Tuning cortical E/I balance for translational modeling of psychiatric disorders

目的：认知缺陷是与重度脑梗死相关的长期残疾的主要决定因素。 神经精神疾病，包括精神分裂症（Sz）。这保证了对VA的兴趣增加 研究界，鉴于退伍军人中精神疾病的发生率较高， 治疗占全国VA精神保健费用的40%左右。当前治疗 治疗策略（第一代和第二代抗精神病药）不能令人满意地解决与SZ相关的认知问题。 皮层脑电图模式异常，最明显的是自发γ波活动（GBA）升高 和减少任务诱发的GBA，已经在一些严重的神经精神疾病的临床研究中观察到。 条件，并已被证明是精神病相关的感觉，认知， 和社会功能领域。因此，可以证明有利的是，用 更多地考虑电生理活动的模式，并测试这些活动的调节是否 模式可以改善功能。调节这种活动的一个关键变量是兴奋性 和抑制性（E/I平衡）皮质神经活动。我们实验室最近的研究表明， 基底前脑小白蛋白神经元（BF-PV）的GABA能投射能够双向调节神经元间的相互作用。 调节E/I平衡。这些研究有助于更好地理解E/I受损的作用， 与Sz相关的认知和社会缺陷以及其他精神疾病的出现之间的平衡， 并为靶向恢复E/I平衡作为一种新的治疗方法提供了理论基础。 研究设计：在这项研究中，我们的总体假设假设， 允许通过直接投射到皮层回路和通过投射到大脑皮层，调节皮层E/I平衡。 丘脑网状核（TRN）。目标1将描述一个强大的系统级模型，以更好地定义如何 皮质活动的异常模式影响与精神疾病相关的认知和社会功能领域 疾病目标2旨在提供对BF-PV调制背后机制的更完整理解 E/I平衡。最后，目标3将测试这种机制的操作，作为一种新的治疗手段， 皮质E/I平衡，并改善Sz的两种认知相关模型的认知。 方法学：在这里，我们将利用电生理学，光遗传学和 行为模式首先，为了直接检验受损的E/I平衡与认知之间的关系， 我们将评估小鼠在认知相关的感觉和认知模式上的表现， 无BF-PV介导的皮质E/I改变。使用免疫组织化学和光遗传学 方法，我们将试图更好地表征参与E/I的BF-PV调制的电路通路 平衡最后，我们将利用Sz的药理学和转基因模型，以确定是否抑制Sz的表达。 BF-PV输出能够恢复E/I平衡，并通过扩展改善认知功能。 影响/意义：正常的大脑功能依赖于神经网络保持稳定的能力， 灵活的活动水平。这些实验将提供一个更好的理解方面的协调 对感觉、认知和社会处理很重要的神经活动。此外，它将描述一个 能够调节E/I平衡的皮层下通路，并将该通路作为一种新的治疗剂进行研究 旨在挽救神经精神障碍中的损伤。数百万美国人目前正遭受 导致异常E/I平衡和相关GBA损伤的病症，超过Sz（例如阿尔茨海默氏症 疾病，自闭症，帕金森氏病），使得这种方法可能有利于研究 其他神经精神疾病的治疗。这项工作是新颖的，将提供宝贵的见解 这些疾病的发病机制，也奠定了基础，为发展的治疗 采取有效的预防和治疗措施。

OBJECTIVE: Cognitive deficits are a major determinant of the long-term disability associated with severe neuropsychiatric disorders, including schizophrenia (Sz). This warrants increased interest in the VA research community, given the higher instance of psychiatric illness among the veteran population, treatment of which accounts for some 40% of VA mental healthcare costs nationally. Current therapeutic strategies (first and second-generation antipsychotics) do not satisfactorily address Sz-related cognitive issues. Abnormalities in the patterns of cortical EEG, most notably elevated spontaneous gamma band activity (GBA) and reduced task-evoked GBA, have been observed in a number of clinical studies of severe neuropsychiatric conditions, and have been indicated to underlie both the psychosis linked impairment of sensory, cognitive, and social domains of function. Thus, it may prove advantageous to address these symptom domains with a greater consideration to the patterns of electrophysiological activity and testing whether modulation of these patterns can improve function. One crucial variable regulating such activity is the balance between excitatory and inhibitory (E/I Balance) cortical neural activity. Recent work from our lab suggests that long range GABAergic projections from basal forebrain parvalbumin neurons (BF-PV) are capable of bi-directionally modulating E/I balance. These studies serve to provide a better understanding of the role of impaired E/I balance in the emergence of cognitive and social deficits associated with Sz, and other psychiatric disorders, as well as provide a rationale for targeting restoration of E/I balance as a novel therapeutic approach. RESEARCH DESIGN: In this study, our Overall Hypothesis postulates that modulation of BF-PV output allows tuning of cortical E/I balance, via direct projections to the cortical circuitry and through projections to the thalamic reticular nucleus (TRN). Aim 1 will characterize a powerful systems-level model to better define how abnormal patterns of cortical activity impact cognitive and social domains of function relevant to psychiatric disease. Aim 2 seeks to provide a more complete understanding of the mechanism behind BF-PV modulation of E/I balance. Finally, Aim 3 will test manipulations of this mechanism as a novel therapeutic means to restore cortical E/I balance, and improve cognition in two translationally relevant models of Sz. METHODOLOGY: Here we will utilize an innovative combination of electrophysiological, optogenetic, and behavioral paradigms. First, to directly examine the relationship between impaired E/I balance and cognition, we will assess performance of mice on translationally relevant sensory and cognitive paradigms both with and without BF-PV mediated alteration of cortical E/I. Using, both an immunohistochemical and optogenetic approach, we will attempt to better characterize the circuit pathway involved in BF-PV modulation of E/I balance. Finally, we will utilize both pharmacological and transgenic models of Sz, to determine if inhibition of BF-PV output is capable of restoring, E/I balance, and by extension improve cognitive function. IMPACT/SIGNIFICANCE: Normal brain function relies on the ability of neural networks to maintain stable, yet flexible, levels of activity. These experiments will provide a better understanding of aspects of coordinated neural activity that are important for sensory, cognitive, and social processing. Further, it will characterize a subcortical pathway capable of modulating E/I balance and interrogate this pathway as a novel therapeutic target to rescue impairments in neuropsychiatric disorders. Millions of Americans are currently suffering from conditions that lead to abnormal E/I balance, and associated GBA impairment, beyond Sz (e.g. Alzheimer's disease, Autism, Parkinson's disease), making it likely that this approach will benefit research into the treatment of other neuropsychiatric disease states as well. This work is novel and will provide valuable insight into the pathogenesis of such disorders, and also lay groundwork for the development of therapeutic interventions for effective prevention and treatment.