This field of research is of particular interest to Dr. Mauricio Cunha, to which he has dedicated himself for the last ten years and refers to the study of the effects of physical exercise on the central nervous system, aiming to elucidate the molecular, cellular and systemic mechanisms involved in such effect. Physical exercise is considered the main non-pharmacological strategy in the treatment of non-communicable diseases, mainly stress-related diseases. Clinical studies have been reporting the effects of physical exercise in the management of mood disorders for over a century, although the biological mechanisms behind these effects remain to be elucidated. Over the past 20 years, scientists in exercise physiology have been pointing to the need to translate phenomena observed in clinical trials to experimental models on the experimental bench using animal and cell culture assays. This process of “reverse translation” aims to understand the physiological and cellular aspects behind the intriguing effects of physical exercise, especially with regard to outcomes in the central nervous system.
David Henry Thoreau, in 1851, already made incredible allusions to the effects of physical exercise on human behavior, although the understanding of this phenomenon was a great mystery for much of the scientific community at that time. Thoreau was among those intellectuals who understood physical activity as a fundamental component to keep the mind active and the source of inspiration flowing.
"I find that the moment my legs begin to move, my thoughts begin to flow"
Although Thoreau's allusions were clear indications of the importance of physical exercise in cognitive and creative capacities, the first studies in rodents seeking to understand the neurobehavioral effects induced by physical exercise date back only to the 1980s. These pioneering studies used the so-called voluntary running wheels and running treadmills adapted for rodents, a experimental models of physical activity and physical exercise at strictly phenomenological studies. Voluntary running wheels use the animal's innate behavior of turning the wheels continuously and progressively throughout its period of activity (in some strains of mice, they can run up to 13 kilometers per night). This strategy has some limitations, such as the difficulty in controlling intensity and volume in running patterns. In addition, some strains of rodents exploit the wheel apparatus more than others. Running treadmills adapted for rodents, on the other hand, use planned and structured physical exercise with controlled intensity and volume. This type of aerobic intervention generates changes in the body patterns, although it also presents a series of limitations. On treadmills, for example, animals from the same lineage present different running patterns. Another point to note is that a group of animals can be injured on the apparatus (approximately 5%). Furthermore, in many lineages, the running on the treadmill must be induced through external stimuli (such as tail shock or some other mechanical stimulus). Although there are limitations in these experimental physical exercise models, over the last two decades they have been providing a revolution in the understanding of the biological mechanisms that mediate adaptations to physical exercise. In this sense, these experimental models have generated a great impact on the elucidation of the etiology and treatment of some pathologies, including diseases associated with chronic stress.
In fact, preclinical studies investigating the mechanism of action behind the neurobehavioral effects of physical exercise are more recent and date back only to the early 2000s. Currently, scientific studies report that the effects of physical exercise on behavior appear to be dependent on the modulation of neurotrophin levels, such as BDNF (brain-derived neurotrophic factor), adult hippocampal neurogenesis and neuronal plasticity, redox modulation and the production of anti-inflammatory mediators.
During PhD and postdoctoral studies, Dr. Cunha studied the neurobehavioral effects induced by voluntary wheel running in rodents. Cunha’s research group reported the antidepressant effect of voluntary wheel running for 21 days (but not 14 days) in Swiss mice and spontaneous hypertensive rats (SHR). Interestingly, the effect of voluntary wheel running lasted for 7 days in mice even after the wheel was removed. In these studies, through pharmacological strategies (enzyme inhibitors), the research data suggested that the antidepressant effect induced by a free exposition to voluntary wheel running in mice could be dependent on the bioavailability of biological amines (serotonin and norepinephrine) and activation of intracellular protein kinases (cyclic AMP-dependent protein kinase and calcium-calmodulin complex-dependent protein kinase 2). Recently have been demonstrated the antidepressant effect of voluntary wheel running in animals allocated in group of 3 animals or in animals socially isolated. In this sense, we have demonstrated that the antidepressant effect of such intervention appears to be dependent on a redox modulation, with an increase in the antioxidant tripeptide glutathione (GSH) levels in the cerebral cortex.
