GABAergic ventrolateral preoptic projection to dorsomedial hypothalamus recapitulates post-ischemic neuroprotection by hypothermia

Therapeutic hypothermia by exogenous cooling induces potent neuroprotection. Post-stroke, therapeutic hypothermia so far did not translate into clinically applicable therapies due to hypothermia-associated side-effects compromising patient outcome. The hypothalamus contains two major thermoregulatory centers in the ventrolateral preoptic area (vlPOA) and dorsomedial hypothalamus (DMH), which are connected via gamma-aminobutyric acid (GABA)-ergic fibers. Using chemogenetic and optogenetic approaches, we explored the role of this GABAergic projection in regulating body temperature responses, cerebral blood flow, and ischemic injury in Vgat-cre mice exposed to transient middle cerebral artery occlusion (MCAo). Using a chemogenetic approach, we show that the inhibition of a set of GABAergic DMH^VGAT neurons, which under physiological conditions induces hyperthermia, is essential to drive hypothermia, which decreases cerebral blood flow post-MCAo and protects against ischemic reperfusion injury via mechanisms involving preservation of astrocytic homeostatic functions. This phenotype is recapitulated by the optogenetic activation of the GABAergic vlPOA^VGAT neurons, which similarly induces hypothermia and protects against ischemic injury. The GABAergic vlPOA^VGAT DMH pathway provides a potent target for neuroprotective therapies. We hypothesize that modulating central temperature responses via this pathway may not elicit the undesirable side effects associated with exogenous brain cooling. (Figure presented.)