INTRODUCTION

The presence of a positive effect of motor load on cognitive functions and emotional regulation, both in healthy people and in the case of pathologies of the nervous system, has been known for a long time. Relatively recent studies based on meta-analyses (Beckett et al., 2015; Basso and Suzuki, 2017; Valenzuela et al., 2020) confirm this view. They convincingly show improved memory, increased learning ability, reduced anxiety, and relief of symptoms of depression. Anxiolytic and cognitive-enhancing effects of intensive locomotion have been demonstrated not only in humans but also in rodents (da Costa et al., 2020), fish (Mes et al., 2020), insects (Stevenson et al., 2005; Mezheritsky et al., 2020), molluscs (Korshunova et al., 2016), and nematodes (Laranjeiro et al., 2017, 2019; Kumar et al., 2021). These facts indicate that the relationship between movement and cognitive functions was formed early in evolution and has adaptive significance in systematically distant animal species.

Since 2016, we have been developing a view (Korshunova et al., 2016; Dyakonova et al., 2019; Aonuma et al., 2020; Mezheritsky et al., 2020) according to which changes in the state and behavior of the organism caused by intensive locomotion really have biological and physiological significance. The activation of cognitive functions accompanying the movement can be explained by the need to react quickly to a faster change in environmental conditions. However, the effects that persist for a long time or manifest themselves after a certain period of time are hardly explained by physiological changes aimed at implementing the current behavior. We assume that such influences were formed in evolution as a proactive adaptation or preadaptation to a possible entry into a new environment since intensive locomotion itself could lead to animals finding themselves in less familiar conditions. Survival in a new environment certainly requires activation of both cognitive and motor functions.

In the last decade, many works have been performed indicating the existence of delayed and even remote effects of increased motor activity in individual development, in both humans and other animals, including some invertebrates. In addition, it is shown that the motor activity of parents affects the functioning of the nervous system of descendants. It is assumed that epigenetic mechanisms associated with changes in DNA methylation, as well as acetylation and methylation of histones in various brain regions and germ line cells, play an important role in these effects. Our review is devoted to the analysis of the long-term effects of intensive locomotion on cognitive and emotional behavior that are transmittable to the next generation as well as possible mechanisms for the preservation of these induced changes in the nervous system.

In the first chapter, we will consider data on the delayed (hours and days) and long-term (months and years) effects of intense motor activity on the nervous system. The second chapter will be devoted to the analysis of possible epigenetic mechanisms that cause such long-term changes. In the third chapter, we will consider works devoted to the epigenetic inheritance of changes caused by intensive locomotion on the maternal and paternal lines and its mechanisms. In the final chapter, we will discuss hypotheses about the adaptive meaning of long-term and inherited changes in the central nervous system caused by intensive locomotion as well as prospects for studying the cellular and molecular mechanisms of this behavioral modulation.

LONG-TERM CHANGES IN BEHAVIOR AND CENTRAL NERVOUS SYSTEM CAUSED BY INTENSIVE LOCOMOTION

It has been repeatedly shown in rodents that previous locomotion has a positive effect on learning and memory of both healthy animals and animals with model neurodegenerative diseases (Anderson et al., 2000; Laurence et al., 2015; meta-analysis da Costa et al., 2020). More than 20 years have passed since the discovery of the cellular mechanism associated with the proactive activation of these cognitive functions by intensive movement (van Praag et al., 1999a, 1999b; van Praag, 2008). An increase in neurogenesis in the hippocampus caused by running and the appearance of new neurons that contribute to the formation of new cell ensembles are the basis of this mechanism. Later, it was shown that motor activity causes changes in serotonergic, dopaminergic, noradrenergic, acetylcholinergic, orexinergic, and endocanabinoid neurotransmitter systems (Lin and Kuo, 2013; Chieffi et al., 2017; Watkins, 2018), and it also affects growth factors, such as brain neurotrophic factor (BDNF), insulin-like growth factor-1, and vascular endothelial growth factor (Trejo et al., 2001; Fabel et al., 2003; Pietrelli et al., 2018). At the same time, the rapid and delayed effect of intensive locomotion on these signaling systems may differ (for more information, see the review of Heijnen et al., 2016). One of the central neuroactive substances that provide the effects of intense motor activity in mammals is serotonin (Klempin et al., 2013; Kondo and Shimada, 2015). Analysis at the cellular level showed that motor activity increases extracellular serotonin content by a mechanism similar to the action of pharmacological antidepressants, serotonin reuptake inhibitors (Baganz et al., 2010). In this case, the key role is assigned to the autoreceptors 5-HT1A (Baganz et al., 2010).

