TSH-TSHR信号通路对海马神经再生的调控作用及其机制研究

亚临床甲状腺功能亢进症与认知损伤密切相关，其机制尚不明确。海马神经再生在神经可塑性及学习记忆中发挥重要作用。我们前期研究发现，人群中低水平促甲状激素(TSH)与认知损伤率的增加密切相关，TSH-TSH受体(TSHR)信号通路缺陷可引起小鼠学习记忆受损及海马神经新生神经细胞数目减少。因此提出假设：TSH-TSHR信号通路参与调控海马神经再生。本项目拟应用海马组织条件性Tshr基因敲除小鼠模型、海马立体定位注射病毒小鼠模型以及原代神经祖细胞，研究TSH-TSHR信号通路对海马依赖性学习记忆行为、海马神经再生各阶段新生细胞的调控作用；基于上述动物模型前期蛋白组学的分析结果，进一步研究TSH-TSHR信号通路对海马新生细胞凋亡过程的调控作用，并利用挽救实验对关键分子加以验证。本研究将从新角度阐明亚临床甲状腺功能亢进症相关认知损伤的发病机制，为甲状腺疾病相关性认知功能损伤的预防及治疗提供理论依据。

Subclinical hyperthyroidism is associated with cognitive impairment, but the underlying mechanism is still unclear. Our previous studies have observed higher prevalence of cognitive impairment among individuals with low levels of thyroid-stimulating hormone (TSH) in the population; defects in the TSH-TSHR signaling pathway impaired hippocampal-dependent learning and memory impairment in mice, accompanied with a significant reduction in hippocampal neurons. Therefore, we hypothesize that the TSH-TSHR signaling pathway is involved in the regulation of hippocampal neurogenesis, which plays essential roles in hippocampal neuroplasticity. In the current study, we intend to refine our understanding of the effect of the TSH-TSHR signaling pathway on hippocampal-dependent learning and memory by utilizing hippocampal neuron specific knockout mouse model, hippocampal stereotactic injection virus model and primary neural progenitor cell culture. In addition, we will investigate the regulation of the TSH-TSHR signaling pathway on the apoptosis process of hippocampal neonatal cells and verify the molecular pathway by rescue experiments. This study will clarify a novel mechanism of cognitive impairment caused by subclinical hyperthyroidism, and provide a theoretical basis for the prevention and treatment of cognitive impairment related to thyroid disease.