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A Hypothalamic Circuit That Controls Body Temperature

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A Hypothalamic Circuit That Controls Body Temperature Correction NEUROSCIENCE Correction for “A hypothalamic circuit that controls body tem- perature,” by Zheng-Dong Zhao, Wen Z. Yang, Cuicui Gao, Xin Fu, Wen Zhang, Qian Zhou, Wanpeng Chen, Xinyan Ni, Jun-Kai Lin, Juan Yang, Xiao-Hong Xu, and Wei L. Shen (first published January 4, 2017; 10.1073/pnas.1616255114). The authors note that the grant number X-0402–14-002 should instead appear as 31400955. www.pnas.org/cgi/doi/10.1073/pnas.1701881114 CORRECTION www.pnas.org PNAS | February 28, 2017 | vol. 114 | no. 9 | E1755 Downloaded by guest on September 30, 2021 A hypothalamic circuit that controls body temperature Zheng-Dong Zhao (赵政东)a,b,c,1, Wen Z. Yanga,b,c,1, Cuicui Gaoa,b,c, Xin Fua,b,c, Wen Zhangd, Qian Zhoua,b,c, Wanpeng Chena,b,c, Xinyan Nia, Jun-Kai Lind, Juan Yanga, Xiao-Hong Xud, and Wei L. Shen (沈伟)a,2 aSchool of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China; bInstitute of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, China; cUniversity of Chinese Academy of Sciences, Beijing, 100049, China; and dInstitute of Neuroscience, State Key Laboratory of Neuroscience, Chinese Academy of Sciences Center for Excellence in Brain Science and Intelligence Technology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, China Edited by David J. Mangelsdorf, The University of Texas Southwestern Medical Center, Dallas, TX, and approved December 9, 2016 (received for review October 3, 2016) The homeostatic control of body temperature is essential for survival hasbeenfoundtohaveonlyaminimalornoeffectonTcore (5, 6). in mammals and is known to be regulated in part by temperature- However, the precise nature of the POA projections that play a role sensitive neurons in the hypothalamus. However, the specific neural in suppressing thermogenesis have not been elucidated. Thus, al- pathways and corresponding neural populations have not been fully though several relevant brain regions have been suggested to act elucidated. To identify these pathways, we used cFos staining to in concert with the POA to regulate Tcore (1, 2), including the dor- identify neurons that are activated by a thermal challenge and found somedial hypothalamus (DMH), the periventricular nucleus, and induced expression in subsets of neurons within the ventral part of the the raphe pallidus nucleus, functional connections between the lateral preoptic nucleus (vLPO) and the dorsal part of the dorsomedial POA and other thermoregulatory regions are largely unknown. hypothalamus (DMD). Activation of GABAergic neurons in the vLPO In the present study, we began by defining sites in which cFos using optogenetics reduced body temperature, along with a decrease staining was induced by changes in environmental temperature. in physical activity. Optogenetic inhibition of these neurons resulted in These studies identified temperature-activated neurons in the fever-level hyperthermia. These GABAergic neurons project from the ventral part of the lateral preoptic nucleus (vLPO) and the dorsal vLPO to the DMD and optogenetic stimulation of the nerve terminals part of the DMH (DMD). We confirmed that DMD neurons in the DMD also reduced body temperature and activity. Electrophys- responded to cold by using fiber photometry, and tested the ability iological recording revealed that the vLPO GABAergic neurons sup- of these and POA neurons to affect Tcore, energy expenditure (EE), pressed neural activity in DMD neurons, and fiber photometry of and physical activity by using optogenetics (7) or designer receptors calcium transients revealed that DMD neurons were activated by cold. exclusively activated by designer drugs (DREADDs) (8). These Accordingly, activation of DMD neurons using designer receptors functional studies identified neural pathways in which heat-activated exclusively activated by designer drugs (DREADDs) or optogenetics GABAergic neurons in the vLPO inhibit cold-activated neurons increased body temperature with a strong increase in energy expen- in the DMD to suppress thermogenesis and lower Tcore. diture and activity. Finally, optogenetic inhibition of DMD neurons Results triggered hypothermia, similar to stimulation of the GABAergic neu- rons in the vLPO. Thus, vLPO GABAergic neurons suppressed the ther- Activation of GABAergic POA Neurons Is Sufficient To Drive Hypothermia. mogenic effect of DMD neurons. In aggregate, our data identify The POA is known to receive input from cold- and heat-sensitive vLPO→DMD neural pathways that reduce core temperature in re- neurons (1). However, although recent data have identified some of sponse to a thermal challenge, and we show that outputs from the the neural substrates for temperature sensing (5, 6), components of DMD can induce activity-induced thermogenesis. the neural circuit(s) that respond to thermal challenges have not been thermoregulation | preoptic area | dorsomedial hypothalamus | Significance fiber photometry | energy expenditure Thermal homeostasis is essential for survival in