Function of Neocortical GABAergic Interneurons in Local Circuit Activations

描述（由申请人提供）： GABA能中间神经元与许多疾病状态有关，形成了一个小但关键的皮质神经元群体。对哺乳动物皮层中大量中间神经元进行分类的尝试已经揭示了它们的许多基本性质，但对神经元网络中不同类别的中间神经元的功能知之甚少。虽然已经表明GABA能中间神经元可以影响大的大脑区域的功能，但尚不清楚它们是如何做到这一点的。本文的研究旨在阐明新皮层中间神经元在回路激活过程中的功能。这些激活，在此期间，神经元同步去极化和消防动作电位，显示时空刻板，并已与重要的神经功能。GABA能中间神经元被认为对控制兴奋性细胞的输出很重要，参与回路激活，但其确切作用尚不清楚。该应用使用尖端光学技术，将重点研究中间神经元如何影响局部回路中的神经元活动。具体来说，我将测试的假设，特定的亚类的中间神经元是至关重要的，以确定不同的功能，皮层电路激活。使用其中GABA能中间神经元的亚群用GFP标记的转基因小鼠系，我将使用三种方法降低或增加靶中间神经元的活性：1）全细胞膜片钳，2）双光子激光消融和3）兴奋性或抑制性神经递质的单/双光子解开。 公共卫生相关性：由于抑制性神经元的功能改变被认为是许多神经系统疾病的基础，包括精神分裂症和癫痫，我观察到的回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.