Role of the median preoptic nucleus in the autonomic response to heat-exposure*

The preoptic area (POA) is a critical brain region for the regulation of body temperature in mammals. Neurons in the POA are believed to integrate information concerning environmental temperature, endocrine and metabolic status, as well as inflammatory and environmental threats, to optimize body temperature through adaptive behaviors, thermogenesis and active and passive heat-loss mechanisms. According to a prevalent model [1], body temperature homeostasis during heat-exposure is proposed to be mediated by warm-activated glutamatergic neurons in the median preoptic nucleus (MnPO), which then act on local GABAergic neurons in the medial preoptic area that inhibit heat production by brown adipose tissue (BAT) and shivering and promote passive heat-loss by increasing cutaneous blood flow. In a land-mark study, Tan et al. (2016) showed that roughly 60% of preoptic neurons activated by heat exposure are located in a region they call the ventral medial preoptic area (VMPO), and that these neurons express the neuropeptides pituitary adenylate cyclase-activating polypeptide (PACAP) and brain-derived neurotrophic factor (BDNF). The VMPO as used by Tan et al appears to correspond to the anteroventral portion of the MnPO (avMnPO). Selective stimulation of BDNF/PACAP cells in this region was sufficient to replicate several behavioral and autonomic aspects of the response to heat-exposure, including inhibition of BAT thermogenesis and increased passive heat-loss through cutaneous vasodilatation of the tail. Interestingly, the inhibition of BAT thermogenesis during stimulation was at least partly due to the activation of a monosynaptic inhibitory pathway from BDNF VMPO neurons to the dorsal hypothalamic area/dorsomedial hypothalamus, and activation of this pathway had no effect on cutaneous blood flow. In a paper published in October in the Journal of Physiology, we used optogenetic stimulation to address the role of glutamatergic neurons in the MnPO in thermoregulation [2]. Our experiments showed that activation of glutamatergic MnPO neurons decreases core temperature substantially, an effect we attributed to cutaneous vasodilatation. In addition to hypothermia, in many animals stimulation also caused water consumption [3], which we found was due to activation of a largely separate set of glutamatergic neurons in the more dorsal part of the MnPO. The hypothermic effect, by contrast, was due to activation of glutamatergic neurons in the avMNPO. Intriguingly, this location is identical to the location of BDNF/PACAP neurons activated by heat-exposure in Tan et al. (2016), raising the possibility that at least the vasodilation component of the hypothermic response observed in Tan et al was due to activation of glutamatergic neurons that express BDNF/PACAP. Interestingly, Tan et al. (2016) reported that 69% of BDNF VMPO neurons, and 83% of all heat-activated VMPO neurons, are GABAergic, while Zhao et al. (2016), reported that two-thirds of MnPO neurons that express Fos during heatexposure also express BDNF, but that only a third of MnPO BDNF neurons express vesicular GABA transporter (VGAT), with the remainder expressing vesicular glutamate transport 2 (VGluT2) [5]. Taken together, these data suggest that there is a population of glutamatergic BDNF/PACAP neurons which our results suggest may constitute a specific vasomotor thermoregulatory pathway. Moreover, the collective evidence suggests that heatactivated GABAergic MnPO neurons inhibit thermogenesis by inhibiting excitatory DHA/DMH neurons that control BAT, whereas glutamatergic MnPO neurons promote cutaneous vasodilatation through a separate network of neurons.