Neural mechanisms mediating locomotor performance during forced wheel running in adolescent ratsstress responses and role of the dopaminergic system

Abstract

Regular practice of physical activity during adolescence is known to produce significant benefits for health. However, the causal mechanisms producing these effects remain poorly understood. This knowledge gap is partly due to the lack of uniformity and parametrization of the experimental models of exercise employed in research. One of the current challenges is to unravel the neural mechanisms that controls and modulates physical activity. Thus, the main aim of the present doctoral thesis has been to develop a forced wheel exercise model in rodents to determine the neurobiological mechanisms underlying physical activity. Then, the stress responses and the role of the dopaminergic system during forced running were evaluated. For this purpose, three research studies have been carried out. In study 1 we aimed to develop and evaluate a phase of habituation to exercise in forced running wheel in order to improve the locomotor performance of young rats. For this purpose, we have developed an 8-days habituation protocol based on a progressive increase of the speed and time of running. After the protocol, we evaluated its effect in the locomotor performance by an incremental exercise test. The results determined that eight days of habituation significantly improved the locomotor performance of Sprague-Dawley rats during the test. Also, our data reveal that the implementation of the habituation phase is a key component to achieve successful locomotor responses (100% of rodents) during longer and more demanding training programs. Acute exercise, and particularly forced modalities, are considered stress conditions. These stress responses might act either diminishing or enhancing motor functions. Thus, in study 2, we aimed to determine whether plasmatic stress biomarkers, lactate and glucose, vary during the exercise habituation protocol and during the incremental test. Furthermore, we assessed chronic transcriptomic changes in hypothalamic Crh and Avp mRNA expression after habituation, by in-situ hybridization and qPCR. Our data showed that plasmatic and hypothalamic stress biomarkers remain unchanged during the habituation protocol. According to these results, stress responses do not appear to be involved in the improved locomotor performance observed after the habituation program. Interestingly, non-habituated rats showed significantly higher levels of plasmatic lactate and glucose during the incremental test, which implies that the implementation of an adaptive phase prior to forced exercise programs might minimize non-specific stress responses. Therefore, the mechanisms regulating the observed locomotor responses during forced running appears to be dependent on the central nervous system. In particular the dopaminergic system is known to play a key role in the development and maturation of neural circuits associated with cognitive and motor learning behaviors during adolescence through the activation of D1 and D2 receptors, thus, central dopamine is an important candidate to modulate exercise capacity during adolescence. The aim of the study 3 was to determine whether the D1 and D2 receptors contribute to modulate exercise capacity during adolescence and whether this modulation occurs through the striatum, which is the main input structure of the basal ganglia circuitry involved in motor control, and one of the brain regions with the highest expression of dopamine receptors. The results showed that the dopamine system is involved in the regulation of locomotor performance through a recruitment of striatal D1 and extrastriatal D2 receptor signaling. Collectively, study 1 and 2 provide a novel rodent model to study the neurobiology of exercise, in which similar training loads can be applied to all the animals, achieving successful levels of motor performance and avoiding non-specific of exercise stress responses. And study 3 explores the neural mechanisms associated to exercise capacity during adolescence, which is dopamine-dependent and mechanistically linked to the activation of striatal D1 and extra-striatal D2 receptors.