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

项目总结 大脑皮质兴奋性和抑制性(E/I)的失衡是常见的 在精神障碍中观察到的。然而，无论是电路机制还是细胞类型都不起作用 对于E/I失衡的疾病都有明确的规定。我们将重点放在6b层(L6b)神经元上 大脑皮层抑制增益控制器的有力候选者。虽然L6b神经元，也被称为 亚板神经元，先前已知在死后大脑中显示异常分布 精神分裂症(SZ)和自闭症谱系障碍(ASD)的组织、解剖和 对神经元的生理学了解甚少。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，通过横跨所有六个皮质将轴突投射到第一层 支配抑制性中间神经元的各层在皮质内形成功能性突触连接 回路，并对外部感官刺激做出反应。更有趣的是，我们的初步数据发现 在CNV小鼠模型中，6b层(L6b)的神经元数量减少， 16p11.2重复，已知显示GABA能突触传递和 与SZ和ASD高度相关。这些数据表明，L6b神经元可能起着关键作用 通过前馈抑制和这些神经元的失调来控制皮质增益 导致心理和行为症状。我们将确定这一创新假说， L6b神经元作为新皮质中一种新的抑制性增益控制器 精神障碍中的皮质失衡。我们将结合多种方法，包括 基于光遗传学的多个全细胞膜片钳记录，体内钙成像，以及 L6b神经元的药物遗传学操作以确定L6b神经元的作用 以及它们在病理条件下的影响。我们提议的工作将提供一个新的 对精神障碍中失调的皮质抑制的概念性理解 提出L6b神经元作为关键的皮质增益控制器。

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.