Long effect of intensive locomotion on behavior and cognitive functions, which lasts up to several hours, has also been found in some protostomes. Thus, in the mollusk Limnaea stagnalis, it is shown to facilitate decision-making in a new environment 2 h after intensive muscle crawling in shallow water. Animals in a dry asymmetrically lit arena made fewer approximate turns before choosing the direction of movement (Aonuma et al., 2020). This result is consistent with the data of biochemical and electrophysiological studies on the serotonergic system of these animals (Dyakonova et al., 2019; Aonuma et al., 2020). Two-hour rest after intensive locomotion was manifested in changes in serotonin metabolism and electrical activity of serotonin motor neurons. This model shows for the first time a change in the biophysical properties of serotonergic neurons in conditions of complete isolation from the nervous system as additional example of the delayed effects of intensive locomotion (Dyakonova et al., 2019). Nematode C. elegance also shows not only fast effects but also the effects of species-specific intensive locomotion, swimming, which manifest after hours and even months (Laranjeiro et al., 2017, 2019; Kumar et al., 2021). Thus, a single swimming experience for 90 min increased life expectancy (Laranjeiro et al., 2017), a four-time swimming experience led to improved learning and memory (Laranjeiro et al., 2019), and faster regeneration of damaged axons in physically active nematodes was also shown (Kumar et al., 2021).

Not only delayed (hours and days) but also distant in time (months and years) effects of motor activity are studied on rodents. In one such study (Merkley et al., 2014), it was shown that early life experience, such as the period of voluntary running in young rats (1 month old), can change the course of adult neurogenesis for the rest of the animal’s life. In running animals, the maturation rate increased and the survival rate of new neurons increased with a constant number of proliferating neuronal precursors. This effect persisted up to the age of 11 months, which was the last investigated point in the ontogenesis of these animals in this work. In another study (Shevtsova et al., 2017) on a large sample of animals (n = 80, young rats, without specifying the genetic line), it was once again confirmed that adult neurogenesis plays a significant role in learning and memory, and it was also shown that physical activity at an early age has a positive effect on cognitive processes in later life.

In studies on human, there is also a growing number of papers that focus on the long-term impact of physical activity at a young age on brain health and cognitive functions in the elderly. In one such study, 9344 women, whose average age was 72 years, were involved (Middleton et al., 2010). The authors concluded that women who had a more active lifestyle in adolescence had less pronounced cognitive impairment in their 30s, 50s, and old age. The researchers noted adolescence as the most significant age for subsequent cognitive preservation.

The question of how similar the physiological and molecular mechanisms of the long-term behavioral effects of intensive locomotion are in different species remains open. Meanwhile, the identification of physiological, biochemical, and genetic mechanisms common between humans and available laboratory models, especially those related to the cutting edge of medical research, can potentially facilitate the development of new therapies for neurological and mental disorders. Some difficulties for the translational approach are already obvious. If the activation of adult neurogenesis plays an important role in providing cognitive effects after motor exercise in rodents, then the participation of this mechanism remains questionable in humans. An increasing number of researchers are inclined to the idea of the absence of neurogenesis in the adult human brain (Franjic et al., 2021). For the same reason, activation of neurogenesis cannot explain the long-term cognitive effects of intensive locomotion in some invertebrates, for example, mollusks and nematodes. However, neurogenesis does not fully explain the beneficial cognitive effects of running even in rodents. Thus, Choi et al. (2018) showed that increased neurogenesis leads to a significant improvement in learning, similar to the result of running, only with the additional introduction of brain growth factor (BDNF).

EPIGENETIC MECHANISMS OF THE INFLUENCE OF MOTOR ACTIVITY ON BRAIN FUNCTION

An increasing number of studies indicate the involvement of epigenetic mechanisms in the long-term effects of motor activity on the brain, which play an important role in the regulation of synaptic plasticity, learning, and memory (Gomez-Pinilla et al., 2011; Abel and Rissman, 2013; Ieraci et al., 2015). One of the aims of epigenetics is to study the molecular mechanisms of gene expression modulation through chromatin modification, DNA methylation, acetylation and methylation of histones, and many other chemical influences (Jones and Takai, 2001; Jaenisch and Bird, 2003; Goldberg et al., 2007). Most epigenetic regulators belong to evolutionarily conservative molecules. Groups of small noncoding RNAs, microRNAs, are also considered as powerful epigenetic regulators of brain plasticity and memory mechanisms (Konopka et al., 2010; Wang et al., 2012; Saab and Mansui, 2014). For the first time, microRNAs were identified as regulators of development in C. elegans (Lee et al., 1993; Reinhart et al., 2000). Short, noncoding RNAs were then found in other organisms as well (Pasquinelli et al., 2000).

