A Glutamatergic Hypothalamomedullary Circuit Mediates Thermogenesis, but Not Heat Conservation, during Stress-Induced Hyperthermia

Abstract

Stress elicits a variety of autonomic responses, including hyperthermia (stress fever) in humans and animals. In this present study, we investigated the circuit basis for thermogenesis and heat conservation during this response. We first demonstrated the glutamatergic identity of the dorsal hypothalamic area (DHAVglut2) neurons that innervate the raphe pallidus nucleus (RPa) to regulate core temperature (Tc) and mediate stress-induced hyperthermia. Then, using chemogenetic and optogenetic methods to manipulate this hypothalamomedullary circuit, we found that activation of DHAVglut2 neurons potently drove an increase in Tc, but surprisingly, stress-induced hyperthermia was only reduced by about one-third when they were inhibited. Further investigation showed that DHAVglut2 neurons activate brown adipose tissue (BAT) but do not cause vasoconstriction, instead allowing reflex tail artery vasodilation as a response to BAT-induced hyperthermia. Retrograde rabies virus tracing revealed projections from DHAVglut2 neurons to RPaVglut3, but not to RPaGABA neurons, and identified a set of inputs to DHAVglut2 → RPa neurons that are likely to mediate BAT activation. The dissociation of the DHAVglut2 thermogenic pathway from the thermoregulatory vasoconstriction (heat-conserving) pathway may explain stress flushing (skin vasodilation but a feeling of being too hot) during stressful times. Machado et al. describe that DHAVglut2 neurons are critical for the regulation of body temperature and stress-induced hyperthermia through their direct projections to glutamatergic neurons in the RPa, which in turn regulate thermogenesis from brown adipose tissue, but not cutaneous vasoconstriction.