous activity will be mania or a phobia.

The non-overgrown association cortex might secondarily develop the opposite of denervation supersensitivity as the result of continual bombardment with autonomous activity from the other side of the Rolandic fissure. This could account for the common observation of hypoprefrontality in cases of schizophrenia.

Picture credit: Wiki Commons

#7. What is Intelligence? Part I. DNA as Knowledge Base [genetics, engineering]

EN   GE

Red: theory; black, fact

The Known Intelligences 

There may be three intelligences: the genetic, the synaptic, and the artificial. The first includes genetic phenomena and may be the scientifically accessible reality behind the concept of God. The synaptic is the intelligence in your head, and seems to be the hardest to study and the one most in need of elucidation. The artificial is the computer, and because we built it ourselves, we understand it. Thus, it can provide a wealth of insights into the nature of the other two intelligences and a vocabulary for discussing them.

The Artificial Intelligence 

Artificial intelligence systems are classically large knowledge bases (KBs), each animated by a relatively small, general-purpose program, the "inference engine." The knowledge bases are lists of if-then rules. The “if” keyword introduces a logical expression (the condition) that must be true to prevent control from immediately passing to the next rule, and the “then” keyword introduces a block of actions the computer is to take if the condition is true. Classical AI suffers from the problem that as the number of if-then rules increases, operation speed decreases dramatically due to an effect called the combinatorial explosion.

DNA Through an AI Lens

A genome can be compared to a KB in that it contains structural genes and cis-acting control elements. The latter trigger the transcription of the structural genes into messenger RNAs in response to environmental factors and these are then translated into proteins that have some effect on cell behavior. The analogy to a list of if-then rules is obvious. A control element evaluates the “if” condition and the conditionally translated protein enables the “action” taken by the cell if the condition is true.

Avoiding Slowdowns at Scale

Note that the structural gene of one rule precedes the control element of the next rule along the DNA strand. Would this circumstance not also represent information? However, what could it be used for?

It could be used to order the rules along the DNA strand in the same sequence as the temporal sequence in which the rules are normally applied, given the current state of the organism’s world. This seems to be a possible solution to the combinatorial explosion problem, leading to much shorter delays on average for the transcriptase complex to arrive where it is needed. I suspect that someday, it will be to this specific arrangement that the word “intelligence” will refer.

A Rule-ordering Mechanism 

The process of putting the rules into an efficient sequence may involve trial-and-error, with transposon jumping providing the random variation on which selection operates. 

A variant on this process would involve the enhancement by de-methylation of recombination sites that have recently produced successful results. These results would initially be encoded in the organism's emotions, as a proxy to reproductive success. In this form, the signal can be rapidly amplified by inter-individual positive feedback effects such as competition. It would then be converted into patterns of DNA de-methylation in the germ line. DNA methylation is known to be able to cool recombination hot spots, so de-methylation should do the opposite.

Rule Creation 

A longer-timescale process involving meiotic crossing-over may create novel rules of conduct by breaking DNA between promoter and structural gene of the same rule, a process analogous to the random-move generation discussed in my post on dreaming. Presumably, the longest-timescale process would be creating individual promoters and structural genes with new capabilities of recognition and effects produced, respectively. This would happen by point mutation and classical selection.

Implementing Jump Instructions In DNA 

How would the genetic intelligence handle conditional rule firing probabilities in the medium to low range, which would call for jump instructions as opposed to merely incrementing the instruction pointer?

This could be done by cross linking nucleosomes via the histone side chains in such a way as to cluster the cis control elements of likely-to-fire-next rules near the end of the relevant structural gene, by drawing together points on different loops of DNA. The analogy here would be to a science-fictional “wormhole” from one part of space to another via a higher-dimensional embedding space. In this case, “space” is the one-dimensional DNA sequence with distances measured in kilobases, and the higher-dimensional embedding space is the three-dimensional physical space of the cell nucleus.

A Possible Mechanism of Jump Instructions 

The cross linking is presumably created and/or stabilized by the diverse epigenetic marks known to be deposited in chromatin. Most of these marks will certainly change the electric charge and/or the hydrophobicity of amino acid residues on the histone side chains. Charge and hydrophobicity are crucial factors in ionic bonding between proteins. A variety of such changes are possible.

Another way of accounting for the diversity of epigenetic marks, mostly due to the diversity of histone marks, is to suppose that they can be paired up into negative-positive, lock-key partnerships, each serving to stabilize by ionic bonding all the wormholes in a subset of the chromatin that deals with a particular function of life. The number of such pairs would equal the number of functions. Their lock-key specificity would prevent wormholes, or jumps, from forming between different functions, which would cause chaos.

Evolutionary History of Jump Instructions 

If the eukaryotic cell is descended from a spheriodal array of prokaryotes with internal division of labor and specialization, then by one simple scheme, the specialist subtypes would be defined and organized by something like mathematical array indexes. For parsimony, assume that these array indexes are the different kinds of histone marks, and that they simultaneously are used to stabilize specialist-specific wormholes. A given lock-key pair would wormhole specifically across regions of the shared genome not needed by that particular specialist.

