Layer 6b, a novel inhibitory gain controller in the neocortex

项目摘要 大脑皮层兴奋性和抑制性（E/I）失衡通常是 在精神疾病中观察到。然而，无论是电路机制或细胞类型负责， 对于疾病中E/I失衡有明确的规定。我们专注于层6 b（L 6 b）神经元， 皮质抑制增益控制器的强有力的候选者。虽然L 6 b神经元，也被称为 亚板神经元，以前已知在死后脑中显示异常分布 组织的精神分裂症（SZ）和自闭症谱系障碍（ASD），解剖和 对神经元的生理学知之甚少。我们基于光遗传学的切片 电生理学和体内双光子轴突钙成像表明，这些 神经元在成人大脑中持续存在，通过穿过所有六个皮层， 层，支配抑制性中间神经元，在皮质内形成功能性突触连接 电路，并响应外部感官刺激。更有趣的是，我们的初步数据发现， 在CNV的小鼠模型中，第6 b层（L 6 b）中的神经元数量减少， 16p11.2复制，已知其显示缺乏GABA能突触传递， 与SZ和ASD高度相关。这些数据表明，L 6 b神经元可能发挥关键作用， 在皮层增益控制中，通过前馈抑制和这些神经元的失调， 引起心理和行为症状。我们将确定这个创新的假设， L 6 b神经元作为一种新的抑制性增益控制器在新皮层，他们负责 精神疾病中的皮质失衡我们将结合联合收割机多种方法，包括 基于光遗传学的多个全细胞膜片钳记录，体内钙成像，和 L 6 b神经元的药物遗传学操作以确定L 6 b神经元的作用 及其在病理条件下的意义。我们提出的工作将提供一个新的 精神疾病中皮质抑制失调的概念性理解，作者 提出L 6 b神经元作为关键皮层增益控制器。

Project summary Cortical excitatory and inhibitory (E/I) imbalance in the brain has been commonly observed in psychiatric disorders. However, neither circuit mechanisms or cell types responsible for the E/I imbalance in the disease are clearly specified. We focus on layer 6b (L6b) neurons as a strong candidate for cortical inhibitory gain controller. Although L6b neurons, also called subplate neurons, are previously known to show abnormal distribution in postmortem brain tissues of schizophrenia (SZ) and autism-spectrum disorders (ASD), the anatomy and physiology of the neurons are poorly understood. Our optogenetics-based slice electrophysiology and in vivo two-photon axonal calcium imaging demonstrate that these neurons persist in adult brains, project axons toward up to layer 1 by crossing all six cortical layers, innervate inhibitory interneurons, form functional synaptic connection within cortical circuit, and respond to external sensory stimuli. More interestingly, our preliminary data found that the number of neurons in layer 6b (L6b) was decreased in a mouse model of a CNV, 16p11.2 duplication which is known to show deficient GABAergic synaptic transmission and highly associated with SZ and ASD. These data suggest that L6b neurons may play a key role in cortical gain control via feed-forward inhibition and the dysregulation of these neurons may cause psychological and behavioral symptoms. We will determine this innovative hypothesis, L6b neuron as a novel inhibitory gain controller in the neocortex and they are responsible for cortical imbalance in psychiatric disorders. We will combine multiple approaches including optogenetics-based multiple whole-cell patch clamp recordings, in vivo calcium imaging, and pharmacogenetic manipulation of the L6b neurons to determine the roles of the L6b neurons and their implications in pathological conditions. Our proposed work will provide a new conceptual understanding of dysregulated cortical inhibition in psychiatric disorders, by presenting L6b neuron as a key cortical gain controller.