Parabrachial neuron types categorically encode thermoregulation variables during heat defense

Abstract

Heat defense is crucial for survival and fitness. Transmission of thermosensory signals into hypothalamic thermoregulation centers represents a key layer of regulation in heat defense. Yet, how these signals are transmitted into the hypothalamus remains poorly understood. Here, we reveal that lateral parabrachial nucleus (LPB) glutamatergic prodynorphin and cholecystokinin neuron populations are progressively recruited to defend elevated body temperature. These two nonoverlapping neuron types form circuits with downstream preoptic hypothalamic neurons to inhibit the thermogenesis of brown adipose tissues (BATs) and activate tail vasodilation, respectively. Both circuits are activated by warmth and can limit fever development. The prodynorphin circuit is further required for regulating energy expenditure and body weight homeostasis. Thus, these findings establish that the genetic and functional specificity of heat defense neurons occurs as early as in the LPB and uncover categorical neuron types for encoding two heat defense variables, inhibition of BAT thermogenesis and activation of vasodilation.

Parabrachial opioidergic projections to preoptic hypothalamus mediate behavioral and physiological thermal defenses

“…These FISH based experiments indicate that Pdyn + and Penk + cells in the LPBN express Slc17a6 and are partially overlapping subpopulations of glutamatergic LPBN cells. A recent report on PBN→POA neurons implicated cholecystokinin (Cck) expressing LPBN neurons in heat defense ( Yang et al, 2020 ). We examined if Pdyn labeled neurons in LPBN were co-labeled by probes for Cck and found that 70% ± 0.7 (mean ± SEM, n = 150 cells, n = 3 mice) of LBP Pdyn labeled neurons were co-labeled by Cck probes (Supplemental Figure 2—figure supplement 2D–F ) suggesting that mRNA for Cck and pDyn is expressed in overlapping neuronal populations.…”

“…Taken together these results indicated that Pdyn+ and Penk+ PBN→POA neurons represent subsets of the glutamatergic warm-activated PBN neurons. A recent report presented data indicating the Pdyn vs Cck expression in the PBN marked a functional division of neurons driving vasodilation and BAT regulation ( Yang et al, 2020 ). In contrast to those results, we found that Pdyn and Cck expression overlap in many lateral PBN neurons and that activation of Pdyn+ PBN→POA neurons induces tail vasodilation.…”

“…Likely postsynaptic targets in POA for warm-activated PBN cells include the recently identified warmth activated neurons in the POA that express the neuropeptides brain-derived neurotrophic factor (BDNF) and pituitary adenylate cyclase-activating polypeptide (PACAP) ( Tan et al, 2016 ) as well as neurons in nearby areas implicated in mediating various homeostatic functions. Yang et al show that blocking glutamatergic neurons in the POA blocked the effects on body temperature of activating PBN→POA ( Yang et al, 2020 ). Also, prior studies have shown that hM3-Gq-DREADD induced stimulation of glutamatergic VMPO neurons (expressing the receptor for the hormone leptin) causes a reduction in core body temperature similar in magnitude to the effect seen by activation of Pdyn PBN→POA terminals we observed in the present study.…”

“…An area of future investigation will be to examine if subpopulations of POA cells may independently drive individual behavioral and physiological components of thermal regulation such as suppression of locomotion, postural extension, vasodilation, and alterations in metabolism. Yang et al report that functional division of the circuits mediating aspects of physiological responses to warmth defense at the level of the PBN ( Yang et al, 2020 ).…”

Dorsomedial hypothalamic BDNF neurons integrate thermal afferent signals to control energy expenditure

“…CC-BY 4.0 International license made available under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is The copyright holder for this preprint this version posted April 11, 2021. ; https://doi.org/10.1101/2021.04.11.439314 doi: bioRxiv preprint control signals and vasodilation control signals (Yang et al 2020). Signals are integrated in the preoptic area (POA) and then POA neurons directly target neurons in the DMH or the raphe pallidus nucleus (RPa) to drive different aspects of thermal effector activities, such as brown adipose tissue (BAT) thermogenesis and vasodilation (Tan & Knight 2018;Morrison & Nakamura 2019).…”