HIV-1 Neurotoxicity: Mechanism & Modulation by Cannabinoids

HIV-1神经毒性：机制和大麻素的调节 几乎一半的艾滋病毒感染者患有艾滋病毒相关的神经认知障碍（HAND）， 表现为认知功能的恶化;目前没有治疗方法。我们的长期目标是 通过识别HIV潜在的新的神经生理学变化，为HAND患者的临床护理提供信息， 相关的认知能力下降，从而确定治疗干预的目标。在此前的融资中， 在此期间，我们发现HIV感染细胞释放的HIV蛋白和炎性细胞因子， 突触网络，揭示了药物开发的新靶点。这一新的建议是围绕 描述暴露于HIV期间内源性大麻素（eCB）系统新变化的初步数据 蛋白质达特。暴露于达特损害了eCB介导的兴奋性神经递质释放的抑制， 而不是抑制性突触eCB系统抑制异常的突触活动，因此， 神经保护系统可能加剧与HAND中认知下降相关的突触丧失。的 该提案的目标是确定HIV感染过程中eCB信号变化的驱动机制。 神经毒性，并评估这些变化对网络和认知功能的后果。 在目的1中，我们将确定HIV Tat诱导的eCB系统损伤的机制。我们假设 HIV达特引起神经胶质细胞释放炎性细胞因子，激活神经元信号通路， 大麻素1型受体（CB 1 R）介导突触前抑制受损。药理学和分子 方法将被用来确定炎症细胞因子及其下游的贡献， CB 1 R功能受损的信号通路。这些研究将提供深入了解细胞的行动， HIV神经毒素达特和神经炎症对eCB系统的影响具有广泛的意义。 在目标2中，我们将确定不平衡的eCB信号如何影响网络活动和认知功能， 接触HIV达特。我们假设暴露于HIV达特下调了CB 1 R介导的突触前神经元凋亡。 抑制兴奋性突触，从而增加对兴奋性毒性突触活动的脆弱性。我们的假设 预测在表达达特的转基因小鼠中，eCB信号在来自脑的突触记录中将受损 eCB信号的丢失将增加EEG中检测到的癫痫样活动的频率 录音.将确定这种异常活性对Tat诱导的认知下降的贡献。这些 研究将在HAND模型中将eCB信号传导的变化与网络兴奋性联系起来，并将异常的 由达特诱导的突触活动导致认知能力下降。 这些研究的完成将确定HIV达特诱导的使eCB信号失衡的途径。这些 这些研究将为探索使兴奋性正常化以改善神经功能的药物的临床潜力提供基础。 手的认知功能。最后，在神经炎性反应中发生的eCB信号的变化 条件可以显著改变外源性大麻素对CNS功能的影响。

Summary: HIV-1 Neurotoxicity: Mechanism & Modulation by Cannabinoids Almost half of HIV-infected individuals experience HIV-associated neurocognitive disorder (HAND) which manifests as a deterioration of cognitive function; currently, there is no treatment. Our long-term goal is to inform clinical care of HAND patients by identifying novel neurophysiological changes that underlie HIV- associated cognitive decline, thereby identifying targets for therapeutic intervention. In the previous funding period we found that HIV proteins and inflammatory cytokines, factors released by HIV-infected cells, altered synaptic networks, revealing novel targets for drug development. This new proposal is oriented around preliminary data describing novel changes in the endocannabinoid (eCB) system during exposure to the HIV protein Tat. Exposure to Tat impaired eCB-mediated suppression of neurotransmitter release at excitatory but not inhibitory synapses. The eCB system suppresses aberrant synaptic activity thus, degradation of this neuroprotective system may exacerbate the synapse loss that correlates with cognitive decline in HAND. The goal of this proposal is to determine the mechanisms driving changes in eCB signaling during HIV neurotoxicity and to evaluate the consequences of these changes on network and cognitive function. In Aim 1 we will determine the mechanism of HIV Tat-induced impairment of the eCB system. We hypothesize that HIV Tat evokes release of inflammatory cytokines from glia to activate neuronal signaling pathways that impair cannabinoid type 1 receptor (CB1R)-mediated presynaptic inhibition. Pharmacological and molecular approaches will be used to determine the contribution of inflammatory cytokines and their downstream signaling pathways to impaired CB1R function. These studies will provide insight into the cellular actions of the HIV neurotoxin Tat and have broad implications for the effects of neuroinflammation on the eCB system. In Aim 2 we will determine how unbalanced eCB signaling affects network activity and cognitive function during exposure to HIV Tat. We hypothesize that exposure to HIV Tat downregulates CB1R-mediated presynaptic inhibition at excitatory synapses, thereby increasing vulnerability to excitotoxic synaptic activity. Our hypothesis predicts that in transgenic mice expressing Tat eCB signaling will be impaired in synaptic recordings from brain slices, and the loss of eCB signaling will increase the frequency of epileptiform activity detected in EEG recordings. The contribution of this aberrant activity to Tat-induced cognitive decline will be determined. These studies will relate changes in eCB signaling to network excitability in a model of HAND and link the aberrant synaptic activity induced by Tat to cognitive decline. Completion of these studies will identify a pathway induced by HIV Tat that unbalances eCB signaling. These studies will provide a foundation to explore the clinical potential of drugs that normalize excitability to improve cognitive function in HAND. Finally, the changes in eCB signaling that occur under neuroinflammatory conditions could significantly alter the effects of exogenous cannabinoids on CNS function.