김정섭 (한국뇌연구원, DGIST)

한빛사논문

조회1,099

한국뇌연구원, DGIST

Exp. Mol. Med., 01 February 2024 | https://doi.org/10.1038/s12276-024-01156-8 Synaptotagmin-4 induces anhedonic responses to chronic stress via BDNF signaling in the medial prefrontal cortex

Jeongseop Kim ^1,2,4, Sihwan Seol ^3,4, Tae-Eun Kim ^1,2, Joonhee Lee ³, Ja Wook Koo ^1,2,* and Hyo Jung Kang ^3,*

¹Emotion, Cognition & Behavior Research Group, Korea Brain Research Institute (KBRI), Dong-gu, Daegu 41062, Republic of Korea.
²Department of Brain Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Dalseong-gun, Daegu 42988, Republic of Korea.
³Department of Life Science, Chung-Ang University, Seoul 06974, Republic of Korea.
⁴These authors contributed equally: Jeongseop Kim, Sihwan Seol.

^*Corresponding authors: correspondence to Ja Wook Koo or Hyo Jung Kang

Abstract

Stressful circumstances are significant contributors to mental illnesses such as major depressive disorder. Anhedonia, defined as loss of the ability to enjoy pleasure in pleasurable situations, including rewarding activities or social contexts, is considered a key symptom of depression. Although stress-induced depression is associated with anhedonia in humans and animals, the underlying molecular mechanisms of anhedonic responses remain poorly understood. In this study, we demonstrated that synaptotagmin-4 (SYT4), which is involved in the release of neurotransmitters and neurotrophic factors, is implicated in chronic stress-induced anhedonia. Employing chronic unpredictable stress (CUS), we evaluated two subpopulations of mice, susceptible (SUS, anhedonic) and resilient (RES, nonanhedonic), based on sucrose preference, which was strongly correlated with social reward. The FosTRAP (targeted recombination in active populations) system and optogenetic approach revealed that neural activity in the medial prefrontal cortex (mPFC) was significantly associated with CUS-induced anhedonic behavioral phenotypes. By conducting weighted gene coexpression network analysis of RNA sequencing data from the mPFC of SUS and RES mice, we identified Syt4 as a hub gene in a gene network that was unique to anhedonia. We also confirmed that Syt4 overexpression in the mPFC was pro-susceptible, while Syt4 knockdown was pro-resilient; the pro-susceptible effects of SYT4 were mediated through a reduction in brain-derived neurotrophic factor (BDNF)-tropomyosin receptor kinase B (TrkB) signaling in the mPFC. These findings suggest that SYT4-BDNF interactions in the mPFC represent a crucial regulatory mechanism of anhedonic susceptibility to chronic stress.

논문정보

형식Research article
게재일2024년 02월 (BRIC 등록일 2024-02-01)
연구진국내 연구진
분야 생명과학 > 신경생물학

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