Brain Metabolism and Alcohol Use Disorder

About This Grant

BRAIN METABOLISM AND ALCOHOL USE DISORDER ABSTRACT Glucose through glycolysis and the Tricarboxylic Acid (TCA) cycle in the mitochondria supplies energy to the brain. Glycolysis disfunction has been associated with neurodegeneration, stress and depression. Moreover, Volkow and colleagues reported that glucose metabolism is reduced in the brain of human subjects suffering from alcohol use disorder (AUD). Using animal models of AUD, we found that the kinase mTORC1 plays a crucial role in mechanisms underlying excessive alcohol seeking and drinking, relapse, and alcohol habit and reward. mTORC1 is activated by alcohol in the nucleus accumbens (NAc), and specifically in dopamine D1 receptor expressing (D1+) NAc neurons. We recently found that the activation of mTORC1 in the NAc of mice in response to long-term of intermittent access to 20% alcohol 2-bottle choice (IA20%2BC) promotes the translation of microRNA (miR) machinery transcripts in D1+ NAc neurons which in turn promotes the expression of a number of miRs including the miR, miR34a-5p. We further showed that alcohol-mediated activation of mTORC1 in D1+ NAc neurons represses the translation of several transcripts including Aldolase A a crucial enzyme in glycolysis which we found to be a target of miR34a-5p. We discovered that Aldolase A translation repression in D1+ NAc neurons is accompanied by the attenuation of NAc Lactate, the end product of glycolysis. We also found that metabolites in the mitochondria TCA cycle are attenuated in the NAc by IA20%2BC. Finally, we showed that overexpression of miR34a-5p increases whereas systemic administration of L-Lactate reduces heavy alcohol intake. Together, these data suggest that the pathway consisting of: mTORC1­/miR34a5p­/Aldolase A¯, is activated by alcohol in the NAc D1+ neurons, which inhibits glycolysis and promotes heavy alcohol use. Here, we plan to test the overall hypothesis that alcohol alters glycolysis, energy production and the metabolic signature in the Nac, which in turn contribute to behavioral phenotypes associated with AUD. We will utilize state of the art tools in combination with behavioral paradigms in female and male mice to address the following aims: Aim 1 will focus on glycolysis and examine cell-type specificity, cellular compartmentalization and molecular, and behavioral consequences of alcohol-mediated attenuation of glycolysis. Aim 2 will focus on alcohol interaction with the mitochondria in the Nac and will examine ATP levels and mitochondria morphology in mice with a history of alcohol use. In Aim 3, we will conduct a large scale comprehensive transcriptomic/metabolomic (multiomic) study to uncover the metabolic map which includes metabolites and metabolic enzymes in the Nac of mice consuming alcohol. This is a groundbreaking discovery proposal that will uncover alcohol-dependent metabolic adaptations in the brain. Results generated from the project will lay the foundation for a new dimension in alcohol research in the CNS.