Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Beijing 100191, China.
Research Triangle Institute, Research Triangle Park, NC 27709, USA.
Prog Neuropsychopharmacol Biol Psychiatry. 2024 Jun 8;132:110995. doi: 10.1016/j.pnpbp.2024.110995. Epub 2024 Mar 19.
Multiple lines of evidence suggest that the trace amine-associated receptor 1 (TAAR1) holds promise as a potential target for stress-related disorders, such as treating major depressive disorder (MDD). The role of TAAR1 in the regulation of adult neurogenesis is recently supported by transcriptomic data. However, it remains unknown whether TAAR1 in dentate gyrus (DG) mediate chronic stress-induced negative effects on hippocampal plasticity and related behavior in mice. The present study consisted of a series of experiments using RNAscope, genetic approaches, behavioral tests, immunohistochemical staining, Golgi-Cox technique to unravel the effects of TAAR1 on alterations of dentate neuronal plasticity and cognitive function in the chronic social defeat stress model. The mice subjected to chronic defeat stress exhibited a noteworthy decrease in the mRNA level of TAAR1 in DG. Additionally, they exhibited compromised social memory and spatial object recognition memory, as well as impaired proliferation and maturation of adult-born dentate granule cells. Moreover, the selective knockout TAAR1 in DG mostly mimicked the cognitive function deficits and neurogenesis impairment induced by chronic stress. Importantly, the administration of the selective TAAR1 partial agonist RO5263397 during stress exposure attenuated the adverse effects of chronic stress on cognitive function, adult neurogenesis, dendritic arborization, and the synapse number of dentate neurons in DG. In summary, our findings suggest that TAAR1 plays a crucial role in mediating the detrimental effects of chronic stress on hippocampal plasticity and cognition. TAAR1 agonists exhibit therapeutic potential for individuals suffering from cognitive impairments associated with MDD.
有多项证据表明，追踪胺相关受体 1（TAAR1）有望成为与应激相关疾病的潜在靶点，例如治疗重度抑郁症（MDD）。转录组数据最近支持了 TAAR1 在调节成年神经发生中的作用。然而，TAAR1 在齿状回（DG）中是否介导慢性应激对小鼠海马可塑性和相关行为的负面影响仍不清楚。本研究包括一系列实验，使用 RNAscope、遗传方法、行为测试、免疫组织化学染色、高尔基-考克斯技术，以揭示 TAAR1 对慢性社交挫败应激模型中齿状神经元可塑性和认知功能改变的影响。接受慢性挫败应激的小鼠在 DG 中 TAAR1 的 mRNA 水平显著下降。此外，它们表现出社交记忆和空间物体识别记忆受损，以及成年产生的齿状颗粒细胞增殖和成熟受损。此外，DG 中选择性敲除 TAAR1 主要模拟了慢性应激引起的认知功能缺陷和神经发生损伤。重要的是，选择性 TAAR1 部分激动剂 RO5263397 在应激暴露期间给药可减轻慢性应激对认知功能、成年神经发生、树突分支和 DG 齿状神经元突触数量的不利影响。总之，我们的研究结果表明，TAAR1 在介导慢性应激对海马可塑性和认知的有害影响中起着至关重要的作用。TAAR1 激动剂为患有与 MDD 相关的认知障碍的个体提供了治疗潜力。
