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, particulariy microglia and both receptors have been implicated in the regulafion neuroprogenitor stem cell (NPC) proliferafion, differentiafion and neurogenesis. Chronic ethanol also increases brain microglial markers and proinflammatory cytokine expression. Interesfingly, endotoxin (LPS), causes brain microglial activafion, 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 inhibifion of neurogenesis using ethanol fime course and dose response comparisons of changes in neurogenesis and CBIR as well as administrafion of CBIR agonists and antagonists as well as CBIR knockout (KO) transgenic mice (CB1-/-). Confocal microscopy will allow determinafion 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 activafion, 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 inducfion 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 activafion in ethanol regulation of neurogenesis by blocking degradation of endogenous cannabinoid as well as anfi-inflammatory drugs and anfi-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 inhibifion of neurogenesis will be determined. It is expected that NPC downregulafion of CBR1 will be independent of endogenous CB sfimulation and related to changes in proinflammatory gene inducfion 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 potenfial in vivo neurogenic therapies.
|House, Alan J; Daye, Laura R; Tarpley, Michael et al. (2015) Design and characterization of a photo-activatable hedgehog probe that mimics the natural lipidated form. Arch Biochem Biophys 567:66-74|
|Zhang, Chengjin; Frazier, Jared M; Chen, Hao et al. (2014) Molecular and morphological changes in zebrafish following transient ethanol exposure during defined developmental stages. Neurotoxicol Teratol 44:70-80|
|Spruiell, Krisstonia; Richardson, Ricardo M; Cullen, John M et al. (2014) Role of pregnane X receptor in obesity and glucose homeostasis in male mice. J Biol Chem 289:3244-61|
|Spruiell, Krisstonia; Jones, Dominique Z; Cullen, John M et al. (2014) Role of human pregnane X receptor in high fat diet-induced obesity in pre-menopausal female mice. Biochem Pharmacol 89:399-412|
|Zhang, Chengjin; Ojiaku, Princess; Cole, Gregory J (2013) Forebrain and hindbrain development in zebrafish is sensitive to ethanol exposure involving agrin, Fgf, and sonic hedgehog function. Birth Defects Res A Clin Mol Teratol 97:8-27|
|Zhang, Chengjin; Turton, Qwan M; Mackinnon, Shanta et al. (2011) Agrin function associated with ocular development is a target of ethanol exposure in embryonic zebrafish. Birth Defects Res A Clin Mol Teratol 91:129-41|
|Guo, Yizhu; Wang, Xin; Zhang, Xinyan et al. (2011) Ethanol promotes chemically induced oral cancer in mice through activation of the 5-lipoxygenase pathway of arachidonic acid metabolism. Cancer Prev Res (Phila) 4:1863-72|