Gene expression depends on the state of chromatin. Chromatin reorganization is possible due to the addition-removal of chemical groups to histones (CH3CO–; CH3–, etc.) and DNA (CH3–). This is due to regulatory enzymes, such as histone acetyltransferases (HAT) and histone deacetylases (HDAC). HAT, as a rule, activates gene transcription, whereas HDAC suppresses it. In neurons, there is a delicate balance between the activity of HAT and HDAC, which have the opposite effect on the state of chromatin and, consequently, gene expression. For example, during neurodegeneration, a critical loss of HAT occurs, which deflects the balance of histone acetylation towards excessive deacetylation, reducing the expression of many genes (Saha and Pahan, 2006). Elsner et al. (2011) suggest that the neuroprotective properties of exercise may also be associated with chromatin remodeling, in particular with the induction of histone acetylation through HDAC and HAT modulation. It was shown that, in aging mice, the level of HDAC activity in the hippocampus was increased (Sant’ Anna et al., 2013) and HDAC inhibition, in turn, stimulated memory improvement (Levenson and Sweatt, 2005; Reolon et al., 2011). A single run reduced the activity of HDAC, increased the activity of HAT (histone H4) in the hippocampus of rats immediately and 1 h after exercise, which indicates the state of hyperacetylation of histones. It has also been demonstrated that physical activity increases the phosphoacetylation of histone H3 in granular neurons of the fascia dentata of the hippocampus (Collins et al., 2009).

One-time physical activity increased HAT activity not only in the hippocampus but also in the frontal cortex in young adult rats, while regular running reduced HDAC activity (Spindler et al., 2014). The frontal cortex plays a key role in cognitive functions of higher level, such as decision-making, attention, and working memory (Chayer and Freedman, 2001). HAT activity in the frontal cortex increased 1 h after a single run, while HDAC activity remained unchanged. At the same time, regular running reduced HDAC activity immediately after exercise and after 1 h but did not affect HAT. The study revealed that this area of the brain, like the hippocampus, is sensitive to exercise-induced epigenetic modulation (Spindler et al., 2014). The results of this work are also consistent with the hypothesis that both single and prolonged motor load is associated with hyperacetylation of histones in different areas of the brain.

In addition, it should be noted that older rats also had a lower level of histone 4 acetylation due to increased HDAC activity in the hippocampus (Lovatel et al., 2013; Sant’ Anna et al., 2013) and the frontal cortex (taking into account the time of day) (Sant’ Anna et al., 2013). Stable physical activity (20 min a day for 2 weeks) increased the level of H4 acetylation and had a positive effect on memory (Lovatel et al., 2013).

In another study (Elsner et al., 2017), the effect of physical activity on histone acetylation in the striatum of rats at different stages of development—at the age of 39 days after birth (adolescence), 3 months (young adults), and 20 months (elderly)—was evaluated. Male rats were subjected to two different exercise protocols: a single run on a treadmill (20 min) and a daily run (20 min for 2 weeks). A single-time training induced persistent effects in the striatum of rats only in the adolescent group, reducing the activity of histone deacetylases (HDAC) 1 and 18 h after training but without affecting the level of histone 4 acetylation. Daily physical activity did not change any markers of histone acetylation in the adolescent and adult groups at different points in time after exercise. Thus, the data suggest that exercise affects HDAC activity in the striatum depending on age and protocol.

The effect of physical exercise on histone methylation has been studied poorly. Histones can be methylated either by lysine (K) or arginine (R) residues using histone methyltransferases (HMTs). Site-specific methylation of amino acid residues can condense or weaken the structure of chromatin, for example, mono-methylation of histone H3 at K9 (H3-K9) is associated with activation of transcription, while di- and tri- methylation of H3-K9 is associated with suppression (Bannister et al., 2005; Gupta et al., 2010). Elsner et al. 2013 tested the effects of aging and exercise on levels of DNA methyltransferase (DNMT1 and DNMT3b) and H3-K9 methylation in the hippocampus in rats aged 3 and 20 months. DNMT1 is thought to support methylation in daughter DNA after replication, whereas DNMT3b catalyzes de novo methylation (Bestor, 2000). On the other hand, DNMT1 can also catalyze methylation de novo (Vertino et al., 1996), and DNMT3a and DNMT3b can maintain methylation (Rhee et al., 2000). The level of DNMT1 and H3-K9 methylation was initially reduced in the hippocampus in mature rats compared to young ones. The authors suggest that the decrease in H3-K9 methylation in the hippocampus in 20-month-old rats may be due to the monomethylation of H3-K9, indicating an age-related decrease in transcription of genes. During the experiment, the animals were subjected to two exercise protocols: a single run on a treadmill (20 min) and a daily run (20 min for 2 weeks). A single exercise session reduced the levels of DNMT3b and DNMT1 in young adult rats without any effect in mature animals. Both training protocols reduced H3-K9 methylation levels in the young, whereas a single running session increased H3-K9 methylation in mature rats after 1 and 18 h after training. As noted above, histone methylation can exhibit opposite effects, leading either to gene activation or repression, depending on the type of methylation, but whether mono-, di- or trimethylation occurs in this case and whether it depends on age remains obscure.

