It can be considered firmly established that a long run in humans and mice leads to the activation of the pacemaker.

How do endocannabinoids turn off inhibition?

If signals of excitation (glutamate) and inhibition (GABA) arrive at the receiving neuron simultaneously, the inhibitory signal can "overpower" – the receiving neuron will not be excited, as shown in the upper figure. However, changes in the level of calcium in the postsynaptic neuron (why the level of calcium changes is a separate issue) can stimulate the production of the endocannabinoid 2-AG. It is released from the membrane of the postsynaptic neuron and diffuses to the presynapse. By binding to their CB-1 receptors, endocannabinoids inhibit the release of GABA. As a result, the inhibitory effect on the postsynaptic neuron ceases, and it can respond to an excitatory signal. This phenomenon is called depolarization-induced suppression of inhibition (DSI).

And that’s not all! The work of the ECS demonstrated a new systemic mechanism of our brain. As you know, among the psychotropic effects of the pacemaker there is an anxiolytic one – the feeling of anxiety decreases. But the decrease in anxiety is caused by various ligands that activate the GABA / A receptors (which is quite logical). However, when the pacemaker is activated, the GABA-ergic system is inhibited, and the feeling of anxiety does not increase, on the contrary, it weakens until it completely disappears. Let us emphasize that not only in humans, whose feelings of anxiety are determined using psychological tests and questionnaires, but also in laboratory animals, after activation of the pacemaker, those forms of behavior that are usually interpreted as indicators of anxiety are weakened. Consequently, in our brains, in the brains of humans and other animals, there is another system for regulating the level of anxiety, in addition to the systems of GABA / A receptors and endogenous opiates. This is what is extremely interesting and promising in practice.

Running activates the endocannabinoid system

Not so long ago, works appeared that testify to the leading role of the ECS in the pleasure obtained after a long run. The "marathon runner effect" is well known. Long-term running creates an elated mood, euphoria in a person. Some people like this so much that they continue to run long and super-long distances and at such an age when their cardiovascular system can no longer withstand such loads – amateur marathoners regularly die at a distance. Obviously, people develop a real addiction to running. Previously, this phenomenon was associated with the activation of endogenous opiates – endorphins and enkephalins. However, now enough data has been accumulated to assert that the pacemaker plays the main role in the formation of dependence on running loads.

It is well known that the squirrel wheel is an appetizing stimulus for laboratory mice and rats; they love to run in a wheel, if in simple words. What are the brain mechanisms of the mice ‘drive to run? After running in a wheel, anxiolytic and analgesic effects were also manifested in mice after blockade of opiate receptors, but blockade of ECS receptors dramatically weakened these effects (Proceedings of the National Academy of Sciences USA, 2015, 112, 42, 13105-13108, doi: 10.1073 / pnas. 1514996112). Consequently, the anxiolytic effect of running is associated with the work of the pacemaker, not endogenous opiates. Removal of pacemaker receptors reduces spontaneous locomotor activity in mice (Biological Psychiatry, 2013, 73, 9, 895–903, doi: 10.1016 / j.biopsych.2012.10.025). It is possible that mice with remote or blocked endocannobinoid receptors, that is, with the pacemaker “off”, get little pleasure from running. This assumption is supported by the fact that activation of the pacemaker receptors decreases both the time spent in the wheel and the speed of their running (Pharmacology, Biochemistry and Behavior, 2012, 101, 4, 528-537, doi: 10.1016 / j.pbb.2012.02. 017). If the emotional background is improved by the introduction of agonists of the ECS receptors, which act similarly to endocannabinoids, then there is no need to run a lot, and so the mood is excellent. However, let us make a reservation that the decrease in the motor activity of mice in the wheel after activation of the pacemaker may be a manifestation of the sedative effect of cannabinoids.

It can be considered firmly established that a long run in humans and mice leads to the activation of the pacemaker. But after all, when running, a rhythmic vibration of the head occurs, in which the vestibular apparatus is located, which perceives and transmits information about the accelerations of our body to the brain. Maybe euphoria is caused not by muscle loads, or hyperventilation of the lungs, or other physiological changes during running, but by constant irritation of the vestibular apparatus? This assumption is not without foundation. For example, after running, plasma levels of anandamide increase in humans and dogs, but not in ferrets (Journal of Experimental Biology, 2012, 215, 1331-1336; doi: 10.1242 / jeb.063677). The authors of this work believe that interspecies differences in the activation of the pacemaker are associated with differences in locomotor (motor) behavior. But it is possible that the specific features of the pacemaker activation are associated with the biomechanics of running – in short-legged ferrets, the vertical displacement of the head has a lower amplitude than in humans and dogs.

