Median preoptic area neurons are required for the cooling and febrile activations of brown adipose tissue thermogenesis in rat

Ellen Paula Santos Da Conceição,Pierfrancesco Chiavetta,Georgina Cano,Shaun F Morrison,Domenico Tupone

doi:10.1038/s41598-020-74272-w

Abstract

Within the central neural circuitry for thermoregulation, the balance between excitatory and inhibitory inputs to the dorsomedial hypothalamus (DMH) determines the level of activation of brown adipose tissue (BAT) thermogenesis. We employed neuroanatomical and in vivo electrophysiological techniques to identify a source of excitation to thermogenesis-promoting neurons in the DMH that is required for cold defense and fever. Inhibition of median preoptic area (MnPO) neurons blocked the BAT thermogenic responses during both PGE2-induced fever and cold exposure. Disinhibition or direct activation of MnPO neurons induced a BAT thermogenic response in warm rats. Blockade of ionotropic glutamate receptors in the DMH, or brain transection rostral to DMH, blocked cold-evoked or NMDA in MnPO-evoked BAT thermogenesis. RNAscope technique identified a glutamatergic population of MnPO neurons that projects to the DMH and expresses c-Fos following cold exposure. These discoveries relative to the glutamatergic drive to BAT sympathoexcitatory neurons in DMH augment our understanding of the central thermoregulatory circuitry in non-torpid mammals. Our data will contribute to the development of novel therapeutic approaches to induce therapeutic hypothermia for treating drug-resistant fever, and for improving glucose and energy homeostasis.

Highlights

Within the central neural circuitry for thermoregulation, the balance between excitatory and inhibitory inputs to the dorsomedial hypothalamus (DMH) determines the level of activation of brown adipose tissue (BAT) thermogenesis
This increase in BAT sympathetic nerve activity (SNA) activated BAT thermogenesis resulted in a rise of TBAT (Fig. 1A,B; ∆TBAT = + 1.45 ± 0.24 °C from a pre-PGE2 value of 35.1 ± 0.3 °C, F (40,11) = 38.85, p < 0.0001; individual comparison (IC)(−120 s vs 600 s), n = 12, t* = 9.095, p < 0.05), and an elevated energy expenditure, reflected by an increase in expired C O2 (Fig. 1A,B; ∆EXP CO2 = + 0.9 ± 0.1%, from a pre-PGE2 level of 4.4 ± 0.4%, F(40,11) = 45.36, p < 0.0001; IC(−120 s vs 600 s), n = 12, t* = 10.17, p < 0.05)
The present study provides evidence that glutamatergic neurons in the median preoptic area (MnPO) provide an excitatory drive to the BAT sympathoexcitatory neurons in the DMH that is required for the activation of BAT SNA and BAT thermogenesis, that occurs during cold defense in rats

Summary

Introduction

Within the central neural circuitry for thermoregulation, the balance between excitatory and inhibitory inputs to the dorsomedial hypothalamus (DMH) determines the level of activation of brown adipose tissue (BAT) thermogenesis. An increase in the activity of thermogenesis-promoting neurons in the dorsomedial hypothalamus/dorsal hypothalamic area (DMH/DA) is a key feature of the neural circuits responsible for the activation of BAT thermogenesis in response to a cold environment and during the febrile response to infection[3,5]. We demonstrate the existence of a novel glutamatergic excitatory input to the DMH/DA from neurons in the median preoptic area (MnPO), which is necessary for the cold-evoked and febrile increases in BAT sympathetic nerve activity (SNA) and BAT thermogenesis. This discovery provides important new insights into the neural circuit mechanisms underlying the thermoregulatory control of BAT thermogenesis and BAT metabolism

Methods

Results

Conclusion