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 DMHVGAT 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 vlPOAVGAT neurons, which similarly induces hypothermia and protects against ischemic injury. The GABAergic vlPOAVGAT 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. Thumbnail: Graphical abstract: GABAergic vlPOAVGAT → DMH pathway activation lowers body core temperature, limits post-ischemic infarct volume, and enhances neuronal survival by reducing reperfusion damage. Hypothermia was chemogenetically or optogenetically induced in mice exposed to 90 or 30 min middle cerebral artery occlusion (MCAo). Structural and functional consequences of GABAergic vlPOAVGAT → DMH pathway modulation were assessed.