Before giving other arguments in favor of the hypothesis of the activation of the pacemaker during motion sickness, it is necessary to say a few words about the work of the vestibular sensory system.

The vestibular system provides the brain with information about the position of the head in space, about the action of gravity, as well as about linear and angular accelerations. This is necessary to maintain the stability of the body and for the spatial orientation of the animal. The vestibular apparatus transmits this information to the vestibular nuclei – subcortical centers regulating balance, oculomotor reflexes (visual observation of the surrounding world) and vestibulo-visceral reactions mediated through the hypothalamus, with the mechanism of which manifestations of motion sickness are associated – dizziness, nausea and vomiting.

Let us emphasize that motion sickness is accompanied by emotional disorders, and not necessarily a depressive one. Another type of manifestation of seasickness is an agitated form, which is characterized by excessive instability of the emotional sphere, excessive talkativeness, unmotivated laughter, "theatricality" of posture, speech, and even mobility that is not justified by the situation.

The neurons of the vestibular nuclei send information to the reticular formation (the general activating system of the brain), through the thalamic nuclei to the parietal area of ​​the cerebral cortex (not the sensory, but the associative area of ​​the cortex), and also – what is of particular interest to us now – to the cerebellum.

A very short course in the anatomy and physiology of the vestibular system

The peripheral organ of the vestibular system – the vestibular apparatus – lies deep in the temporal bone. It consists of two otolithic organs and three semicircular canals. The canals adjoin a rounded cavity – vestibule (in Latin vestibule). In the sacs of the vestibule there are two clusters of sensitive cells, the hairs of which are immersed in a gelatinous membrane with calcium carbonate crystals (otoliths). These are the otolith organs. They perceive linear accelerations – one of them is located in the horizontal plane (with a vertical position of the head), and the other is oriented vertically. Three semicircular canals lie in three mutually perpendicular planes, they perceive angular accelerations.The fluid filling the semicircular canals and the calcium carbonate crystals in the otolithic organs are displaced under the action of forces that cause acceleration. This shift is perceived by hair receptor cells that transmit excitation to the central nervous system.

Afferent and efferent connections of the vestibular apparatus

Having passed through the vestibular ganglion, nerve impulses come to the neurons of the vestibular nuclei in the medulla oblongata: upper (ankylosing spondylitis), lower (Roller’s nucleus), lateral (Deiters nucleus) and medial (Schwalbe’s nucleus). These nuclei represent a single functional complex that combines information from the vestibular ganglia and from proprioceptors located in the muscles, ligaments and articular sacs, as well as from the oculomotor muscles.

Cerebellum and pacemaker

The cerebellum is one of the most mysterious structures in the brain. More than 50% of all human neurons are located in the cerebellum. Damage to the cerebellum causes severe motor, cognitive and emotional disorders. But after some time (months and years), the lost functions are restored to almost the same volume! It is believed that this indicates their importance – since other brain structures have to take over the functions of the cerebellum, then it is impossible without them.

The cerebellum is important, in particular, for the formation of obsessive fears (Neuroscience and Biobehavioral Review, 2015, 59, 83–91, doi: 10.1016 / j.neubiorev.2015.09.019), in which extinguishing inhibition is impaired. And the pacemaker is involved in the regulation of this function, as we noted above (see the third paragraph of the chapter "The system of endogenous cannabinoids.) There are a lot of pacemaker receptors in the cerebellum (Cerebellum, 2006, 5, 2, 134-145; Cerebellum, 2015, 14, 3, 341–353, doi: 10.1007 / s12311-014-0629-5.) It is quite possible that the vestibular activation of the cerebellum leads to such a strong activation of the pacemaker that it is this that relieves pain, removes worries, reduces anxiety, improves mood, then eat creates comfort.

Summing up

Of course, in reality, everything is much more complicated. Many aspects of the work of the pacemaker remained outside the scope of the article – the influence of various mediators, the pacemaker in different brain structures, sex differences, etc. Without a hint of a solution, the most important question, in my opinion, remains – the systemic mechanisms of regulation of the pacemaker. What effects activate ECS? The substrate mechanism is known (the introduction of cannabinoids into the body), to which mankind has come with its own mind, without the help of scientists. The role of transmembrane calcium current is known. But what external influences, besides running, can activate the pacemaker? What changes in the functioning of the body can affect this system? All this remains to be clarified.

