Circuit mechanisms underlying cortical communications

皮层通讯的电路机制

• 批准号: 10703952
• 负责人: Soohyun Lee
• 金额: $ 133.21万
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10703952
• 关键词: Address; Anatomy; Animal Behavior; Animals; Area; Behavior; Behavioral; Brain; Calcium; Cells; Characteristics; Communication; Dendrites; Development; Developmental Process; Disinhibition; Elements; Esthesia; Feedback; Goals; Heterogeneity; Image; Interneurons; Mediating; Motor; Movement; Mutate; Neocortex; Neurons; Perception; Play; Process; Research; Rodent; Role; Sensory; Somatosensory Cortex; Somatostatin; Specificity; Synapses; System; Thalamic Nuclei; Transgenic Mice; Vasoactive Intestinal Peptide; Vibrissae; Work; base; high risk; hippocampal pyramidal neuron; neural circuit; optogenetics; presynaptic; programs; rabies viral tracing; recruit; risk variant; selective attention; sensory cortex; somatosensory

To understand the principles of long-range connectivity in cortical communication, our efforts have focused on the following four projects during FY22. Functional connectivity of diverse long-range inputs to sensory cortex is aimed at achieving a mechanistic understanding of the functional connectivity of feedback / top-down projections to the primary sensory cortex. We have systematically examined the synaptic strength from different brain areas to diverse neuronal types in the primary somatosensory cortex (S1) and determined how the primary sensory cortex uses input-area-dependent, preferential recruitment of specific types of GABAergic interneurons to parse information from diverse feedback projections. Based on this framework, we investigate how cortical feedback projections to S1 are altered in a transgenic mouse line in which one of the neurodevelopmental (NDD) high risk genes is mutated in different types of GABAergic interneurons (INs). The goal of the second project, cortical development of inhibitory-to-inhibitory connections, is to address the developmental process of cortical inhibitory-to-inhibitory synaptic specificity during early development. Disinhibition mediated by vasoactive intestinal polypeptide (VIP)-positive GABAergic interneurons (INs) is a robust circuit motif found in all cortical areas. VIP INs inhibit other types of cortical GABAergic INs, but its inhibition of dendrite-targeting somatostatin (SST)-positive INs is particularly strong, leading to the disinhibition of pyramidal neurons. This cortical disinhibitory circuit motif has been shown to play an important role in sensorimotor integration, selective attention, gain control, and circuit plasticity. However, the mechanisms by which this robust circuit motif emerges throughout the cortex during early development is largely unknown. Ongoing work investigates which factors are critical for the stability and plasticity of strong inhibitory connections from VIP INs to SST INs during early development. The third project, the structural organization of cortical subnetworks, is aimed at understanding the principles that govern the functional heterogeneity of principal neurons in sensory cortex. Neuronal activity in the superficial layer of the primary sensory cortex is highly heterogenous in relation to various aspects of the animal's behavior. We asked whether functionally heterogeneous subnetworks are constrained by specific long-range and local presynaptic ensembles. This study provides the circuit-based mechanism for the organization of cortical subnetworks. Using single cell-initiated, monosynaptic rabies virus tracing combined with calcium imaging, we found that behavior state-encoding (spontaneous movement) neurons show characteristic long-range and local presynaptic networks. Our results reveal connectivity rules that support functional heterogeneity of cortical principal cells. In the fourth project, we investigate the role of higher-order thalamic nucleus in sensory perception. Somatosensation is an active process. Despite that action and sensation are tightly integrated contingent on the animals goal during active sensation, the neuronal substrates and circuits that mediate such interaction remain poorly understood. Anatomical studies suggest that whisker-dependent sensorimotor integration takes place in multiple closed loops in the brain. The posteromedial (POm) thalamic nucleus, the higher-order thalamic nucleus in the rodent somatosensory system, is an anatomical hub broadly connected with multiple sensory and motor brain areas, yet it weakly responds to passive sensory stimulation and whisker movements. To understand the role of POm in sensory perception, we developed a self-initiated, two-alternative forced-choice task in freely moving animals during active sensing. Using optogenetic and chemogenetic manipulation, we show that POm thalamic nucleus plays a significant role in sensory perception and the projection from the primary somatosensory cortex to POm is critical for the contribution of POm in sensory perception during active sensing. Ongoing work investigates dynamic neuronal activity of POm cells during active sensing.

为了了解皮层通信中的远程连接原理，我们在2022财年的工作重点是以下四个项目。 各种远程输入到感觉皮层的功能连接旨在实现对反馈/自上而下投射到初级感觉皮层的功能连接的机械理解。我们系统地研究了初级躯体感觉皮层（S1）中不同脑区与不同神经元类型的突触强度，并确定了初级感觉皮层如何使用输入区依赖性，优先招募特定类型的GABA能中间神经元来解析来自不同反馈投射的信息。基于这个框架，我们研究如何在转基因小鼠系中改变皮层反馈投射到S1，其中一个神经发育（NDD）高风险基因在不同类型的GABA能中间神经元（IN）中发生突变。 第二个项目的目标，皮层发育的神经元-抑制性连接，是要解决的发展过程中，皮层神经元-抑制性突触的特异性在早期发展。由血管活性肠多肽（VIP）阳性GABA能中间神经元（INs）介导的去抑制是在所有皮层区域发现的一个强大的回路基序。VIP INs抑制其他类型的皮质GABA能INs，但其对树突靶向生长抑素（SST）阳性INs的抑制特别强，导致锥体神经元的去抑制。这种皮层去抑制回路基序在感觉运动整合、选择性注意、增益控制和回路可塑性中发挥重要作用。然而，这种强大的电路基序在早期发育过程中出现在整个皮层的机制在很大程度上是未知的。正在进行的工作调查哪些因素是至关重要的稳定性和可塑性的强抑制性连接，从VIP IN的SST IN在早期发展。 第三个项目，皮层子网络的结构组织，旨在了解控制感觉皮层主要神经元功能异质性的原则。初级感觉皮层浅层的神经元活动与动物行为的各个方面有关，具有高度的异质性。我们问是否功能异质的子网络的限制特定的长程和局部突触前合奏。本研究为皮层子网络的组织提供了基于回路的机制。使用单细胞启动的，单突触狂犬病病毒示踪结合钙成像，我们发现，行为状态编码（自发运动）神经元显示出特征性的长程和局部突触前网络。我们的研究结果揭示了支持皮层主细胞功能异质性的连接规则。 在第四个项目中，我们研究了丘脑高级核在感觉知觉中的作用。躯体感觉是一个活跃的过程。尽管在主动感觉期间，动作和感觉紧密地结合在一起，取决于动物的目标，但介导这种相互作用的神经元基底和回路仍然知之甚少。解剖学研究表明，胡须依赖的感觉运动整合发生在大脑的多个闭合回路中。丘脑后内侧核（POm）是啮齿动物躯体感觉系统中的高级丘脑核，是与多个感觉和运动脑区广泛连接的解剖学枢纽，但它对被动感觉刺激和胡须运动的反应较弱。为了了解POm在感官知觉中的作用，我们开发了一个自我启动的，两个选择的强迫选择任务，在自由移动的动物在主动感知。利用光遗传学和化学遗传学操作，我们表明，POm丘脑核在感觉知觉中起着重要的作用，从初级躯体感觉皮层到POm的投射是POm在主动感知过程中对感觉知觉的贡献的关键。正在进行的工作研究动态的POM细胞在主动感知的神经元活动。