To maintain body core temperature (TCORE) in mammals, the central nervous system thermoregulatory networks respond to skin cooling by increasing brown adipose tissue and shivering thermogenesis, and by reducing heat loss via cutaneous vasoconstriction. However, there are several conditions (e.g., hibernation, torpor, REM sleep) in which these ?standard? thermoregulatory responses to protect TCORE appear to be superseded by a ?thermoregulatory inversion? in which cold exposure causes inhibition of thermogenesis and warm exposure stimulates thermogenesis. We hypothesize that blockade of POA thermoregulatory function is required for the initiation of thermoregulatory inversion and that such paradoxical thermoregulation is governed by a new central thermoregulatory pathway. We will employ in vivo neurophysiological studies in anesthetized rats, a parallel demonstration of thermoregulatory inversion in a free-behaving rat model, and state-of-the-art anatomical studies to understand the relevant neural pathways regulating thermoregulatory inversion. This study will open a new field of research in thermoregulation and will elucidate a new mechanism for a rapid, controllable, stable and reversible induction of hypothermia for the treatment of ischemic stroke, brain trauma and to block persistent, high neurogenic fevers.
In normal thermoregulatory reflex responses, a cold stimulus to the skin elicits an activation of thermogenesis (shivering and brown adipose tissue activation) to protect against a fall in core temperature. Similarly, exposure to a warm environment inhibits thermogenesis. However, there are examples in nature where these skin thermal stimuli produce inverted thermoregulatory responses. Hibernation is the most representative example of thermoregulatory inversion, in which exposure to cold weather induces an inhibition of thermogenesis in hibernating animals that allows their core temperature to fall. Similarly, exposure to a warm environment can trigger an arousal from hibernation by activating thermogenesis. We have recently demonstrated the ability to pharmacologically induce a hibernating-like state in rats, a non-hibernating species. In this proposal, we will study the state of thermoregulatory inversion to understand the central neural circuit mechanisms which underlie its reversed thermoregulatory reflex responses. Supported by a series of strong preliminary data, we will show a novel thermoregulatory pathway, and identify neurotransmitters involved in mediating inverted thermoregulatory responses in the rat, which is not normally capable of entering a torpor-like state. The knowledge acquired from this study will provide the basis for developing approaches to pharmacologically induce a therapeutic hypothermia for the treatment of ischemic stroke and intractable high fevers, including neurogenic fever.