A secondary function of the array indexes would be to implement wormholes that execute between-blocks jumps within the specialist's own program-like KB. With consolidation of most genetic material in a nucleus, the histone marks would serve only to produce these secondary kind of jumps while keeping functions separate and maintaining an informational link to the ancestral cytoplasmic compartment. The latter could be the basis of sorting processes within the modern eukaryotic cell.

#6. Mental Illness as Communication [neuroscience, genetics]

NE   GE

Red, theory; black, fact

The effects of most deleterious mutations are compensated by negative feedback processes occurring during development in utero. However, if the population is undergoing intense Darwinian selection, many of these mutations become unmasked and therefore contribute variation for selection. (Jablonka and Lamb, 2005, The MIT Press, "Evolution in Four Dimensions")

Basic Darwinism Is So Inefficient

However, since most mutations are harmful, a purely random process for producing them, with no pre-screening, is wasteful. Raw selection alone is capable of scrubbing out a mistake that gets as far as being born, at great cost in suffering, only to have, potentially, the very same random mutation happen all over again the very next day, with nothing learnt. Repeat ad infinitum. This quarrels with the engineer in me, and I like to say that evolution is an engineer. 

Evolution of Evolution 

Nowadays, evolution itself is thought to evolve. A simple example of this is the evolution of DNA repair enzymes, which were game-changers, allowing much longer genes to be transmitted to the next generation reliably, resulting in the emergence of more complex lifeforms.

What I Would Like to See

A further improvement would be a screening, or vetting process for genetic variation. Once a bad mutation happens, you mark the offending stretch of DNA epigenetically in all the close relatives of the sufferer, to suppress further mutations there for a few thousand years, until the environment has had time to change significantly.

Obviously, you also want to oppositely mark the sites of beneficial mutations, and even turn them into recombination hotspots for a few millennia, to keep the party going. Hotspots may even arise randomly and spontaneously, as true, selectable epi-mutations. 

A Problem With Mutation Hotspots on the DNA Strand

The downside of all this is that even in an adaptive hotspot, most mutations will still be harmful, leading to the possibility of "hitchhiker" genetic diseases that cannot be efficiently selected against because they are sheltered in a hotspot. Cystic fibrosis may be such a disease, and as the hitchhiker mechanism would predict, it is caused by many different mutations, not just one. It would be a syndrome defined by the overlap of a vital structural gene and a hotspot, not by a single DNA mutation. I imagine hotspots to be much more extended along the DNA than a classic point mutation.

It is tempting to suppose that the methylation islands found on DNA are these hotspots, but the scanty evidence available so far is that methylation suppresses recombination hotspots, which are generally defined non-epigenetically, by the base-pair sequence.

Mental Illness In Evolution 

The human brain has undergone rapid, recent evolutionary expansion, presumably due to intense selection, presumably unmasking many deleterious mutations affecting brain development that were formerly silent. Since the brain is the organ of behavior, we expect almost all these mutations to indirectly affect behavior for the worse. Does that explain mental illness?

Mental illnesses are not random, but cluster into definable syndromes. My reading suggests the existence of three such syndromes: schizoid, depressive, and anxious. My theory is that each is defined by a different recombinant hot spot, as in the case of cystic fibrosis, and may even correspond to the three recently-evolved association cortices of the human brain, namely parietal, prefrontal, and temporal, respectively. 

How Mental Illness Could Be Beneficial 

The drama of mental illness would derive from a communication role in warning nearby relatives that they may be harbouring a bad hotspot, causing them to find it and cool it by wholly unconscious processes. Mental illness would then be the push-back against the hotspots driving human brain evolution, keeping them in check and deleting them as soon as they are no longer pulling their weight fitness-wise. The variations in the symptoms of mental illness would encode the information necessary to find the particular hot spot afflicting a particular family.

A Possible Mechanism

Now all we need is a communication link from brain to gonads. The sperm are produced by two rounds of meiosis and one of mitosis from the stem-like, perpetually self-renewing spermatogonia, which sit just outside the blood-testes barrier and are therefore exposed to all blood-borne hormones. These cells are known to have receptors for the hypothalamic hormone orexin A, as well as many other receptors for signalling molecules that do or could plausibly originate in the brain as does orexin A. Orexin A is lipophilic and rapidly crosses the blood-brain barrier by diffusion. Some of the other receptors are:

• retinoic acid receptor α
• glial cell-derived neurotrophic factor (GDNF) receptor
• CB2 (cannabinoid type 2) receptor
• p75 (For nerve growth factor, NGF)
• kisspeptin receptor.

PS: for brevity, I left out mention of three sub-functions necessary to the pathway: an intracellular gonadal process transducing receptor activation into germ line-heritable epigenetic changes, a process for exaggerating the effects of bad mutations into signals for purposes of interpersonal communication, and a process of decoding the communication in the brains of the recipients.

Photo by Charlotte Noelle on Unsplash