After exercise, global acetylation of histone 3 in the BDNF promoter regions in the hippocampus and DNA demethylation in the IV promoter region of the BDNF gene were also observed in rodents; this correlates with an increase in BDNF expression after running (Gomez-Pinilla et al., 2011; Abel and Rissman, 2013; Ieraci et al., 2015). An expression of DNA methyltransferases and histone deacetylases was reduced (Abel and Rissman, 2013; Ieraci et al., 2015). In addition, 2 weeks of physical activity caused the demethylation of CpG islands located in promoter of VEGFA (Sølvsten et al., 2016), a vascular endothelial growth factor, which, as described above, plays an important role in the positive effect of exercise on neurogenesis.

In the work of Sølvsten et al. (2018), a 2-week protocol of voluntary access to a treadmill was used to study exercise-induced mRNA expression of a number of growth factors in the hippocampus and frontal cortex of rats. There were differences in BDNF, VEGFA, IGF 1 (insulin-like growth factor 1), and FGF2 (fibroblast growth factor) in the hippocampus compared with the control group of animals. The expression was higher in running rats. There was no difference in BDNF transcripts in the prefrontal cortex, but there was a difference in others neurotrophins, NGF (nerve growth factor) and FGF2. Also, an increase in the expression of the Tet1 gene encoding the TET1 protein of the same name from the TET family, which is involved in the process of DNA demethylation, was recorded in the hippocampus (Kriaucionis and Heintz, 2009). At the same time, the level of DNMT3b was lower in the hippocampus in physically active rats.

Swimming improved the memory of rats exposed to neonatal administration of isoflurane (0.75%), a drug that causes neurocognitive deficiency, and induced acetylation of histones H3 (at K9, K14) and H4 (at K5, K8, K12) in the hippocampus (Zhong et al., 2016). The animals were tested 3 months after the introduction of isoflurane. The most persistent epigenetic effect of swimming was observed on H3K9 and H4K5. Also, after motor activity in the hippocampus, an increase in the expression of CREB-binding protein (CBP) was recorded, the activity of which is associated with synaptic plasticity, long-term memory, and stimulation of histone acetylation (Alarcon et al., 2004; Barrett et al., 2008; Bousiges et al., 2010).

Thus, it has been shown that physical activity modulates epigenetic mechanisms associated with learning and memory through acetylation, mainly of histones 3 (for lysine 4, 5, 14, and most often 9) and 4 (for lysine 5 and less for 8 and 12); demethylation of DNA in the promoter regions of the BDNF and VEGF genes; an increase in the level of histone acetyltransferase (HAT) and, vice versa, a decrease in histone deacetylases (HDAC) and DNA methyltransferases (especially DNMT3b). At the moment, the role of histone methylation and demethylation in the cognitive effects of motor activity is not completely clear.

A number of studies confirm the important role of microRNAs in the cognitive effects of intense motor activity (Bao et al., 2014; Cosín-Tomás et al., 2014; Hu et al., 2015; Donga et al., 2018). MicroRNAs (or miR), as a rule, bind the corresponding mRNAs, thereby suppressing the synthesis of their proteins (He and Hannon, 2004); however, they can also play an activating role in the expression of other genes (Vasudevan et al., 2007). MicroRNAs are involved in the regulation of many important processes in the central nervous system, particularly, in connection with cognitive functions and modulating synaptic plasticity and memory processes (Konopka et al., 2010, Wang et al., 2012; Saab and Mansui, 2014; Xua et al., 2018). Thus, compensation of microRNA expression for impaired traumatic brain injury (TBI) was revealed in the hippocampus in mice after running in a wheel (Bao et al., 2014). Mice were subjected to TBI and placed in an environment where they had free access to the wheel for 2 weeks. Learning and memory improvements were assessed using the Morris Water Maze Test (MWM) on day 15. It was recorded that motor activity led to the restoration of cognitive deficits (Zohar et al., 2003) associated with TBI and a change in microRNA expression in the hippocampus. The authors (Bao et al., 2014) conclude that the modulation of microRNA levels mediated by motor activity may be involved in cognitive improvement in mice suffering from TBI. The data suggest that a decrease in the expression of miR-21 and miR-34a (possibly in combination with other microRNAs) was associated with the process of cognitive recovery after injury. The results of the following study are consistent with this assumption since there was an increase in miR-21 expression in the hippocampus of mice with TBI and its decrease after running, which, in turn, correlated with an improvement in spatial memory (Hu et al., 2015). Also, an association between an increase in miR-34a expression and neurocognitive dysfunction, Alzheimer’s disease, was confirmed (Liu et al., 2012; Cosín-Tomás et al., 2017; Jian et al., 2017; Xua et al., 2018; Sarkar et al., 2019).

Motor activity improved the performance of cognitive tasks in a transgenic line of rapidly aging mice (SAMP8), reducing the accumulation of APP protein (beta-amyloid precursor) and miR-132 expression, also apparently associated with the regulation of cognitive functions (Donga et al., 2018).

