Inhibition of the hypothalamic ventromedial periventricular area activates a dynorphin pathway-dependent...

To maintain core body temperature in mammals, CNS thermoregulatory networks respond to cold exposure by increasing brown adipose tissue and shivering thermogenesis. However, in hibernation or torpor, this canonical thermoregulatory response is replaced by a new, emerging paradigm, thermoregulatory inversion (TI), an alternative homeostatic state in which cold exposure inhibits thermogenesis and warm exposure stimulates thermogenesis. Here, we demonstrate that in the non-torpid rat, either exclusion of the canonical thermoregulatory integrator in the preoptic hypothalamus or inhibition of neurons in the ventromedial periventricular area (VMPeA) induces the TI state through an alternative thermoregulatory pathway. Within this pathway, we have identified a dynorphinergic input to the dorsomedial hypothalamus from the dorsolateral parabrachial nucleus that plays a critical role in mediating the cold-evoked inhibition of thermogenesis during TI. Our results reveal a novel thermosensory reflex circuit within the mammalian CNS thermoregulatory pathways and support the potential for pharmacologically inducing the TI state to elicit therapeutic hypothermia in non-hibernating species, including humans.