Stress in space: Investigating stress-evoked neuronal activity in the rodent hindlimb unloading model of microgravity

Manned spaceflight poses significant physiological and psychological challenges, with microgravity, irradiation, confinement, and social isolation contributing to stress-related health risks. Microgravity in particular causes cardiovascular, muscular, immune, and cognitive changes, often accompanied by elevated glucocorticoid (GC) stress-hormone levels mediated by the hypothalamic-pituitary-adrenal (HPA) axis. However, conflicting evidence exists regarding GC elevation, and little is known about how stress-responsive neurons adapt during and after microgravity exposure. This study investigates how simulated microgravity, modeled in rodents by hindlimb unloading (HU), impacts corticotropin-releasing factor-positive neurons of the paraventricular nucleus (PVN-CRF neurons), key regulators of the HPA axis. We have developed a modification of the HU paradigm that facilitates longitudinal in vivo recording of brain activity using implanted electrodes of fiber-optic cannulae. Using fiber photometry to track PVN-CRF neuron activity in real time, we hypothesize that HU causes prolonged increases in PVN-CRF activity and heightened reactivity to subsequent stressors, with greater effects seen in longer HU durations. These findings will shed light on the neural adaptations to microgravity and the long-term effects on stress circuits. By identifying how stress responses are altered in microgravity, this research may guide strategies to mitigate stress-linked health challenges in spaceflight.