Pons-Espinal et al. (2019) showed that another microRNA, miR-135, modulates neurogenesis after physical activity in mice. Increased expression of miR-135 in fascia dentata of the hippocampus prevented the proliferation of neuronal precursors induced by running, whereas inhibition of miR-135 stimulated proliferation, leading to neurogenesis (but not astrogliogenesis), in the fascia dentata even in mice without access to the treadmill. Moreover, inhibition of miR-135 activated the proliferation of neuronal precursors in the fascia dentata of adult mice (Pons-Espinal et al., 2019).

An increase in the secretion of certain neurotransmitters in response to increased locomotion can be considered as a trigger for changes at the epigenetic level. Indeed, possible epigenetic targets have been found for a number of neurotransmitters involved in regulation of motor behavior. Thus, glutamate through NMDA and AMPA receptors, activation of kinase cascades and phosphorylation of CREB can affect the expression of gadd45 genes encoding the GADD45 family of proteins involved in epigenetic control of genes during the development of the nervous system in ontogenesis and in case of brain injuries (Sultan and Sweatt, 2013; Moroz et al., 2021; Dyako-nova, 2022).

Serotonin (5-HT) is involved in epigenetic regulation in various ways. One of the ways of 5-HT action on chromatin is realized through membrane receptors. Thus, for snails of the genus Helix, it was found that learning is associated with acetylation and methylation of H3. Nonspecific blockade of serotonin receptors caused memory deterioration and a decrease in the level of methylation and acetylation of histones, while blockade of histone deacetylases prevented memory deterioration associated with the introduction of a serotonin antagonists (Grinkevich and Vorobiova, 2014). Aplysia also demonstrated a link between the introduction of 5-HT, increased expression of synapsin mRNA, changes in synapse activity, and acetylation of H3 and H4 (Guan et al., 2002; Hart et al., 2011). Another pathway is associated with the recently discovered phenomenon of serotonylation in the cell nucleus and enzyme transglutaminase 2 is involved in this process (Ivashkin et al., 2019; Farrelly et al., 2019; Voronezhskaya, 2021). Serotonylation of histone 3 by glutamine 5 (H3Q5ser) was detected in the work of Farrelly et al. (2019). The H3Q5ser enhances the binding of transcription factors to chromatin, thereby activating gene expression in the nervous system of rodents and humans. The significance of serotonylation in the mechanism of influence of intensive locomotion remains unknown and requires additional study.

INTERGENERATIONAL INFLUENCE OF MOTOR ACTIVITY ON THE FUNCTIONS OF THE NERVOUS SYSTEM AND ITS MECHANISMS

The transmission of epigenetic changes that have arisen in response to environmental stimuli to offspring is called intergenerational and transgenerational epigenetic inheritance. There are differences between the two concepts. Environmental factors affecting pregnant females (F0) can directly affect not only the developing embryo (first generation, F1) but also its germ cells. In this case, the epigenetic transmission of any phenotypic traits to the F1 and F2 generations will be called intergenerational. We can talk about “pure” inheritance only in the case of transgenerational transmission; it will be generation F3 for females. Environmental factors affecting males (F0) can also directly affect germ cells; therefore, “pure” epigenetic (transgenerational) inheritance can only be considered for generation F2 (Lacal and Ventura, 2018; Perez and Lehner, 2019). In the literature, the transgenerational effect of parental intensive motor activity on the central nervous system has been studied extremely little, so we mainly considered intergenerational transmission in this paper.

Prenatal Physical Activity of Females Affects the Behavioral Phenotype and Cognitive Characteristics of Offspring

It has been repeatedly shown that prenatal physical activity of female rodents affects offspring: improves memory (Parnpiansil et al., 2003; Lee et al., 2006; Kim et al., 2007; Akhavan et al., 2008; Robinson and Bucci, 2014), enhances neurogenesis in the hippocampus (Bick-Sander et al., 2006; Lee et al., 2006; Kim et al., 2007) and BDNF expression (Parnpiansil et al., 2003; Aksu et al., 2012; Gomes da Silva et al., 2016), and also reduces anxiety (Aksu et al., 2012).

A recent study has once again confirmed the effect of running in a wheel in pregnant female mice (C57BL/6J) on the behavior, memory, and neurogenesis of their offspring (Yau et al., 2019). It turned out that the offspring (F1), both female and male, had reduced depressive-like behavior (the assessment was made according to the “forced swimming” test); at the same time, only males showed improved memory. Male offspring also had an increase in the number of immature neurons in the ventral hippocampus, and females had increased cell proliferation in the dorsal part of the hippocampus. It is noteworthy that the dorsal part of the hippocampus is more associated with cognitive functions, while the ventral part is associated with an emotional state (Anacker and Hen, 2017). Thus, the results confirmed that the activity of pregnant rats affects the behavior and neurogenesis of offspring of both sexes, with the above gender difference.

