Project 4

虽然许多研究已致力于METH和HIV-1病毒诱导的毒性的表征，但关于急性和慢性METH对CNS功能完整性的神经生理学作用以及HIV-1样感染与METH神经药理学的联合作用知之甚少。阐明负责这些相互作用的细胞机制对于理解导致METH和HIV-1诱导的神经毒性的神经生理学事件的顺序是必不可少的，因此，以合理的方式确定METH在HIV-1病毒感染中的潜在作用。本部分的目的是确定：（a）METH对鼠海马的作用是否是治疗方案和最后一次给药后时间的函数;（B）METH是否产生加速NeuroAIDS功能缺陷进展的累加或协同作用;和（c）选择的CNS促炎细胞因子（IL 6，INF α）或HIV-1外壳蛋白gp 120是否是METH神经毒性和NeuroAIDS发病机理之间协同作用的基本要素。我们将研究海马（CA 1和齿状回）神经元使用细胞外和细胞内技术在体内和体外制剂。我们将确定它们的神经元兴奋性，膜，膜和突触特性和体外制剂。我们将确定它们的神经元兴奋性，膜和突触特性，局部回路相互作用和突触可塑性。此外，我们将在体内研究海马突触可塑性和皮层下结构传入神经元对海马齿状回功能的调节作用。这些数据将有助于确定METH治疗的基本特性，如METH的剂量，METH治疗的历史，癫痫发作活动的治疗阈值，以及海马生理学。这些研究还将确定METH与特定神经元群体和神经递质系统的特定隔离之间的相互作用，这些神经元群体和神经递质系统容易成为NeuroAIDS和METH神经药理学的目标。通过表征METH治疗和HIV-1样感染对海马功能的影响，这些研究将为HIV-1样感染和METH神经药理学的联合作用提供重要信息，并将为未来确定治疗和预防这些疾病的有益方法提供关键数据。

Though much research has been devoted to the characterization of METH- and HIV-1 viral-induced toxicity; very little is known about the neurophysiological effects of acute and chronic METH on the functional integrity of the CNS and the combined effects of HIV-1 like infection with METH neuropharmacology. Elucidating the cellular mechanisms responsible for these interactions is essential for understanding the sequence of neurophysiological events leading to METH and HIV-1- induced neurotoxicity and thus,, determining in a rational manner, the potential role of METH in HIV-1 viral infection. The objectives of our component are to determine: (a) whether the effects of METH on the murine hippocampus are a function of the treatment schedule and the time following the last drug administration; (b) whether METH produces additive or synergistic effects accelerating the progression of the functional deficits of NeuroAIDS; and (c) whether selected CNS pro- inflammatory cytokines (IL6, INFalpha) or the HIV-1 coat protein gp120 are essential elements in the synergy between METH neurotoxicity and NeuroAIDS pathogenesis. We will study hippocampal (CA1 and dentate gyrus) neurons using extracellular and intracellular techniques in both in vivo and in vitro preparations. We will determine their neuronal excitability, membrane, membrane and synaptic properties and in vitro preparations. We will determine their neuronal excitability, membrane and synaptic properties, local circuit interactions and synaptic plasticity. In addition, we will characterize hippocampal synaptic plasticity and the neuronal modulatory effects of afferent inputs from subcortical structures on hippocampal dentate function in vivo. These data will help determine whether basic properties of the METH treatment such as the dose of METH, the history of METH treatment, the treatment threshold for seizure activity, and on hippocampal physiology. The studies will also identify the interactions between METH and of specific isolation of specific neuronal populations and neurotransmitter systems prone to be targets of NeuroAIDS and METH neuropharmacology. By characterizing the effects of METH treatment and HIV-1-like infection on hippocampal function, these studies will contribute important information about the combined effects of HIV-1 like infection and METH neuropharmacology and will provide critical data for the future identification of beneficial approaches for the treatment and prevention of these conditions.