So, limiting ourselves to the topic of this article, we summarize what has been established with a high degree of reliability:1) rocking in the cradle or in the mother’s arms calms the child;2) motion sickness is accompanied by emotional disturbances;3) prolonged running has an analgesic and anxiolytic effect on adults and mice;4) running is accompanied by rhythmic stimulation of the vestibular apparatus;5) information from the vestibular organ comes to the cerebellum;6) the cerebellum is involved in the formation and regulation of emotions;7) the pacemaker is developed in the cerebellum;8) after running in humans and mice, activation of the pacemaker is noted;9) activation of the pacemaker causes analgesia and anxiolysis.

Based on all of the above, we make the assumption that rhythmic irritation of the vestibular system stimulates the pacemaker with subsequent analgesic and anxiolytic effects.

To check this assumption, it is necessary to carry out a series of experiments in which it is sufficient to control three parameters: 1) displacement of the subjects’ head; 2) pacemaker activity; 3) the dynamics of anxiety.

The reader may ask: why are there so many letters if the experiments have not yet been performed? Indeed, as far as I know, there is no such data yet. I just wanted to understand the ECS, and, having prepared this text, I began to imagine its work in general terms.

Or maybe someone, after reading this article, will put the proposed experiments! And then the mother sitting by the cradle will be able to find out exactly why her beloved baby loves to be cradled.

The inheritance of acquired traits within the Darwinian mechanism of natural selection has a theoretical basis due to the concept of genetic assimilation. This article simulates the main effects of the interaction between learning (as an acquired trait) and evolution. These effects are as follows: 1) Genetic assimilation of skills acquired as a result of individual learning over a number of generations of the evolutionary process. Through genetic assimilation, individually acquired skills become inherited; 2) The screening effect, which leads to the fact that strong learning inhibits the evolutionary search for the optimal genotype, since it increases the chances of finding a good phenotype regardless of the genotype of the individual; 3) The effect of loading on learning, which leads to a decrease in the fitness of an individual in such a way that this decrease is the greater, the greater the change in the phenotype during the learning process. The presence of a training load can lead to an acceleration of evolutionary optimization.

When modeling, an evolving population of model individuals was considered, each individual has a genotype and phenotype, which are chains of symbols of long length L. There are optima for genotypes and phenotypes. Individual genotypes are optimized through evolution, phenotypes are optimized through learning.

At the beginning of evolution, the genotypes of individuals are random. The phenotypes of individuals at the beginning of a generation are determined by their genotypes (in the considered model, the initial phenotypes are equal to the genotypes). Over the course of a generation, the phenotypes of individuals approach the optima through learning. Genotypes do not change over a generation. At the end of a generation, individuals are selected for the next generation in accordance with their adaptations, determined by the final phenotypes of individuals obtained as a result of training. By inheritance, the genotypes of parent individuals are transmitted (with mutations) to offspring individuals.

Here is the result of computer modeling of genetic assimilation. The SG genotypes and SP phenotypes were considered to determine the minimized parameter E, equal to E (SG) and E (SP), respectively. The fitness of an individual is

f = exp [–E (SP)] + Er, (1)where E (SP) is the parameter E, determined by the final phenotype of the individual SP, and the large term Er significantly weakens the selection force.

Fig. 1. Dependence of the parameter E, determined by the genotypes of individuals, E (SG), on the generation number G. 1 – evolution together with learning, 2 – pure evolution without learning.

In the process of evolution and learning, the parameter E was minimized, i.e. the fitness of individuals was maximized. Cases were considered of 1) evolution together with learning and 2) “pure” evolution, ie. evolution without learning. The length of the chains of genotypes and phenotypes L is 100. The population size is 100 individuals. Typical values ​​of the sought minima of the parameter E are –70. The Er value is 1013.

In fig. 1 shows the dependence of the parameter E, determined by the genotypes of individuals, E (SG), on the generation number in the presence of learning (curve 1) and for "pure evolution" in the absence of learning (curve 2). Fig. 1 shows that minimizing the parameter E during evolution with learning is much more efficient than evolution without learning.

The mechanism of genetic assimilation in the presence of learning is characterized by Fig. 2. This figure shows the dynamics of the distributions of the parameter E for genotypes and phenotypes in the first generation of evolution in the presence of learning. It can be seen that learning significantly decreases the value of E and the distribution of n (E) by phenotypes shifts to lower values ​​of E, and after selection, the distribution of n (E) by genotypes also shifts, following the distribution by phenotypes. The skill of decreasing the E parameter is “recoded” from phenotypes to genotypes, i.e. genetic assimilation occurs.

Fig. 2. Dynamics of the distribution of individuals by parameter E at different moments of the first generation of the evolutionary process. 1 – initial distribution for initial genotypes, 2 – distribution for phenotypes at the end of the generation after training, 3 – distribution for genotypes after selection.

The specificity of the studied genetic assimilation is associated with the large Er term in expression (1).

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