In the male offspring of obese female mice, a decrease in BDNF levels and suppression of neurogenesis, spatial learning, and memory were detected; running six times a week for 1 month reduced these deviations (Tozuka et al., 2010; Kim et al., 2018).

Segabinazi et al. (2019) evaluated the effect of physical activity in female rats before and during pregnancy on learning, memory, BDNF, levels of rilin, and DNA methylation in the hippocampus of male offspring (F1). Animals were randomly divided into four groups: (1) females having a passive lifestyle before and during the gestational period; (2) females running on a treadmill before pregnancy; (3) females running only during pregnancy; and (4) physically active females before and during pregnancy. Maternal motor load in the group “before pregnancy” and in the group “during pregnancy” improved the learning performance of offspring. However, there were no changes in the BDNF level in the hippocampus of the offspring of different groups. It is noteworthy that running before pregnancy had the strongest effect on the spatial memory of the offspring. Also, running before pregnancy significantly reduced DNA methylation in the hippocampus of the offspring, unlike other groups of active females, in which only a downward trend was observed. A more pronounced increase in the level of rilin was recorded in the group of offspring from females running before pregnancy, although the offspring of females physically active during pregnancy also showed a significant increase. Thus, the most significant physiological and cognitive effect of physical activity on offspring is observed in the period preceding pregnancy. On the contrary, the offspring of females who ran both before and during pregnancy did not differ from the passive animals in control. The authors explain this result by the stress experienced by a female subjected to excessive forced physical activity; this is consistent with results of other works (Wasinski et al., 2016; Jang et al., 2018).

Improvement of cognitive functions in the offspring of physically active mothers has also been shown in humans (Wolfe et al., 1994; Clapp, 1996; Weissgerber et al., 2006). For example, in women (Clapp, 1996) who had an active lifestyle throughout pregnancy, children (at the age of five) performed better on the intelligence test (Wechsler scale) and showed better oral language and mathematical skills (Jukic et al., 2013; Esteban-Cornejo et al., 2016).

Thus, in mammals, it has already been shown quite convincingly that intensive locomotion before and during pregnancy can positively affect the cognitive functions of the brain and the health of the offspring (Davenport et al., 2018). Most researchers focus on the molecular and cellular changes occurring in the hippocampus and the associated improvements in memory, learning, and the emotional sphere. A number of studies have also noted high levels of BDNF and VEGF in the frontal cortex of offspring (Uysal et al., 2011; Aksu et al., 2012; Akhavan et al., 2013; Gomes da Silva et al., 2016). Little is yet known about the possible mechanisms of these effects. Recent work suggests the involvement of serotonin in maternal effects of motor activity, at least in humans and some vertebrates with developed cortical folding (Xing et al., 2020). In this article, the authors successfully demonstrated the need for serotonin and its HTR2A receptor for the proliferation of basal precursors in the subventricular cortex of the developing embryo. It is likely that the expression of HTR2A in basal progenitors of neurons, which determines the effect of serotonin on the number of precursors and, as a consequence, the number of neurons in the cerebral cortex, may link the motor activity of mothers with the best cognitive indicators of offspring. In addition to receptor mechanisms, direct modification by intracellular serotonin of protein targets in oocytes by the mechanism of serotonylation cannot be excluded: direct attachment of serotonin to some protein ligands, in particular histones (Voronezhskaya, 2021).

Influence of Male Motor Activity on the Behavior and Cognitive Functions of Offspring

In the last decade, there has been a lot of evidence of the influence of the paternal lifestyle on the phenotype of offspring (Curley et al., 2011; Mychasiuk et al., 2012, 2013). Male mice fed high-fat foods had offspring suffering from obesity, insulin resistance, and reproductive system disorders for the two next generations (Fullston et al., 2012, 2013, 2015). Physical activity (swimming) significantly leveled the effects of obesity, improving the health of males (F0), which positively affected the health of offspring at different stages of development from the embryo to the adult organism (McPherson et al., 2013, 2015).

It has also been shown that there may be intergenerational transmission of depressive and anxious behavioral phenotypes from males to the F1 generation (Dietz et al., 2011, 2012; Short et al., 2016). A recent study reported that the active motor behavior of male mice reduced the anxious behavioral phenotype of offspring (Short et al., 2017). Mice (C57BL/6) ran in a wheel for 4 weeks for 50–60 km per week. The male offspring of running males (F1) showed significantly less anxiety in comparison with the control. Females (F1) showed no differences in any test. Three microRNAs (miR-19b, miR-455, miR-133a) and two transport RNAs (tRNA-Gly and tRNA-Pro) were also identified in the sperm of males (F0), most likely influencing the posttranscriptional regulation of genes that changed the trajectory of brain development of offspring (F1 males) and related affective behavior. The expression of 76 genes (9.0%) was increased in the sperm of males running in the wheel, while eight genes (0.9%) had reduced expression. In general, the data of Short et al. (2017) suggest that anxiolytic effects can be transmitted to offspring depending on sex, while this topic requires further study.

