Defining functional circuits between CN molecular subpopulations and the cerebral cortex

定义 CN 分子亚群和大脑皮层之间的功能回路

• 批准号: 10529338
• 负责人: ALEXANDRA L. JOYNER
• 金额: $ 68.46万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-21 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10529338
• 关键词: Behavior; Biological Assay; Brain; Cerebellar Nuclei; Cerebellar vermis structure; Cerebellum; Cerebral cortex; Cognition Disorders; Cognitive; Dementia; Development; Disease; Electrophysiology (science); Genetic; Housing; Instruction; Lateral; Lobule; Maps; Molecular; Molecular Genetics; Mus; Neurons; Output; Pontine structure; Schizophrenia; Social Behavior; Structure; Synapses; Thalamic structure; Therapeutic; Work; autism spectrum disorder; excitatory neuron; insight; mutant; neural circuit; neuropathology; optogenetics; single-cell RNA sequencing; social; social deficits; tool

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.

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， 小脑半球和蚓部的中央区域容纳主要的小脑-小脑回路。 小脑神经病理学已在包括自闭症谱系障碍在内的认知障碍中检测到 (ASD)，精神分裂症和痴呆症，以及右侧一个小叶中浦肯野神经元的调制 小脑导致社会和认知行为的改变。小脑核的兴奋性神经元 (eCN)是小脑的输出神经元，通过脑桥与大脑皮层互连， 丘脑，但他们的发展，电生理学和分子遗传学知之甚少。在 特别是，小脑核和大脑皮层之间的功能关系还没有被发现。 演示。为了了解小脑的功能和调节活动， 大脑皮层，有必要定义eCN的分子多样性，了解eCN如何 亚群（subP）发育，绘制其电路并将小脑-小脑功能与特定eCN相关联 subP.这些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。本项目将定义eCN的分子subP，并确定subP如何以及何时形成 在正常发育期间和在eCN的一个子集丢失的发育突变体中（En 1/2 突变体），使用单细胞RNA测序（scRNA-seq）。然后将开发鼠标线来操纵 eCN subP和应用于映射eCN的subP的突触伴侣和光遗传学， 抑制/激活特定eCN。将使用电生理学和认知/社会行为测定， 确定eCN的特定subP和大脑皮层区域之间的功能相互作用。 本研究首次明确了小脑核团的subP区的分子结构， 它们对大脑皮层功能的影响。 相关性（参见说明）： 小脑，除了大脑皮层，还涉及认知和社会障碍，包括 孤独症和精神分裂症，然而，人们对连接这两种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， 发展，并确定它们如何影响小脑功能。我们的结果将提供 深入了解小脑-小脑回路如何发挥作用，并可能在疾病中进行治疗性修改。

项目成果

4D MEMRI atlas of neonatal FVB/N mouse brain development.

• DOI: 10.1016/j.neuroimage.2015.05.029
• 发表时间: 2015-09
• 期刊: NeuroImage
• 影响因子: 5.7
• 作者: Szulc KU;Lerch JP;Nieman BJ;Bartelle BB;Friedel M;Suero-Abreu GA;Watson C;Joyner AL;Turnbull DH
• 通讯作者: Turnbull DH

Engrailed homeobox genes regulate establishment of the cerebellar afferent circuit map.

• DOI: 10.1523/jneurosci.0653-10.2010
• 发表时间: 2010-07-28
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Sillitoe RV;Vogel MW;Joyner AL
• 通讯作者: Joyner AL

Conditional loss of Engrailed1/2 in Atoh1-derived excitatory cerebellar nuclear neurons impairs eupneic respiration in mice.

• DOI: 10.1111/gbb.12788
• 发表时间: 2022-03
• 期刊: Genes, brain, and behavior
• 作者: Taylor AP;Lee AS;Goedecke PJ;Tolley EA;Joyner AL;Heck DH
• 通讯作者: Heck DH

Cell division angle regulates the tissue mechanics and tunes the amount of cerebellar folding.

细胞分裂角度调节组织力学并调节小脑折叠的量。

• DOI: 10.1101/2023.07.21.549165
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Cook,AmberG;Bishop,TaylorV;Crowe,HannahR;Stevens,Daniel;Reine,Lauren;Joyner,AlexandraL;Lawton,AndrewK
• 通讯作者: Lawton,AndrewK

Cerebellum lineage allocation, morphogenesis and repair: impact of interplay amongst cells.

小脑谱系分配、形态发生和修复：细胞间相互作用的影响。

• DOI: 10.1242/dev.185587
• 发表时间: 2022
• 期刊: Development (Cambridge, England)
• 作者: Joyner,AlexandraL;Bayin,NSumru
• 通讯作者: Bayin,NSumru