RC3 Ethanol-Cannabinoid Interaction in the Regulation of Neurogenesis

RC3 乙醇-大麻素相互作用在神经发生调节中的作用

• 批准号: 8508761
• 负责人: Somnath Mukhopadhyay
• 金额: $ 14.42万
• 依托单位: NORTH CAROLINA CENTRAL UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8508761
• 关键词: Adult; Agonist; Alcohol consumption; Alcohol dependence; Alcoholism; Alcohols; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Brain; Bromodeoxyuridine; CNR2 gene; Cannabinoids; Cell Death; Cell Proliferation; Chronic; Cognitive deficits; Confocal Microscopy; Dose; Down-Regulation; Drug usage; Endocannabinoids; Endotoxins; Ethanol; Gene Expression; Genes; Hippocampus (Brain); Immune; Immunohistochemistry; Inflammatory; Knock-out; Lead; Mediating; Mental Depression; Microglia; Mus; Nerve Degeneration; Neurobiology; Neuroglia; Neurons; Pathology; Pharmaceutical Preparations; Prosencephalon; Proteins; Reaction Time; Regulation; Role; Saline; Signal Pathway; Signal Transduction; Stem cells; Testing; Time; Transgenic Animals; Transgenic Mice; alcohol abuse therapy; alcohol effect; alcohol response; cannabinoid receptor; cytokine; gene induction; in vivo; inhibitor/antagonist; insight; neurogenesis; neuroinflammation; progenitor; receptor; receptor expression; response

Chronic ethanol treatment has been shown to inhibit adult brain hippocampal and forebrain neurogenesis and to decrease brain CBI cannabinoid receptor (CBIR) expression. There are two different types of cannabinoid receptors in brain, CBIR and CB2 cannabinoid receptor (CB2R). In brain CBIR are primarily neuronal, whereas CB2 cannabinoid receptor (CB2R) are primarily present on glia, particularly microglia and both receptors have been implicated in the regulation neuroprogenitor stem cell (NPC) proliferation, differentiation and neurogenesis. Chronic ethanol also increases brain microglial markers and proinflammatory cytokine expression. Interestingly, endotoxin (LPS), causes brain microglial activation, increased CB2R, increased proinflammatory cytokine expression and loss of neurogenesis. These studies and others support the overall hypothesis that CBIR and CB2R contribute to ethanol-mediated inhibition of neurogenesis. To test this hypothesis we have developed the following 3 specific aims: Aim 1. To define the role of CBI receptors in ethanol inhibition of neurogenesis. This aim will characterize the role(s) of CBI R in ethanol inhibition of neurogenesis using ethanol time course and dose response comparisons of changes in neurogenesis and CBIR as well as administration of CBIR agonists and antagonists as well as CBIR knockout (KO) transgenic mice (CB1-/-). Confocal microscopy will allow determination of NPC neurogenesis and receptor expression on NPC. Aim 2. To determine the role of CB2R in ethanol and endotoxin (LPS) inhibition of neurogenesis. This aim will test the hypothesis that ethanol induced microglial activation, expression of CB2 receptors and proinflammatory cytokines reduce neurogenesis. Preliminary studies and others indicate that LPS induction of proinflammatory cytokines increases CB2R and inhibits neurogenesis. Ethanol potentiates LPS induction of proinflammatory cytokines, but the effect on CB2R and neurogenesis are not known. Time course and dose response comparisons of changes in neurogenesis, microglia, and CB2R expression will be determined in neurogeneic regions. Ethanol alone, LPS alone and combined ethanol-LPS provide progressively increased proinflammatory responses for comparisons with neurogenesis. CB2R agonists and antagonists as well as CB2R-K0 transgenic mice (CB2-/-') will be employed to characterize the role(s) of the CB2R receptors in ethanol ¿ LPS inhibition of neurogenesis. Aim. 3. To define the role of endogenous cannabinoids on ethanol inhibition of neurogenesis. This aim will determine the role of endogenous cannabinoids activation in ethanol regulation of neurogenesis by blocking degradation of endogenous cannabinoid as well as anti-inflammatory drugs and anti-oxidants known to block endotoxin and/or ethanol effects. Studies suggest ethanol increases endogenous CB that act on and down regulate CBR1, yet CBR1 activation increases neurogenesis. How ethanol, endogenous CB and CBR1 impact ethanol inhibition of neurogenesis will be determined. It is expected that NPC down regulation of CBR1 will be independent of endogenous CB stimulation and related to changes in proinflammatory gene induction and loss of neurogenesis. Together these studies will provide a detailed insight into the signaling pathway that regulates the effects of ethanol and cannabinoids on neurogenesis as well as discovering potential in vivo neurogenic therapies.

慢性乙醇治疗已被证明可以抑制成人大脑海马和前脑神经发生，并降低脑CBI大麻素受体（CBIR）的表达。大脑中有两种不同类型的大麻素受体，CBIR和CB2大麻素受体（CB2R）。在大脑中，CBIR主要是神经元，而CB2大麻素受体（CB2R）主要存在于胶质细胞，特别是小胶质细胞上，这两种受体都参与调节神经祖干细胞（NPC）的增殖、分化和神经发生。慢性乙醇也会增加脑小胶质细胞标志物和促炎细胞因子的表达。有趣的是，内毒素（LPS）引起脑小胶质细胞激活，CB2R增加，促炎细胞因子表达增加和神经发生丧失。这些研究和其他研究支持了CBIR和CB2R参与乙醇介导的神经发生抑制的总体假设。为了验证这一假设，我们制定了以下3个具体目标：