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Curr Biol. 2019 Apr 1;29(7):1243-1251.e4. doi: 10.1016/j.cub.2019.02.048. Epub 2019 Mar 7.

Reward Inhibits Paraventricular CRH Neurons to Relieve Stress.

Author information

1
School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; Institute of Neuroscience, Chinese Academy of Sciences, Shanghai 200031, China; University of Chinese Academy of Sciences, Beijing 100049, China.
2
School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; iHuman Institute, ShanghaiTech University, Shanghai 201210, China; Institute of Neuroscience, Chinese Academy of Sciences, Shanghai 200031, China; University of Chinese Academy of Sciences, Beijing 100049, China.
3
iHuman Institute, ShanghaiTech University, Shanghai 201210, China.
4
School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
5
School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; iHuman Institute, ShanghaiTech University, Shanghai 201210, China; Chinese Institute for Brain Research, Beijing 102206, China. Electronic address: sunwenzhi@cibr.ac.cn.
6
School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China. Electronic address: huji@shanghaitech.edu.cn.

Abstract

Chronic, uncontrollable stress can lead to various pathologies [1-6]. Adaptive behaviors, such as reward consumption, control excessive stress responses and promote positive health outcomes [3, 7-10]. Corticotrophin-releasing hormone (CRH) neurons in paraventricular nucleus (PVN) represent a key neural population organizing endocrine, autonomic, and behavioral responses to stress by initiating hormonal cascades along the hypothalamic-pituitary-adrenal (HPA) axis and orchestrating stress-related behaviors through direct projections to limbic and autonomic brain centers [11-18]. Although stress and reward have been reported to induce changes of c-Fos and CRH expression in PVN CRH neurons [19-23], it has remained unclear how these neurons respond dynamically to rewarding stimuli to mediate the stress-buffering effects of reward. Using fiber photometry of Ca2+ signals within genetically identified PVN CRH neurons in freely behaving mice [24-26], we find that PVN CRH neurons are rapidly and strongly inhibited by reward consumption. Reward decreases anxiety-like behavior and stress-hormone surge induced by direct acute activation of PVN CRH neurons or repeated stress challenge. Repeated stress upregulates glutamatergic transmission and induces an N-methyl-D-aspartate receptor (NMDAR)-dependent burst-firing pattern in these neurons, whereas reward consumption rebalances the synaptic homeostasis and abolishes the burst firing. Anatomically, PVN CRH neurons integrate widespread information from both stress- and reward-related brain areas in the forebrain and midbrain, including multiple direct long-range GABAergic afferents. Together, these findings reveal a hypothalamic circuit that organizes adaptive stress response by complementarily integrating reward and stress signals and suggest that intervention in this circuit could provide novel methods to treat stress-related disorders.

KEYWORDS:

burst firing; calcium signal; corticotrophin-releasing hormone; fiber photometry; monosynaptic retrograde tracing; neural circuits; paraventricular nucleus of hypothalamus; reward; stress; synaptic transmission

PMID:
30853436
DOI:
10.1016/j.cub.2019.02.048

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