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

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Abstract

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 provides neuroprotection by decreasing reperfusion damage. This phenotype is recapitulated by the optogenetic activation of the GABAergic vlPOAVGAT neurons, which similarly induces hypothermia and neuroprotection. 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.

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