Neural circuitry mechanisms regulating adult hippocampal neurogenesis

项目摘要 成年海马神经发生以一种特殊的方式再现了神经发育的整个过程。 成熟齿状回（DG）内的神经源性龛。这些成年人的适当成熟和融合- 天生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 神经元的发育表达基因，如DISC 1（精神分裂症1型中断），导致 认知和情感行为缺陷。DG神经原性小生境由多个细胞群组成 包括一组不同的局部中间神经元，它们具有独特的电生理、分子和神经支配 特性.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，以治疗疾病 由成年海马神经发生失调引起。利用光遗传学和电生理学 最近，我们发现了两种遗传上不同的局部中间神经元输入到未成熟神经元上： 体周靶向小清蛋白（PV）和轴-树突靶向生长抑素（SOM）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各种 在成年海马神经发生期间新生神经元的发育过程是未知的。我们 假设遗传上不同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DISC 1缺陷的新生神经元接受异常的局部神经元信号。 来自PV和SOM神经元的中间神经元输入。此外，我们发现，树突和棘的发展， DISC 1缺陷的新生神经元受到局部PV和SOM中间神经元的不同调节 活动总之，这些数据表明，DISC 1的遗传失调可能会导致异常的基因表达。 新生神经元以神经元间回路特异性方式发育。因此，我们假设， 操纵不同的局部中间神经元及其电路连接的活动将加剧或正常化 DISC 1缺陷新生神经元异常发育的特定方面。我们的结果将揭示 不同的神经回路在编码正常和异常神经发育的特定方面中的作用，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.