HIV gp120 and Prefrontal Cortical Function

描述(申请人提供)：这个多研究者项目的目标是开发一种HIV神经病理学的动物模型，该模型可用于评估：1)认知功能，2)前额叶皮质神经元和非神经元变性，3)前额叶皮质网络细胞和回路的电生理特性。随着改进的联合抗逆转录病毒疗法的出现，艾滋病毒感染已从一种致命疾病转变为一种慢性可控疾病。这一趋势导致了越来越大的 长期接触艾滋病毒神经毒素和艾滋病毒治疗干预措施的老年个人群体。虽然有优秀的组织培养模型来研究艾滋病毒或艾滋病毒治疗对细胞过程的影响，但体内研究艾滋病毒感染或慢性抗逆转录病毒治疗的影响的选择更为有限，特别是当它们与大脑老化有关时。研究这些问题的理想模型将提供机会，检查认知能力与神经功能和神经病理的电生理指标在整个衰老过程中关于艾滋病毒感染的开始和随后疾病过程的进展，并将其联系起来。这项建议中概述的工作将集中在成年和老年大鼠中枢神经系统暴露于HIV包膜蛋白gp120及其对1)两种前额叶皮质依赖行为任务的表现的影响，2)前额叶皮质回路中神经元的兴奋性和突触传递，3)神经毒性损伤对前额叶皮质神经元和非神经元细胞的影响。这项研究最重要的方面是开发一种动物模型，该模型将对许多其他体内研究具有优势，这些研究重点是与艾滋病毒感染及其治疗相关的一系列潜在因素和机制，这些事件的时间进程，以及它们对老化大脑的影响。特别是，这一模式将有助于为成人和老年艾滋病毒/艾滋病患者的治疗干预确定和开发新的目标和新化合物。在所有的调查中，该模型将验证体外组织培养研究的结果，以及它们与完整中枢神经系统正常功能的相关性。 公共卫生相关性：这个多研究者项目的目标是开发一种HIV神经病理学模型，该模型可用于评估：1)行为动物的执行功能，2)前额叶皮质(PFC)的神经元和非神经元变性，以及3)PFC网络中细胞和电路的电生理特性。研究将在成年和老年大鼠身上进行。具体实验将集中在CNS对HIV包膜蛋白gp120的暴露，并表征其对以下方面的影响：1)两个PFC依赖的行为任务的执行；2)PFC回路中的神经元兴奋性和突触传递；3)PFC中神经元和非神经元细胞的神经毒性损伤程度。建议的模型将对许多其他体内研究具有优势，这些研究的重点是与艾滋病毒感染及其治疗相关的一系列潜在因素和机制，这些事件的时间进程，以及它们对老化大脑的影响。

DESCRIPTION (provided by applicant): The goal of this multi-investigator project is to develop an animal model of HIV neuropathology that can be used to assess: 1) cognitive function, 2) neuronal and non-neuronal degeneration in the prefrontal cortex and 3) electrophysiological properties of cells and circuits in prefrontal cortical networks. With the advent of improved combination antiretroviral therapy, HIV infection has been transformed from a fatal illness to a chronic manageable condition. This trend has resulted in an increasingly large population of aging individuals with prolonged exposure to HIV neurotoxins and to HIV therapeutic interventions. While there are excellent tissue culture models for studying the impact of HIV or HIV therapy on cellular processes, the options for in vivo investigation of the effects o HIV infection or chronic antiretroviral therapy are more limited, particularly as they relate to th aging brain. The ideal model for investigating such issues would provide the opportunity to examine and correlate cognitive performance with electrophysiological indices of neural function and neuropathology across the aging continuum with respect to onset of the HIV infection and progression of ensuing disease processes. The work outlined in this proposal will focus on CNS exposure to the HIV envelope protein gp120 in adult and aged rats and its impact on 1) performance of two prefrontal cortex-dependent behavioral tasks, 2) neuronal excitability and synaptic transmission in the prefrontal cortical circuitry and 3) the degree of neurotoxic insult t neuronal and non-neuronal cells in the prefrontal cortex. The most important aspect of this investigation is the development of an animal model that will have advantages for numerous additional in vivo studies focusing on the broad array of potential agents and mechanisms associated with HIV infection and its treatment, the time course of these events, and their impact on the aging brain. In particular this model will facilitate the identification and development of new targets and new compounds for therapeutic interventions in adult and aging HIV/AIDS patients. Across all inquiries, the model will validate the findings of in vitro tissue culture studies and their relevance to normative functions in the intact central nervous system. PUBLIC HEALTH RELEVANCE: The goal of this multi-investigator project is to develop a model of HIV neuropathology that can be used to assess: 1) executive function in behaving animals, 2) neuronal and non-neuronal degeneration in the prefrontal cortex (PFC) and 3) electrophysiological properties of cells and circuits in PFC networks. Studies will be conducted in adult and aging rats. Specific experiments will focus on CNS exposure to the HIV envelope protein gp120 and characterize its impact on: 1) performance of two PFC-dependent behavioral tasks, 2) neuronal excitability and synaptic transmission in the PFC circuitry and 3) the degree of neurotoxic insult to neuronal and non-neuronal cells in the PFC. The proposed model will have advantages for numerous additional in vivo studies focusing on the broad array of potential agents and mechanisms associated with HIV infection and its treatment, the time course of these events, and their impact on the aging brain.