Circuit mechanisms underlying cortical communications

为了了解大脑皮层通信中远程连接的原理，我们在22财年期间重点开展了以下四个项目。 不同的远程输入到感觉皮质的功能连接旨在实现对反馈/自上而下的投射到初级感觉皮质的功能连接的机械性理解。我们系统地研究了初级体感皮质(S1)不同脑区到不同神经元类型的突触强度，并确定了初级感觉皮质如何利用输入区域依赖的、优先招募的特定类型的GABA能中间神经元来解析来自不同反馈投影的信息。基于这一框架，我们研究了在不同类型的GABA能中间神经元(INS)中神经发育(NDD)高危基因之一发生突变的转基因小鼠中，皮层对S1的反馈投射是如何改变的。 第二个项目的目标是研究大脑皮质抑制-抑制联系的发育过程，研究早期大脑皮质抑制-抑制突触特异性的发育过程。由血管活性肠肽(VIP)阳性的GABA能中间神经元(INS)介导的去抑制是在所有皮质区域都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的抑制尤其强烈，导致锥体神经元的去抑制。这一皮层去抑制回路基序已被证明在感觉运动整合、选择性注意、增益控制和回路可塑性中发挥重要作用。然而，在早期发育过程中，这个强大的回路模体出现在整个皮质中的机制在很大程度上是未知的。正在进行的工作是研究哪些因素对VIP INS到SST INS的早期发育过程中强抑制性连接的稳定性和可塑性至关重要。 第三个项目，大脑皮层网络的结构组织，旨在了解支配感觉皮层主神经元功能异质性的原理。初级感觉皮质表层的神经元活动与动物行为的各个方面具有高度的异质性。我们询问了功能上的异构子网络是否受到特定的远程和局部突触前集合的限制。这项研究为大脑皮层网络的组织提供了基于电路的机制。利用单细胞启动、单突触狂犬病病毒示踪结合钙离子成像，我们发现行为状态编码(自发运动)神经元显示出特有的远距离和局部突触前网络。我们的结果揭示了支持大脑皮层主细胞功能异质性的连通性规则。 在第四个项目中，我们研究了高阶丘脑核团在感觉知觉中的作用。体感是一个活跃的过程。尽管动作和感觉是紧密结合的，取决于动物在主动感觉过程中的目标，但调节这种相互作用的神经元底物和电路仍然知之甚少。解剖学研究表明，胡须依赖的感觉运动整合发生在大脑中的多个闭合环路中。丘脑后内侧核是啮齿动物躯体感觉系统中的高级丘脑核团，是广泛连接多个感觉和运动脑区的解剖中枢，但它对被动感觉刺激和胡须运动的反应较弱。为了了解POM在感觉知觉中的作用，我们在主动感觉过程中，在自由活动的动物中开发了一种自我启动的、两种选择的强迫选择任务。利用光遗传学和化学遗传学方法，我们发现POM丘脑核团在感觉知觉中起着重要作用，而初级躯体感觉皮层到POM的投射对于POM在主动感觉过程中在感觉知觉中的贡献是至关重要的。正在进行的工作是研究POM细胞在主动感觉过程中的动态神经元活动。

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.