Defining functional circuits between CN molecular subpopulations and the cerebral cortex

最近的研究为小脑和大脑皮层之间的功能联系提供了证据， 大脑的半球和中央带容纳了大脑-小脑的主要环路。 在包括自闭症谱系障碍在内的认知障碍中发现了小脑神经病变 (ASD)、精神分裂症和痴呆，以及右侧一个小叶浦肯野神经元的调制 小脑导致社交和认知行为的改变。小脑核团的兴奋性神经元 (ECN)是小脑的输出神经元，通过脑桥和大脑皮质相互连接 丘脑，但其发育、电生理学和分子遗传学知之甚少。在……里面 特别是，小脑核团和大脑皮层之间的功能关系尚未得到 演示了。为了了解小脑是如何运作和调节脑组织活动的 大脑皮层，有必要定义ECN的分子多样性，了解ECN是如何 亚群(亚群)发展、映射其回路，并将大脑-小脑功能与特定的ECN联系起来 子P。这类研究的一个主要问题是缺乏专门标记和调节的遗传工具 ECN.该项目将定义ECN的分子亚基，并确定亚基形成的方式和时间 在正常发育期间和ECN子集丢失的发育突变体中(EN1/2 突变体)使用单细胞RNA测序(scRNA-seq)。然后将开发鼠标线来操纵 并应用于定位ECN亚P的突触配对和光遗传学 抑制/激活特定的ECN。电生理学和认知/社会行为分析将用于 确定ECN的特定亚基P与大脑皮层区域之间的功能相互作用。 该项目首次定义了小脑核团的分子亚基P，并对其进行了测定 它们对大脑皮层功能的功能影响。 相关性(请参阅说明)： 除大脑皮层外，小脑还参与认知和社交障碍，包括 然而，自闭症和精神分裂症对连接这两个大脑结构的神经回路知之甚少。 我们将绘制出小脑中不同的神经元亚群如何投射到大脑皮层 并确定它们如何影响大脑-小脑功能。我们的结果将提供 洞察大脑-小脑回路如何发挥作用，并可能在疾病中进行治疗修改。

Recent work has provided evidence for functional connections between the cerebellum and cerebral cortex, with the hemispheres and central zone of the vermis housing the main cerebro-cerebellar circuits. Cerebellar neuropathologies have been detected in cognitive disorders including autism spectrum disorder (ASD), schizophrenia and dementias, and modulation of Purkinje neurons in one lobule in the right lateral cerebellum results in altered social and cognitive behaviors. The excitatory neurons of the cerebellar nuclei (eCN) are the output neurons of the cerebellum that interconnect with the cerebral cortex via the pons and thalamus, but their development, electrophysiology and molecular genetics are poorly understood. In particular, functional relationships between the cerebellar nuclei and cerebral cortex have not been demonstrated. In order to understand how the cerebellum functions and modulates the activity of the cerebral cortex, it is necessary to define the molecular diversity of the eCN, understand how eCN subpopulations (subP) develop, map their circuitry and relate cerebro-cerebellar functions to specific eCN subP. A major problem for such studies is a lack of genetic tools for specifically marking and modulating eCN. This project will define molecular subP of the eCN and determine how and when the subP form during normal development and in developmental mutants in which a subset of eCN are lost (En1/2 mutants) using single cell RNA sequencing (scRNA-seq). Mouse lines will then be developed to manipulate eCN subP and applied to mapping the synaptic partners of subP of eCN and to optogenetics to inhibit/activate specific eCN. Electrophysiology and cognitive/social behavior assays will be used to determine the functional interactions between specific subP of the eCN and regions of the cerebral cortex. This project represents the first definition of the molecular subP of the cerebellar nuclei and determination of their functional impact on cerebral cortex functions. RELEVANCE (See instructions): The cerebellum, in addition to the cerebral cortex, is involved in cognitive and social disorders including autism and schizophrenia, however little is know of the neural circuits that connect the two brain structures. We will map how distinct subpopulations of neurons in the cerebellum project to the cerebral cortex during development and determine how they influence cerebro-cerebellar functions. Our results will provide insights into how cerebro-cerebellar circuits function and might be therapeutically modified in diseases.