Neural circuitry mechanisms regulating adult hippocampal neurogenesis

项目摘要 成年海马神经发生在一个专门的 成熟齿状回(DG)内的神经源性生态位。这些成人的适当成熟和融合- 与生俱来的神经元对认知功能和情绪调节至关重要。因此，成人出生的失调 发育中表达的基因导致的神经元，如DISC1(精神分裂症中中断的1)，导致 认知和情感行为缺陷。DG神经源性生态位由多个细胞群组成 包括一组具有不同电生理、分子和神经支配的局部中间神经元 属性。然而，调节新生儿各种发育过程的特定神经回路 神经元是未知的，但需要这样的知识来指导合理的治疗策略来治疗疾病 由成年海马神经发生失调引起。利用光遗传学和电生理学 方法，我们最近发现了两个遗传上不同的局部中间神经元对未成熟神经元的输入： 周边靶向小白蛋白(PV)和轴树突靶向生长抑素(SOM)的表达 中间神经元。不同的局部中间神经元及其电路连接如何编码和调节不同的 新生神经元在成年海马神经发生过程中的发育过程尚不清楚。我们 假设遗传上不同的中间神经元回路调节新生儿的离散发育过程 神经元。有趣的是，我们发现患有DISC1缺陷的新生神经元接受异常的局部 来自PV和SOM神经元的中间神经元输入。此外，我们发现树突状细胞和棘突的发育 DISC1缺陷型新生神经元受局部PV和SOM中间神经元的差异调节 活动。综上所述，这些数据表明DISC1的遗传失调可能会导致异常 新生神经元以中间神经元回路特有的方式发育。因此，我们假设 操纵不同的局部中间神经元及其回路连接的活动将加剧或正常化 DISC1缺乏症新生神经元异常发育的特定方面。我们的结果将揭示 编码正常和异常神经发育的特定方面的不同神经回路的作用，以及 指导针对成年海马神经发生的治疗策略。

Project Summary Adult hippocampal neurogenesis recapitulates the entire process of neurodevelopment in a specialized neurogenic niche within the mature dentate gyrus (DG). The proper maturation and integration of these adult- born neurons are crucial for cognitive functions and mood regulation. Thus, dysregulation of adult-born neurons by developmentally-expressed genes, such as DISC1 (Disrupted-in-schizophrenia 1), leads to cognitive and affective behavioral deficits. The DG neurogenic niche consists of multiple cell populations including a diverse group of local interneurons with distinctive electrophysiological, molecular, and innervation properties. However, the specific neural circuits that regulate various developmental processes of the newborn neurons are unknown, yet such knowledge is needed to guide rational therapeutic strategies to treat disorders arising from dysregulated adult hippocampal neurogenesis. Using optogenetic and electrophysiological approaches, we recently identified two genetically distinct local interneuron inputs onto immature neurons: perisomatic-targeting parvalbumin (PV) and axo-dendritic targeting somatostatin (SOM) expressing interneurons. How distinct local interneurons and their circuitry connections encode and regulate various developmental processes of newborn neurons during adult hippocampal neurogenesis is unknown. We hypothesize that genetically distinct interneuron circuits regulate discrete developmental processes of newborn neurons. Interestingly, we found that newborn neurons with DISC1 deficiency receive aberrant local interneuron inputs from PV and SOM neurons. Furthermore, we found that dendritic and spine development of newborn neurons with DISC1 deficiency were differentially regulated by local PV and SOM interneuron activities. Together, these data suggested that genetic dysregulation of DISC1 may drive aberrant development of newborn neurons in an interneuron circuit-specific fashion. We therefore hypothesize that manipulating activities of distinct local interneurons and their circuitry connections will exacerbate or normalize specific aspects of aberrant development in newborn neurons with DISC1 deficiency. Our results will reveal the role of distinct neural circuits for encoding specific aspects of normal and aberrant neurodevelopment, and guide treatment strategies targeting adult hippocampal neurogenesis.