海马神经元死亡是慢性脑低灌注(CCH)导致认知障碍的重要因素，但机制不清，临床无特异治疗。本课题组前期发现随着CCH时间延长，大鼠脑灌注有所恢复，但GDNF下调，认知下降，星形胶质细胞活化和神经元死亡形态提示焦亡可能也是海马神经元死亡方式。探索海马神经元死亡的分子机制和可能干预手段是CCH潜在治疗靶点。本课题将分别建立CCH大鼠模型和离体“脑神经血管单元”模型，首先观察海马神经元形态和焦亡相关蛋白表达情况。其次抑制大鼠海马和离体神经元NLRP1/NLRP3或Caspase-1的表达，在干扰基础上再建立CCH动物模型和细胞模型，观察海马神经元形态学、焦亡相关蛋白的表达及认知改变。最后，过表达GDNF信号，观察海马神经元焦亡发生及对认知的影响。本项目旨在探究CCH导致海马神经元焦亡的机制，并探讨抑制NLRP1/NLRP3、Caspase-1及过表达GDNF能否对抗焦亡及改善认知。

Neuron death in the hippocampus is a key factor in cognitive impairment caused by chronic cerebral hypoperfusion (CCH), but its mechanism is not clear, and no specific clinical treatment is available. In previous research we determined that some recovery of cerebral perfusion in rats could be achieved by prolonging the CCH process, resulting in reduced cognitive impairment and down-regulation of glial cell line-derived neurotrophic factor (GDNF). Astrocyte activation and morphological observations associated with neuron death suggest that pyroptosis may be one of the pathways involved in hippocampal neuron death. Thus, it is a potential target for exploration of the molecular mechanisms of hippocampal neuron death and possible intervention in that process in cases of CCH. In the current study a CCH rat model and an in vitro primary “cerebral neurovascular unit” model will be established, and the morphology of hippocampal neurons and the expression of pyroptosis-related proteins will be observed. Expression of nucleotide-binding domain leucine-rich repeat protein (NLRP)1/NLRP3 and caspase-1 in the hippocampus and hippocampal neurons will be inhibited in vitro. On the basis of interference, a CCH animal model and a cell model will be established to investigate the morphology of hippocampal neurons, expression of pyroptosis-related proteins, and associated cognitive changes. Lastly, overexpression of GDNF signaling will be used to assess hippocampal neuron pyroptosis and investigate its effects on cognition. The primary aims of the study are to explore the mechanisms involved in CCH-induced hippocampal neuron pyroptosis, and whether inhibition of NLRP1/NLRP3, caspase-1, and overexpression of GDNF can ameliorate CCH‑induced hippocampal neuron pyroptosis and improve cognition.