Closed-Loop Optogenetic Temperature Control System for Inducing Mild Hypothermia in Rats.

Mild hypothermia is widely recognized as a potent neuroprotective intervention. However, conventional physical cooling methods frequently trigger physiological thermoregulatory defenses, eliciting stress responses that limit clinical utility. Neuromodulation based approaches designed to lower body temperature have attracted interest as a means of circumventing these limitations. The preoptic area (POA) of the hypothalamus is a critical site for mammalian thermoregulation, and the medial preoptic area (MPA) sub region contains a high density of temperature sensitive neurons. Prior work has shown that activation of step function opsins (SSFOs) within this area can be associated with a decline in core temperature. In the present study, optogenetic stimulation in awake rats was associated with a mean temperature reduction of- $2.48~\pm ~0.40{^{\circ }}$ C over a 180 minute period. Relative to chemogenetic manipulations, optogenetic stimulation yielded higher survival rates and more stable temperature trajectories under our experimental conditions. Current protocols offer limited control over the rewarming phase. To address this, we capitalized on the biophysical characteristics of sensitive step function opsins (SSFOs) which exhibit prolonged open states following blue light (465 nm) activation and can be closed by yellow light (589 nm) stimulation to design a closed-loop optogenetic system. This system enables induction, maintenance, and controlled rewarming of reduced core temperature in the rat MPA and provides a platform for further investigation of neuromodulatory strategies in the context of targeted temperature management.