Development of essential bases to study the neural mechanisms of forced exercise and its effects on health in a rat model

Abstract

Physical exercise has been linked to beneficial effects on brain health since the time of Herophilos, more than 2000 years ago. However, the mechanisms by which these benefits act remain poorly understood. The rodent model is suitable for studying mechanistic aspects that involve the brain's response to motor aspects of physical activity, but also the mechanistic consequences that exercise produces in the organism (positive and negative). Furthermore, they share a general plan of central nervous system development, determining that some basic brain derivatives and their functions are conserved between them. For this reason, the present thesis aims to develop essential bases to study the neural mechanisms of forced exercise and its effects on health in a rat model. For this purpose, the first objective (Study 1) was to determine whether the forced running wheel protocols in the published studies include the variables necessary to experimentally reproduce the research. We found that only 13% of exercise protocols were fully reproducible, and no papers reported the complete 21 items, with 18 items being the maximum (2 works). Light cycle inversion (25.9%) was the least described variable along with relative environmental humidity (27.8%). In terms of exercise parameters, the least described variable was related to the load progression protocol (49%) and the phase of the light/dark period in which the exercise took place (55.5%). Also, there was no correlation between the year of publication and the reported items nor the impact factor and the reported items. Given this lack of reproducibility, we developed a new guideline with the recommendations of items to be reported in an experimentally reproducible article. The second objective (Study 2) was to determine the topological position of the TH-positive neurons in the hypothalamic region according to the prosomeric model in the adolescent Sprague Dawley rat. We found that our analysis revealed that the alphanumeric classification is topographically imprecise in several aspects and thus has limited utility, particularly for causal understanding. Also, the prosomeric area map is generally more discriminative than the columnar one, allowing the postulation of causal mechanistic aspects related to the origin of each catecholaminergic population. Finally, our third objective (Study 3) was to determine the conditions for the development of a forced exercise paradigm to maintain exercise capacity through time in adolescent and adult rats. We found that incremental load elicited the maximal locomotor response in adolescents and adult rats. Adolescent rats, however, were the only ones to benefit from an enriched environment while trying to obtain maximum locomotor response. Resting for 24h between tests decreased locomotor performance on the second test in adolescents and adults. Separating tests by 72h decreased the performance on the second test in adolescents and adults. However, implementing running sessions between tests separated by 72h dampened the drop in performance in adolescents and increased the locomotor performance on adults. Active rest rescued the performance impaired by drugs, reaching that of previous tests in adolescents and adults. Together, these results establish essential bases that will allow in future studies the manipulation of hypothalamic pathways by means of techniques such as optogenetics or chemogenetics to establish causal relationships between hypothalamic nuclei and physical exercise, analyzing the differences in critical stages of brain maturation such as the transition from adolescence to adulthood.