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） 实验证据支持抑制性和兴奋性活动的不平衡有助于 许多神经系统疾病，包括癫痫、精神分裂症、焦虑、自闭症谱系障碍和 注意力缺陷/多动症在大脑皮层，γ-氨基丁酸（GABA）能皮层 中间神经元是抑制的主要来源，并且已知在维持脑内的活动平衡中是关键的。 成熟的动物然而，GABA能活性的发育扰动导致 皮层回路的形成与持久的结构和功能缺陷，提供基板， 神经系统疾病，尚未详细探讨。这项研究的长期目标是揭示 出生前和出生后大脑发育中的早期中间神经元功能障碍会导致持续的神经功能障碍， 病理学这个建议的目的是揭示外在线索（养育）和遗传程序 （自然）密谋控制interneuron电路组装在围产期发展的关键窗口。 为此，我们将使用小鼠桶皮质作为一个良好建立的模型，用于研究活动依赖性 回路成熟和一个是内在的和强大的联系到动物的外在环境。感官 经验诱导大脑皮层感觉回路的可塑性， 连通性。然而，在这一过程中，多种特定的中间神经元亚型的确切作用是 不完全理解。我们将把我们的研究重点放在皮层中间神经元，因为我们以前的工作表明， 这些神经元对新生儿的环境扰动非常敏感。在短期内， 这一提议旨在揭示由感觉线索激活的中间神经元亚型的身份（Aim 1）。此外，该项目还将评估活动依赖性遗传程序如何调节 早期连通性（目标2）。最后，我们希望研究皮层中间神经元在形成神经元中的作用。 感觉地图（目标3）。 关于结果，我们的工作预计将确定神经元类型，调节的出现， 功能性中间神经元回路鉴于越来越多的实验证据表明 脑功能障碍，了解这些活动依赖性可塑性的机制， 中间神经元可以为治疗策略的发展提供宝贵的见解，