In another study (Yin et al., 2013), the authors tested the effect of male motor activity (F0) on the cognitive functions of offspring. Running has been shown to affect spatial learning and memory of male offspring. An increase in the content of rilin and BDNF in the hippocampus was also demonstrated. An increase in the content of rilin and BDNF proteins important for brain development (Rice et al., 2001; Binder et al., 2004; Lakomá et al., 2011) and learning and memory processes (Kang et al., 1995; Herz et al., 2006; Niu et al., 2008) was confirmed using three methods: RT-PCR, immunohistochemistry, and Western blotting. Male offspring (females were not tested) showed greater research activity and less anxiety in the open field test. In the Morris Water Maze test, males (F1) demonstrated better spatial learning and memory ability than the offspring of the control group. In addition, it was shown that male offspring of physically active and male rats that lived in an enriched environment had reduced genome methylation in the hippocampus and prefrontal cortex (females were not trained) (Mega et al., 2018).

Benito et al. (2018) confirmed the cognitive intergenerational effect in male mice kept in an enriched environment (free access to the treadmill + sensory diversity). It was initially found that the long-term potentiation of cells in the CA1 zone of the hippocampus, estimated by the frequency of excitatory postsynaptic potentials, is higher in males (F0) contained in an enriched environment than in the control. The offspring (F1) of both sexes were in standard laboratory conditions from birth and were tested at the age of three months. It turned out that long-term potentiation in the hippocampus is also more pronounced in mice (F1) obtained from active males than in the descendants of males kept under standard conditions, which is consistent with the results of other work carried out on 2-week-old animals (Arai et al., 2009). At the same time, an increase in the level of microRNAs associated with neuroplasticity and cognitive functions, in particular miR132 and miR212, was found both in the sperm and in the hippocampus of active mice (F0) (Remenyi et al., 2013; Hernandez-Rapp et al., 2015). In order to test the participation of “cognitive microRNAs” in ensuring the intergenerational effect on the hippocampus, they were injected into fertilized eggs. The offspring obtained from oocytes injected with microRNAs of active males demonstrated an increased level of long-term potentiation, which was reduced to the control level by the introduction of miR212 and miR132 inhibitors. In addition, mice developed from oocytes injected with microRNA from the sperm of active males showed improved memory on two behavioral tests. However, despite the shown effect of miR-212 and miR-132 on long-term potentiation, it seems that these types of RNAs do not have a decisive effect on behavioral indicators since their inhibition showed only a slight tendency to decreased memory. Finally, the level of miR-212/132 is not increased in the offspring of active males, which indicates that the mechanisms mediating the enhancement of synaptic plasticity and memory in generation F0 and F1 may differ and perhaps for this reason there is no further transmission of effects to generation F2.

The extensive work of McGreevy et al. (2019) also convincingly confirms the transfer of the effects of locomotor activity from male rodents to the next generation. They include facilitating the solution of nonspatial and spatial cognitive tasks, neurogenesis, and increased activity of mitochondria in the hippocampus. At the same time, no changes in DNA methylation were detected in the germ cells of F0 males after running. The authors suggest that a possible mechanism of epigenetic inheritance is associated with the activity of microRNAs. Histone modifications were not tested either in the study of Benito et al. or in this work.

Thus, at the moment there is evidence of the influence of motor activity on neurotransmitter balance, neurogenesis, and structural and functional connections in different areas of the mammalian brain, providing long-term effects of intensive locomotion. Several studies have found a global increase in histone acetylation in the hippocampus and prefrontal cortex after intensive locomotion, which indicates chromatin decondensation and may indicate an increase in genome plasticity in nerve cells. Some epigenetic mechanisms of transmission of the effects of intense motor activity to the next generation on the maternal and paternal lines are also shown, which are manifested in neurophysiological changes in the central nervous system and cognitive and emotional behavior of offspring (Yang et al., 2021). Most of the data related to epigenetic inheritance in connection with intensive motor activity is obtained from work with rodents; there are few studies conducted with the participation of humans, while invertebrates in this context have not been studied at all, which gives space for further comparative studies.

SEARCH FOR THE EVOLUTIONARY AND BIOLOGICAL MEANING OF THE INFLUENCE OF LOCOMOTION ON THE FUNCTIONS OF THE NERVOUS SYSTEM AND RESEARCH PROSPECTS

There is currently a lack of a theoretical model explaining why motor activity leads to a long-term and transmitted to the next generation improvement of some cognitive functions and why such an influence could have formed in evolution. The answer to these questions is not only of fundamental interest; it is necessary to predict therapeutic and possible side effects of motor activity in humans.