mammals. Al- dult mammals, including humans, precisely maintain core though it is known that temperature-sensitive neurons in the A hypothalamus can control body temperature, the precise neu- body temperature (Tcore) within a narrow range. This system is essential for survival because a significant deviation of T ral types and dynamics of neurons responding to changes in core environmental temperature are not well defined. In this study, can adversely affect cellular metabolism. Changes in environ- we identified subsets of temperature-activated neurons in two mental temperature activate homeostatic responses that, in turn, hypothalamic nuclei, the preoptic area (POA) and the dorso- regulate energy expenditure, adaptive thermogenesis, and phys- medial hypothalamus (DMH), and showed that modulating ical activity in an attempt to maintain near-optimal T . Pre- core their activity can lead to alterations in core temperature. The vious studies have shown that the preoptic area (POA) of the data further suggest that heat-activated GABAergic neurons in hypothalamus plays an important role in maintaining a stable the POA reduce the activity of cold-activated neurons in the Tcore via afferent inputs from skin thermoreceptors. The direct DMH, which function to increase thermogenesis and physical sensing of changes in skin temperature, in turn, activates POA activity. These data identify a neural circuit that controls core efferent signals that control thermal effector organs (1, 2). For temperature and thermogenesis. example, in response to a heat stress, warmth receptors within the dorsal root ganglion provide excitatory input to POA neu- Author contributions: Z.-D.Z., W.Z.Y., X.-H.X., and W.L.S. designed research; Z.-D.Z., W.Z.Y., rons via relay neurons in the dorsal lateral parabrachial nucleus C.G., X.F., W.Z., Q.Z., W.C., X.N., J.-K.L., and J.Y. performed research; Z.-D.Z., W.Z.Y., C.G., (3). In addition, recordings from in vivo models and in slice pre- X.F., W.Z., Q.Z., and W.C. analyzed data; and Z.-D.Z., W.Z.Y., and W.L.S. wrote parations identify a group of intrinsic warm-sensitive neurons the paper. (WSNs) (20–40%) that may enable animals to directly detect brain The authors declare no conflict of interest. warmth and promote heat loss (4). Thermosensitive transient re- This article is a PNAS Direct Submission. ceptor potential channel M2 (TRPM2), which is expressed in the See Commentary on page 1765. POA, may be part of the heat sensor in WSNs that can limit fever 1Z.-D.Z. and W.Z.Y. contributed equally to this work. and induce hypothermia (5). Furthermore, activation of gluta- 2To whom correspondence should be addressed. Email: [email protected]. matergic neurons in several POA subareas results in severe hypo- This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. thermia, whereas activation of subsets of POA GABAergic neurons 1073/pnas.1616255114/-/DCSupplemental. 2042–2047 | PNAS | February 21, 2017 | vol. 114 | no. 8 www.pnas.org/cgi/doi/10.1073/pnas.1616255114 fully elucidated. For example, there are conflicting data concerning Next, we asked whether inhibiting these neurons was sufficient the potential role of GABAergic neurons in the POA (2, 5, 6). To to drive hyperthermia. Using the Guillardia theta anion chan- SEE COMMENTARY identify these key neural populations, we characterized the pattern of nelrhodopsin 1 (hGtACR1), which robustly silences neural ac- cFos activation following a thermal challenge (SI Appendix,Fig.S1). tivity in response to blue-yellow light (12), we found that blue We found heat-induced cFos expression in the medial preoptic area light delivery was sufficient to silence neurons in slice recordings (MPO) and the vLPO, and it colocalized with the GABAergic marker (Fig. 1C). Remarkably, light stimulation of mice expressing GAD67 (Fig. 1A and SI Appendix,Fig.S5A). Both the MPO and the hGtACR1 in vLPOVgat neurons caused severe hyperthermia with = vLPO have been suggested to play important roles in thermoregula- elevated activity levels (maximal Tcore 40.6 °C, Fig. 1 D and E). tion(1,2,9–11). To test the function of the vLPO neuronal pop- Indeed, we needed to minimize the time in which animals re- ulation, we targeted expression of channelrhodopsin-2 (ChR2) fused ceived light illumination to prevent hyperthermia-induced death. with eYFP to GABAergic neurons within the vLPO by injecting Cre- We also tested the function of MPO GABAergic neurons by dependent adeno-associated virus (AAV) 5 viruses into the vLPO of targeted expressing of ChR2 to GABAergic neurons within the Vgat-IRES-Cre driver mice (Vgat stands for vesicular GABA trans- MPO of Vgat-IRES-Cre driver mice (SI Appendix, Fig. S5B). porter) (Fig. 1B). In slice recordings, we confirmed that the delivery of The GABAergic neurons in the MPO have been suggested to Vgat play important roles in thermoregulation (1, 2). Surprisingly, we blue light to ChR2-expressing vLPO neurons resulted in neural Vgat excitation (Fig. 1C). In vivo, we found that light-induced activation of found that optogenetic activation of these MPO neurons did Vgat not significantly affect T or activity (SI Appendix, Fig.
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