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

目的：认知缺陷是与严重残疾相关的长期残疾的主要决定因素 神经精神障碍，包括精神分裂症(Sz)。这证明了人们对退伍军人管理局的兴趣增加了 研究界，鉴于退伍军人中精神疾病的发生率较高， 其中的治疗约占全国退伍军人精神卫生保健费用的40%。目前的治疗方法 策略(第一代和第二代抗精神病药物)不能令人满意地解决与Sz相关的认知问题。 皮质脑电模式异常，最显著的是自发伽马频段活动(GBA)升高 和减少的任务诱发的GBA，已经在一些严重的神经精神病学的临床研究中观察到 条件，并已被证明是与精神病相关的感觉，认知， 和功能的社会领域。因此，事实可能证明，使用 更多地考虑电生理活动的模式，并测试是否调制这些 图案可以改善功能。调节这种活动的一个关键变量是兴奋性和兴奋性之间的平衡 和抑制(E/I平衡)皮质神经活动。我们实验室最近的研究表明，远距离 基底前脑小蛋白神经元(BF-PV)的GABA能投射 调制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和其他精神障碍相关的认知和社会缺陷的出现的平衡， 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依据。 研究设计：在这项研究中，我们的总体假设是BF-PV输出的调制 允许调节皮质E/I平衡，通过直接投射到皮质回路和通过投射到 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 皮质活动的异常模式影响与精神病学相关的认知和社会功能领域 疾病。目标2旨在提供对BF-PV调制背后的机制的更完整的理解 E/I平衡。最后，目标3将测试这一机制的操作作为一种新的治疗手段来恢复 皮质E/I平衡，并改善Sz的两个翻译相关模型的认知。 方法：在这里，我们将利用电生理、光遗传学和 行为范式。首先，直接考察E/I平衡受损与认知的关系， 我们将评估小鼠在翻译相关的感觉和认知范式上的表现，包括 在无BF-PV介导的皮质E/I改变的情况下，使用免疫组化和光遗传学 方法，我们将尝试更好地描述BF-PV调制E/I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，来确定是否抑制Sz BF-PV输出能够恢复E/I平衡，进而改善认知功能。 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，但 灵活、活跃度高。这些实验将提供对协调的各个方面的更好理解 神经活动对感觉、认知和社会加工很重要。此外，它还将表征一个 调节E/I平衡的皮质下通路及其作为一种新的治疗途径 目标是挽救神经精神障碍的障碍。数百万美国人目前正遭受着 导致异常E/I平衡和相关的GBA损害的条件，超出Sz(例如阿尔茨海默氏症) 疾病、自闭症、帕金森氏症)，使得这种方法很可能有利于对 治疗其他神经精神疾病的状态也是如此。这项工作是新颖的，将提供有价值的见解 探讨这类疾病的发病机制，也为治疗的发展奠定了基础 有效预防和治疗的干预措施。

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.