A number of anthropologists (Raichlen and Alexander, 2017) have an opinion that the improvement of brain functions due to motor activity in modern humans arose as an adaptation of human ancestors in the struggle for food. The search for food coordinates both motor activity and cognitive activity. This is a combination of aerobic activity with control of motor systems, spatial navigation and memory, decision-making and planning, and control of sensory systems and attention. This combination makes foraging a cognitively complex behavior, which can be further complicated by changing environmental conditions due to movement. Anthropologist Daniel Lieberman believe that the biomechanics of the human body is ideally adapted to moderately intense continuous physical activity, such as long-distance running (Bramble and Lieberman, 2004; Lieberman, 2012). Lieberman suggests that long-distance running may be a specific evolutionary adaptation to group hunting over long distances, which is also consistent with the assumptions of other authors. Thus, if we look at the above assumptions from an evolutionary perspective, we can make a conclusion: ancient people, whose cognitive functions were more activated during motor activity, were subjected to positive selection, which served to strengthen the “movement–cognitive activity” link in their descendants.

V.E. Dyakonova formulated the hypothesis that the effects of motor activity took place already at the early stages of animal evolution; therefore, they spread to various taxonomic groups and have a conservative neurochemical basis (Korshunova et al., 2016; Aonuma et al., 2020). Results of experiments conducted on fish (Mes et al., 2020), mollusks (Korshunova et al., 2016; Aonuma et al., 2020), insects (Mezheritskiy et al., 2020), nematodes (Laranjeiro et al., 2017, 2019; Kumar et al., 2021) are consistent with this hypothesis. There is a reason to believe that an ancient, widespread in wildlife and important for many physiological functions, mediator of serotonin is involved in the general activation of behavior, for example, in the situation of an increase in the speed of movement (Aonuma et al., 2020). Obviously, the topic requires further research and development. Nevertheless, the above publications support the hypothesis of a general neurochemical basis for the effects of motor activity.

As already noted, we assume that the epigenetic mechanisms of the influence of motor activity on the functions of the nervous system appeared in the evolution as a proactive adaptation or preadaptation to a possible entry into a new environment. The concept of preadaptation is considered as the possession of certain characteristics by an organism that make it more adapted to future environmental changes. The effects of motor activity that favor development in a new environment were found in systematically distant species. Thus, in mice after intensive locomotion, an activation of research behavior in an open field (Yin et al., 2013) and also facilitation of the memorization of new information and forgetting of old information (Epp et al., 2016) were shown; the freshwater mollusk has demonstrated an ability to better navigate in new conditions that threaten survival (Korshunova et al., 2016; Aonuma et al., 2020); in crickets, it helps to find conspecifics in a new environment by a sound signal (Mezheritsky et al., 2020) and to defeat them in ritual and physical competitions (Hofmann and Stevenson, 2000). These data allow us to consider intensive locomotion as one of the natural ways to increase the adaptability of behavior to possible changes in living conditions in different organisms.

Preadaptation to novelty primarily involves an increase in the plasticity of behavior. In turn, an increase in the plasticity of behavior is largely associated with the plasticity of the functioning of the genome of the nervous system (Espeso-Gil et al., 2021). The data obtained on the nature of epigenetic rearrangements due to motor load are precisely consistent with these expectations. The results indicate a shift in the balance of histone acetylation towards hyperacetylation and a shift in the balance of DNA methylation towards demethylation. Both processes are associated with increased gene expression. The fact that such changes were detected in the descendants of the first but not the next generation is also consistent with the hypothesis of activation of biological mechanisms of preadaptation to new conditions, since staying in familiar conditions should reduce the expediency of their activation.

How, through what mechanisms, can intensive locomotion increase the plasticity of the genome and affect the variability of descendants? Currently, the issue of choosing successful models and objects for research is of key importance for solving this problem. An ideal object for studying the interaction of neurobiological and reproductive mechanisms in adaptations caused by changes in living conditions would be a fast and easily reproducing animal, inexpensive to maintain, with well-studied functions of individual neurons and behavior generators and easy for use in genetic, transcriptional, and proteomic analysis of the changes occurring. Some representatives of primary-mouthed organisms meet these conditions; the studies of the effects of physical activity on these objects have already begun. Such model objects as C. elegance and D. melanogaster have advantages in terms of genetic analysis, optogenetics. Gastropods are convenient for studying the physiology of identified neurons, their proteomics, transcriptomics, and plasticity of behavior at the level of completely isolated nerve cells. Interestingly, the demethylation of the genome in response to abrupt changes in the environment under natural conditions of rapid adaptation of invasive species was shown for the first time among multicellular species on mollusks (Huang, 2017; Ardura, 2018). It can be expected that significant fundamental and practically significant discoveries in this field will be associated with invertebrate model objects.