神经发生调控老化神经环路重建和记忆的分子机理

Generation of new neurons in the dentate gyrus that is considered as a cellular substrate of memory formation is reduced during aging, but, the brain signals responsible for this reduced cellular regeneration are not known. Recently, we have found that reduced capacity of the dentate gyrus to generate new neurons is closely associated with increased activity of death-associated protein kinase (DAPK1) during aging. We subsequently generated the mutant mice with complete deletion of DAPK1gene (DAPK1-/- ). We have shown that the DAPK1-/- mice have greater numbers of new neurons in the dentate gyrus during aging, compared to the age-matched wild-type controls (DAPK1+/+). Using optogenetic approach combined with three electrodes whole-cell patch clamp recordings we have also demonstrated that new neurons are functionally recruited into the circuits and participate in the neuronal network remodeling during aging. As an increase in the dentate neurogenesis is closely associated with improved memory formation. We thus hypothesize that increased activity of DAPK1 is responsible for impaired neurogenesis and memory during aging. We will test this hypothesis and provide new insights into the molecular and circuit basis of cognitive aging and suggest a practical strategy for intervening aging-related memory deficits.

成年齿状回新神经元生长及神经发生参与海马神经环路重建和学习记忆等高级神经功能活动。在老化进程中新生神经元数量减少，但减少新神经元生长能力的脑内信号机制尚不清楚。我们最近研究发现，老化过程中齿状回神经发生障碍与激活死亡相关蛋白（DAPK1）密切相关。我们构建了DAPK1突变小鼠（DAPK1-/-）。与野生型DAPK1+/+小鼠比较，老年DAPK1-/-小鼠齿状回新生神经元数量明显增加。应用光遗传学结合电生理膜片钳记录发现，新生神经元可以整合到神经环路中，并改善环路突触传递的可塑性。因此，我们假设选择性抑制DAPK1信号通路将增加神经发生，从而促进老年神经环路重建和记忆。本项目将应用干细胞和光遗传学技术阐述这一环路记忆的分子假设，从而为干预老化相关记忆障碍提供分子靶标。

成年齿状回新神经元生长及神经发生参与海马神经环路重建和学习记忆等高级神经功能活动。在老化进程中新生神经元数量减少，但减少新神经元生长能力的脑内信号机制尚不清楚。我们最近研究发现，老化过程中齿状回神经发生障碍与激活死亡相关蛋白（DAPK1）密切相关。我们构建了DAPK1突变小鼠（DAPK1-/-）。与野生型DAPK1+/+小鼠比较，老年DAPK1-/-小鼠齿状回新生神经元数量明显增加。应用光遗传学结合电生理膜片钳记录发现，新生神经元可以整合到神经环路中，并改善环路突触传递的可塑性。因此，我们假设选择性抑制DAPK1信号通路将增加神经发生，从而促进老年神经环路重建和记忆。本项目将应用干细胞和光遗传学技术阐述这一环路记忆的分子假设，从而为干预老化相关记忆障碍提供分子靶标。