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

Layer 6b，新皮质中的新型抑制增益控制器

基本信息

批准号：
10347506
负责人：
Atsushi Kamiya
金额：
$ 20.47万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10347506
关键词：
16p 16p11.2 Acute Adolescence Adult Anatomy Animal Model Area Autopsy Axon Behavioral Behavioral Symptoms Belief Brain Calcium Cells Cognitive Copy Number Polymorphism Data Disease Electrophysiology (science)Functional disorder Image Impairment Interneurons Investigation Lead Mediating Mental disorders Methodology Methods Mus Neocortex Neurons Pathogenicity Pathologic Patients Pharmacogenetics Physiology Play Regulation Role Schizophrenia Slice Specific qualifier value Study models Synapses Synaptic Transmission Testing Transgenic Mice Viral Work autism spectrum disorder base brain tissue cell type connective tissue growth factor designer receptors exclusively activated by designer drugs excitatory neuron high risk hippocampal pyramidal neuron imaging approach in vivo in vivo calcium imaging inhibitory neuron innovation mRNA Expression mouse model novel optogenetics patch clamp postnatal psychologic psychological symptom sensory input sensory stimulus social transmission process two-photon

项目摘要

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.

项目概要大脑皮层兴奋性和抑制性 (E/I) 失衡已成为普遍现象在精神疾病中观察到。然而，电路机制或细胞类型均不负责对于疾病中的 E/I 失衡有明确规定。我们关注第 6b 层 (L6b) 神经元皮质抑制增益控制器的有力候选者。虽然 L6b 神经元，也称为此前已知，亚板神经元在死后大脑中表现出异常分布精神分裂症 (SZ) 和自闭症谱系障碍 (ASD) 的组织、解剖学和人们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证明这些神经元持续存在于成人大脑中，通过穿过所有六个皮质将轴突投射到第一层层，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，并对外部感觉刺激做出反应。更有趣的是，我们的初步数据发现在 CNV 小鼠模型中，第 6b 层 (L6b) 的神经元数量减少， 16p11.2 重复已知显示 GABA 突触传递缺陷和与 SZ 和 ASD 高度相关。这些数据表明 L6b 神经元可能发挥关键作用通过前馈抑制进行皮质增益控制，这些神经元的失调可能引起心理和行为症状。我们将确定这个创新假设， L6b 神经元作为新皮质中的新型抑制增益控制器，它们负责精神疾病中的皮质失衡。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 神经元的作用及其对病理状况的影响。我们提出的工作将提供一个新的对精神疾病中皮质抑制失调的概念性理解提出 L6b 神经元作为关键的皮质增益控制器。