Central thermoregulatory mechanisms during heat stress

ABSTRACT Thermoregulation is controlled in the CNS where peripheral thermal information is integrated and thermoregulatory responses are activated. The core thermoregulatory network comprises the lateral parabrachial nucleus, the preoptic area, the dorsomedial hypothalamus and the rostral raphe pallidus and is involved in the most mechanisms of adaptive thermoregulation and in the fever response. The thermoregulatory mechanisms activated during extreme heat exposure, when core body temperature (CBT) reaches 40.5 C or more, are not fully understood. We have identified brain regions that are specifically activated only in such conditions and our preliminary data indicate that these neurons are thermosensitive and are projecting to preoptic thermoregulatory neurons. Our preliminary studies have also revealed that activation of these population of neurons induces a potent hypothermia. The overarching hypothesis of this proposal is that a specific population of neurons are activated at high core body temperature and that they stimulate downstream thermoregulatory preoptic neurons triggering heat loss mechanisms. In Specific Aim 1 we will identify, using genetic tools, the neurons activated during heat stress and characterize their physiological and neurochemical properties. In Specific Aim 2 we will study using transgenic models, viral vectors and optogenetics the network connectivity of these neurons and their role in thermoregulation. By employing pharmacological tools, electrophysiology and transgenic models we will then study the ion channels involved in the thermosensitive firing of the neurons activated at high CBT and will determine their role in thermoregulation (Specific Aim 3). Studying the thermoregulatory neuronal networks and cellular mechanisms activated by extreme heat exposure may lead to better therapies for heat stroke and provide central pharmacological targets for the development of hypothermic agents.