Furthermore, Dr. Cunha have also demonstrated the neurobehavioral effects of exposing rodents (rats and mice) to a treadmill paradigm. In this sense, the reasearch group have recently demonstrated the antidepressant and anxiolytic effect of this intervention in mice and rats. We have also demonstrated that physical exercise on a treadmill is able to improving survival, clinical scores and hypolocomotion induced by inoculation of the a gram-negative, encapsulated, non-motile bacterium Klebsiella pneumoniae in mice, an experimental model of pneumosepsis associated with a “cytokine storm” condition. In this study, the protective effects of physical exercise appear to be mediated, at least in part, by redox and inflammatory modulation.
Although Dr. Cunha have studied the neurobehavioral effects and neurochemical patterns observed in the central nervous system (CNS), an experimental question remained evident in studies: “How does an intervention based on muscle contraction (physical exercise) generate an adaptation in the CNS that results in specific neurobehavioral patterns?”. In this sense, Dr. Cunha has, over the last few years, placed total scientific focus on experimental proposals to answer this question. Therefore, Cunha’s research group has sought to understand the role of the endocrine muscle-skeletal-brain axis in the modulation of neurobehavioral patterns.
The main idea that skeletal muscle can act as an endocrine organ comes from the studies of Goldstein (1961). Goldstein administered intraperitoneally blood from dogs, whose skeletal muscles had previously been electrically stimulated through electrodes, to other control animals that were not electrically stimulated. As a result of his experiments, Goldstein (1961) observed that the dogs administered blood had a reduction in blood glucose, thus suggesting that some molecule secreted by skeletal muscle when stimulated could be a hypoglycemic factor. Subsequently, Cannon and Kluger (1983) administered blood plasma from humans who performed long-term aerobic physical exercise to rats. Cannon and Kluger (1983) concluded that administration of blood plasma increased the rectal temperature of rats, suggesting that some molecule secreted by skeletal muscles, when stimulated by physical exercise, induced a pyrogenic effect. Subsequently, a famous study by Ostrowski et al. (1998) reported that the blood plasma of ultramarathon runners presents a transient increase in interleukin-6 content in skeletal muscle and blood plasma, suggesting that interleukin-6 may be an endocrine molecule secreted by skeletal muscle and with important signaling properties. Therefore, Pedersen et al. (2003) proposed the term "myokine" for Interleukin-6, since it could be synthesized and secreted by skeletal muscle and act as an endocrine signaling molecule. Currently, other nomenclatures are being proposed for these classes of signaling molecules synthesized in skeletal muscle after physical exercise, such as "exerkines".
Recently, our research group has demonstrated that aerobic exercise on a treadmill produced an antidepressant effect in mice, and this appears to be dependent on an increase in the contente of hippocampal FNDC5\Irisin, a classic myokine. We also found that intracerebroventricular administration of recombinant Irisin peptide was able to induce antidepressant and anxiolytic effects, as well as modulate genes related to neuroplasticity. Furthermore, we pointed out that nutritional strategies, such a oral creatine supplementation, were also able to increase the gene expression of FNDC5 in the cerebral hippocampus. Thus, we have indicated the importance of the myokine Irisin for behavioral patterns and associated diseases. We have also recently hinted at the understanding of the latest findings of the Irisin peptide in the field of biomedicine research at a bibliometric review.
In fact, in recent years we have been seeking to understand the importance of new molecules produced through energy metabolism that may be acting as myokines and modulating neurobehavioral patterns. Thus, the research group intends to study, through experimental models in vivo, in vitro, and in silico, the molecular mechanisms responsible for the effect of physical exercise on pathologies associated with chronic stress and thus indicate molecules that may be acting as exercise mimetics and generating protective interventions in neuropathologies.