TAAR1 in dentate gyrus is involved in chronic stress-induced impairments in hippocampal plasticity and cognitive function

• Published in: Progress in neuro-psychopharmacology & biological psychiatry Vol. 132; p. 110995
• Main Authors: Zhang, Yue, Zhang, Xian-Qiang, Niu, Wei-Pan, Sun, Meng, Zhang, Yanan, Li, Ji-Tao, Si, Tian-Mei, Su, Yun-Ai
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 08.06.2024
• Subjects: Adult neurogenesis; Chronic stress; Cognitive function; Dentate gyrus; Major depressive disorder; TAAR1; Chronic stress; Dentate gyrus; Cognitive function; TAAR1; Adult neurogenesis; Major depressive disorder
• ISSN: 0278-5846; 1878-4216
• DOI: 10.1016/j.pnpbp.2024.110995

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. [Display omitted] •TAAR1 mRNA level in the dentate gyrus (DG) was downregulated by chronic social defeat stress (CSDS).•Conditional TAAR1 knockout in DG mice exhibited cognitive deficits and suppressed adult neurogenesis.•RO5263397 treatment mitigated the detrimental effects of CSDS on hippocampal plasticity and cognitive function.•TAAR1 system could be regarded as molecular targets of chronic stress.