Chronic ethanol treatment has been shown to inhibit adult brain hippocampal and forebrain neurogenesis and to decrease brain CB1 cannabinoid receptor (CB1R) expression. There are two different types of cannabinoid receptors in brain, CB1R and CB2 cannabinoid receptor (CB2R). In brain CB1R 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 CB1R 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 CB1 receptors In ethanol inhibition of neurogenesis.
This aim will characterize the role(s) of CB1R in ethanol inhibition of neurogenesis using ethanol time course and dose response comparisons of changes in neurogenesis and CB1R as well as administration of CB1R agonists and antagonists as well as CB1R 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 downregulation 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.
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