THE CAUSAL INVOLVEMENT OF THE BDNF-TRKB PATHWAY IN DENTATE GYRUS IN EARLY-LIFE STRESS-INDUCED COGNITIVE DEFICITS IN MALE MICE
Authors: Sun *Yaxin , Su Yun-Ai , Wang Qi , Zheng Jiaya , Zhang Chenchen , Wang Ting , Liu Xiao , Ma Yunu , Li Xuexin , Zhang Xianqiang , Xie Xiaomeng , Wang Xiaodong , Li Jitao , Si Tianmei 
Published: February 2025

Abstract

Background
Cognitive decline is one of the core symptoms of a variety of mental diseases. How to improve cognitive function is one of the key issues in psychiatric research.Stress, especially early-life stress, increases the prevalence of mental diseases in adult, and is often accompanied by hippocampal- related cognitive dysfunctions. However, its pathological mechanism remains unclear. Abnormal functioning of Brain-derived neurotrophic factor (BDNF) signaling pathway may be one of the mechanisms. Although the abnormal BDNF-TrkB signaling system have been found in hippocampus of the early-life stressed mice, but whether and how it mediates the cognitive dysfunction needs to be further explored.

Aims & Objectives
To figure out the role of hippocampus BDNF-TrkB signaling system in mediating the cognitive dysfunction caused by early-life stress, we constructed an stress model of restricted nesting materials and bedding materials in mice.

Method
Early stress models of restricted nesting materials and bedding were constructed from day 2 to day 9 after birth, and cognitive behavioral tests and molecular biological tests were performed in adult mice. SOR test and Y maze test were used to evaluate the spatial learning and memory ability and spatial working memory ability of mice. Immunohistochemical staining and immunofluorescence staining techniques were used to quantitatively evaluate the expression of BDNF protein in the hippocampus of mice and the number of adult neurons generated in the DG region. To specifically down-regulate the expression of BDNF in the DG region of the mouse hippocampus, AAV2/9-CaMKIIa-Crevirus was injected into the brain of the Bdnftm2Jae/J mice. To specifically up-regulate BDNF in DG, Recombinant Human BDNF (rhBDNF, 0.5 μ g/μ l, 0.5 μ l/site) were injected directly into the brain by microinjection. To further activate or inhibit the BDNF-TrkB signaling pathway in the hippocampal DG region of mice, TrkB receptor agonist 7,8-DHF (1μ g/μ l, 0.5μ l/site) or antagonist ANA-12 (1μ g/μ l, 0.5μ l/site) were injected directly into the brain by microinjection, respectively. Intraperitoneal injection of 7,8-DHF (5 mg/kg), and ANA- 12 (0.5 mg/kg) for validation and supplementation of brain region injection.

Results
Adopting the limited nesting and bedding material paradigm, we first demonstrated that ELS impaired spatial memory, suppressed BDNF expression and neurogenesis in DG in adult mice. Down- regulating BDNF expression (conditional BDNF knockdown) or inhibition of the TrkB receptor (using its anatognist ANA-12) in the DG mimicked the cognitive deficits of ELS. Acute up-regulation of BDNF (exogenous human recombinant BDNF microinjection) levels or activation of TrkB receptor (using its agonist, 7,8-DHF) in the DG restored ELS-induced spatial memory loss. Finally, acute and subchronic systemic administration of 7,8-DHF successfully restored spatial memory loss in stressed mice. Subchronic 7,8-DHF treatment also reversed ELS-induced neurogenesis reduction.

Discussion & Conclusion
Our results suggest that BDNF and its TrkB receptor are causally involved in the cognitive impairment caused by early-life stress. More importantly, our results of subchronic systemic administration of 7,8-DHF highlight the BDNF-TrkB pathway as the potential therapeutic targets for the treatment of cognitive deficits in stress-related psychiatric disorders.

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