Circuit mechanisms underlying cortical communications

皮层通信的电路机制

• 批准号: 10929843
• 负责人: Soohyun Lee
• 金额: $ 236.56万
• 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/10929843
• 关键词: Address; Adult; Affect; Anatomy; Area; Behavior; Behavioral; Brain; Cells; Characteristics; Communication; Dendrites; Development; Developmental Process; Diagnosis; Disinhibition; Elements; Feedback; Glutamates; Goals; Heterogeneity; Human; Impairment; Individual; Intellectual functioning disability; Interneurons; Lead; Link; Maps; Mediating; Motor Cortex; Movement; Mutate; Mutation; Neocortex; Neurons; Neuropharmacology; Patients; Pattern; Perception; Play; Population; Proteins; Regulation; Research; Role; SYNGAP1; Schizophrenia; Sensory; Somatosensory Cortex; Somatostatin; Specificity; Synapses; Synaptic Transmission; Thalamic Nuclei; Thalamic structure; Time; Transgenic Mice; Vasoactive Intestinal Peptide; Work; autism spectrum disorder; cell type; excitatory neuron; high risk; hippocampal pyramidal neuron; in vivo calcium imaging; neocortical; neural; neural circuit; neuroregulation; optogenetics; pharmacologic; postsynaptic; presynaptic; programs; recruit; risk variant; scaffold; selective attention; sensory cortex; sensory feedback; tool; transmission process

To understand the principles of long-range connectivity in cortical communication, our efforts have focused on the following three projects during FY23. 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 SynGAP1 (synaptic Ras GTPase-activating protein 1), one of the neurodevelopmental (NDD) high risk genes, is mutated in different types of GABAergic interneurons (INs). SynGAP1 encodes the synaptic Ras GTPase-activating protein 1 (SynGAP1), a crucial protein involved in the formation of postsynaptic densities and in the activity-dependent regulation of excitatory synaptic strength. SynGAP1 mutations in human patients are commonly found in individuals diagnosed with intellectual disability (ID), schizophrenia and autism spectrum disorder. While the importance of SynGAP1 in the excitatory neurons has been extensively studied, the role of SynGAP1 in cortical GABAergic neurons is largely unknown. We asked whether and how the disruptions of SynGAP1, one of NDD risk genes, in different GABAergic IN subtypes lead to the impairment of input-area-dependent corticocortical communication. We found multiple layers of abnormality in cortico-cortical interactions including glutamatergic synaptic transmission, oscillation in a local network, synchrony between relevant cortical areas, and sensory perception. The goal of the second project, development mechanism of cortical disinhibitory circuits is to address the developmental mechanism of synaptic specificity of cortical disinhibitory connections 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. We found that VIP INs preferentially form synaptic connections to SST INs earlier than to other cell types, and that the emergence of this inhibitory-to-inhibitory connection is governed by activity of the presynaptic VIP INs. The spontaneous activity of VIP INs during early development permanently affects the top-down modulation of S1 during adulthood. The third project, the structural and functional organization of cortical subnetworks, is aimed at understanding the principles that govern the functional heterogeneity of principal neurons in sensory cortex. Neuronal connections within and across brain areas provide the scaffolding for neuronal function. While the connectivity of cortical neurons has been mapped at a macroscale level, linking connectivity rules with activity patterns at the level of single neurons remains challenging. We investigated anatomical wiring rules for the functional heterogeneity of cortical neurons using in vivo two-photon calcium imaging, neuropharmacology, single-cell based monosynaptic input tracing, and optogenetic tools. We characterized the neural representations of behavioral state in S1 during spontaneous movements in both single neurons and across neuronal populations. Representations were independent of sensory feedback, stable over time, and robust to pharmacologic inhibition of neuromodulatory, but not glutamatergic transmission. Analysis of brain-wide presynaptic networks of single neurons with distinct activity profiles during spontaneous movements revealed characteristic patterns of anatomical input. Despite the high degree of convergence from brain-wide inputs at the single-cell level, neurons more sensitive to behavioral state received a smaller proportion of inputs from motor cortical areas and a larger proportion of inputs from thalamic nuclei. Optogenetic inhibition of thalamic inputs suppressed behavioral state-related activity. Our study suggest that behavior state-encoding cortical neurons receive a characteristic brain-wide inputs, and that preconfigured networks constrain neuronal function.

为了了解皮层通信中的远程连接原理，我们在2023财年的工作重点是以下三个项目。 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。基于这一框架，我们调查如何皮质反馈投射到S1的改变在转基因小鼠系中，SynGAP 1（突触Ras GTP酶激活蛋白1），神经发育（NDD）的高风险基因之一，是在不同类型的GABA能中间神经元（IN）突变。SynGAP 1编码突触Ras GTP酶激活蛋白1（SynGAP 1），其是参与突触后密度形成和兴奋性突触强度的活性依赖性调节的关键蛋白。人类患者中的SynGAP1突变通常发现于被诊断患有智力残疾（ID）、精神分裂症和自闭症谱系障碍的个体中。虽然SynGAP 1在兴奋性神经元中的重要性已被广泛研究，但SynGAP 1在皮质GABA能神经元中的作用在很大程度上是未知的。我们想知道在不同的GABA能IN亚型中，NDD风险基因之一SynGAP 1的破坏是否以及如何导致输入区依赖性皮质皮质通讯的损害。我们发现皮质-皮质相互作用的多层异常，包括神经元突触传递、局部网络振荡、相关皮质区域之间的同步和感觉知觉。 第二个项目，皮层去抑制回路的发育机制的目标是解决在早期发育过程中皮层去抑制连接的突触特异性的发育机制。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。我们发现，VIP INs优先形成突触连接到SST INs早于其他类型的细胞，并且这种突触-抑制连接的出现是由突触前VIP INs的活动所控制的。VIP INs在早期发育过程中的自发活动永久地影响了成年期S1的自上而下的调制。 第三个项目，皮层子网络的结构和功能组织，旨在了解控制感觉皮层中主要神经元功能异质性的原则。大脑区域内和跨大脑区域的神经元连接为神经元功能提供了支架。虽然皮层神经元的连接已经在宏观层面上映射，但在单个神经元的水平上将连接规则与活动模式联系起来仍然具有挑战性。我们使用体内双光子钙成像、神经药理学、基于单细胞的单突触输入追踪和光遗传学工具研究了皮质神经元功能异质性的解剖布线规则。我们的特点是在S1的行为状态的神经表征在自发运动在单个神经元和跨神经元群体。代表是独立的感觉反馈，稳定的，随着时间的推移，和强大的药理学抑制的神经调节，但不amatergic传输。在自发运动过程中具有不同活动特征的单个神经元的全脑突触前网络的分析揭示了解剖输入的特征模式。尽管在单细胞水平上，全脑输入的聚合程度很高，但对行为状态更敏感的神经元从运动皮层区域接收的输入比例较小，而从丘脑核团接收的输入比例较大。丘脑输入的光遗传抑制抑制行为状态相关的活动。我们的研究表明，行为状态编码皮层神经元接收一个特征性的全脑输入，预先配置的网络约束神经元的功能。

项目成果

Posteromedial thalamic nucleus activity significantly contributes to perceptual discrimination.

• DOI: 10.1371/journal.pbio.3001896
• 发表时间: 2022-11
• 期刊: PLoS biology
• 影响因子: 9.8

Dissection of brain-wide resting-state and functional somatosensory circuits by fMRI with optogenetic silencing.

• DOI: 10.1073/pnas.2113313119
• 发表时间: 2022-01-25
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Jung WB;Jiang H;Lee S;Kim SG
• 通讯作者: Kim SG