Synaptotagmin-4 induces anhedonic responses to chronic stress via BDNF signaling in the medial prefrontal cortex

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. Depression is a complex mental health disorder that can significantly impact a person's life. One symptom, anhedonia, is particularly difficult to treat. Researchers have been exploring why some people develop anhedonia and others don't, especially under stress. The study, led by Jeongseop Kim and Sihwan Seol, aimed to discover the biological processes behind anhedonia. Using mice, the team exposed them to chronic unpredictable stress and observed their behaviors. They found that not all mice responded to stress with depressive-like behaviors, indicating individual differences in stress resilience. The researchers concluded that SYT4 and BDNF play crucial roles in the development of anhedonia and stress-induced depression. This study advances our understanding of the molecular basis of depression and could lead to new treatments targeting these mechanisms. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.