Function of Neocortical GABAergic Interneurons in Local Circuit Activations

描述(由申请人提供)： 与许多疾病状态有关的GABA能中间神经元形成了一小部分但至关重要的皮质神经元。对哺乳动物皮质中大量的中间神经元进行分类的尝试揭示了它们的许多基本性质，但对不同类别的中间神经元在神经元网络中的功能知之甚少。虽然已经证明GABA能中间神经元可以影响大脑区的功能，但它们是如何做到这一点的尚不清楚。本文提出的研究旨在阐明新皮质中间神经元在回路激活的背景下的功能。在这些激活过程中，神经元同步去极化和放电动作电位，表现出时空刻板印象，并与重要的神经功能有关。GABA能中间神经元被认为对控制兴奋性细胞的输出很重要，它参与了电路激活，但它们的确切作用尚不清楚。这项使用尖端光学技术的应用将专注于研究中间神经元如何影响局部电路中的神经元活动。具体地说，我将测试这一假设，即特定的中间神经元亚类对于确定皮质回路激活的不同特征至关重要。利用GFP标记GABA能中间神经元亚群的转基因小鼠，I将通过三种方法降低或提高靶中间神经元的活性：1)全细胞膜片钳，2)双光子激光消融，3)单/双光子去极化兴奋性或抑制性神经递质。 公共卫生相关性：由于抑制神经元功能的改变被认为是许多神经疾病的基础，包括精神分裂症和癫痫，我观察到的电路激活的变化可能反映了与这些疾病相关的潜在网络病理。

DESCRIPTION (provided by applicant): GABAergic interneurons, which are implicated in many disease states, form a small but crucial population of cortical neurons. Attempts to classify the vast array of interneurons in mammalian cortex have shed light on many of their basic properties, but very little is known about the function of distinct classes of interneurons in neuronal networks. While it has been shown GABAergic interneurons can affect the function of large brain areas, it is not known how they do so. The studies proposed here are aimed at elucidating the function of neocortical interneurons within the context of circuit activations. These activations, during which neurons are synchronously depolarized and fire action potentials, show spatio-temporal stereotypy and have been associated with important neural functions. GABAergic interneurons, which are thought to be important for controlling the output of excitatory cells, participate during circuit activations, but their exact role is unknown. This application, using cutting edge optical techniques, will focus on investigating how interneurons affect neuronal activity in local circuits. Specifically I will test the hypothesis that specific subclasses of interneurons are crucial for determining distinct features of cortical circuit activations. Using transgenic mouse lines in which subsets of GABAergic interneurons are labeled with GFP, I will decrease or increase the activity of target interneurons using three approaches: 1) whole cell patch clamping, 2) two photon laser ablation and 3) one/two photon uncaging of either excitatory or inhibitory neurotransmitters. PUBLIC HEALTH RELEVANCE: Since altered function of inhibitory neurons is thought to underlie a number of neurological disorders, including schizophrenia and epilepsy, the changes I observe in circuit activations may reflect the underlying network pathologies associated with these conditions.