Neural mechanism for the assembly of GABAergic circuits in the cerebral cortex

大脑皮层 GABA 能回路组装的神经机制

• 批准号: 9156640
• 负责人: Natalia Vanesa De Marco Garcia
• 金额: $ 42.38万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9156640
• 关键词: Adult; Affect; Animals; Anxiety; Attention deficit hyperactivity disorder; Brain; Brain Diseases; Calcium; Candidate Disease Gene; Cells; Cerebral cortex; Cues; Data; Defect; Development; Electrophysiology (science); Environment; Epilepsy; Equilibrium; Etiology; Functional disorder; Genes; Genetic Programming; Goals; Interneurons; Laser Scanning Confocal Microscopy; Lead; Link; Mammals; Maps; Mediating; Modeling; Mus; Mutant Strains Mice; NR2B NMDA receptor; Nature; Neonatal; Neurologic; Neurons; Outcome; Perinatal; Process; Property; Rabies; Research; Role; Schizophrenia; Sensory; Signal Transduction; Slice; Source; Staging; Study models; Synapses; Techniques; Testing; Thalamic structure; Vibrissae; Work; autism spectrum disorder; awake; barrel cortex; critical period; experience; gamma-Aminobutyric Acid; in vivo; inhibitory neuron; innovation; insight; mature animal; neonate; nerve supply; nervous system development; nervous system disorder; neurological pathology; neuromechanism; optogenetics; patch clamp; postnatal; pup; receptor expression; research study; sensor; therapeutic development; two-photon

Project Summary (30 lines) Experimental evidence supports the model that an imbalance in inhibitory and excitatory activity contributes to many neurological disorders including epilepsy, schizophrenia, anxiety, autism spectrum disorders and attention deficit/hyperactivity disorder. In the cerebral cortex, gamma-aminobutyric acid (GABA)ergic cortical interneurons are the major source of inhibition and are known to be critical in maintaining activity balance in the mature animal. However, the notion that developmental perturbations in GABAergic activity lead to defects in the formation of cortical circuits with lasting structural and functional deficits that provide the substrate for neurological illness, has not been explored in detail. The long-term goal of this research is to uncover how early interneuron dysfunction in the developing pre and postnatal brain leads to lasting neurological pathologies. The objective of this proposal is to reveal how extrinsic cues (nurture) and genetic programs (nature) conspire to control interneuron circuit assembly during critical windows of perinatal development. To this end, we will use the murine barrel cortex as a well-established model for the study of activity-dependent circuit maturation and one that is inherently and robustly linked to the animal's extrinsic environment. Sensory experience induces plasticity of sensory circuits in the cerebral cortex and is essential for sculpting neuronal connectivity. However, the precise role of a diversity of specific interneuron subtypes in this process is incompletely understood. We will focus our studies in cortical interneurons since our previous work indicates that these neurons are exquisitely sensitive to environmental perturbations in the neonate. In the near term, this proposal is aimed at revealing the identity interneurons subtypes that are activated by sensory cues (Aim 1). In addition, this project will assess how activity-dependent genetic programs regulate the emergence of early connectivity (Aim 2). Finally, we wish to investigate the role of cortical interneurons in the formation of sensory maps (Aim 3). With respect to outcomes, our work is expected to identify neuronal types that regulate the emergence of functional interneuron circuits. Given the accumulating experimental evidence implicating interneuron dysfunction in brain disorders, understanding the mechanisms underlying activity-dependent plasticity for these interneurons can provide invaluable insights for the development of therapeutic strategies

项目摘要（30行） 实验证据支持以下模型，即抑制性和兴奋性活性的失衡有助于 许多神经系统疾病，包括癫痫，精神分裂症，焦虑，自闭症谱系和 注意缺陷/多动障碍。在脑皮质中，γ-氨基丁酸（GABA）ERGIC皮质酸 中间神经元是抑制的主要来源，众所周知对于维持活动平衡至关重要 成熟的动物。但是，GABA能活性的发展扰动导致缺陷的观念 具有持久的结构和功能缺陷的皮质回路的形成，这些缺陷为基材提供了 神经疾病尚未详细探讨。这项研究的长期目标是发现 发育前和产后大脑的早期中间神经元功能障碍导致持久的神经系统 病理。该提案的目的是揭示外部线索（培育）和遗传程序如何 （自然）在围产期发育的关键窗户期间控制中间神经元电路组件。 为此，我们将使用鼠桶皮质作为一个公认的模型，以研究活动依赖性 电路成熟，并且与动物的外在环境固有且牢固地联系在一起。感官 经验诱导大脑皮层中感觉电路的可塑性，对于雕刻神经元至关重要 连接性。但是，在此过程中，特定多种间神经元亚型多样性的精确作用是 不完全理解。由于我们以前的工作表明，我们将重点研究皮质中间神经元 这些神经元对新生儿的环境扰动非常敏感。在短期内 该建议旨在揭示通过感官提示激活的身份中间神经元亚型（AIM 1）。此外，该项目将评估活动依赖性遗传程序如何调节 早期连通性（AIM 2）。最后，我们希望研究皮质中间神经元在形成中的作用 感官地图（AIM 3）。 关于结果，我们的工作有望确定调节出现的神经元类型 功能性的中间电路。鉴于累积的实验证据暗示中间神经元 脑疾病功能障碍，了解这些活动依赖性可塑性的机制 中间神经元可以为制定治疗策略提供宝贵的见解