5/8 NADIA U01 Adolescent Alcohol and Adult Brian Dysfunction

Research project

Description

Alcohol abuse is common in adolescence, a time of marked neurocircuitry development. Recently, we discovered that NADIA adolescent intermittent ethanol (AIE) treatment of rats increased frontal cortical neuroimmune molecules, blunted frontal cortical cFos responses to ethanol, reduced hippocampal neurogenesis, reduced choline acetyltransferase (ChAT, the enzyme synthesizing acetylcholine), and caused deficits in reversal learning in adulthood. Reduced hippocampal neurogenesis and ChAT are unique to AIE and did not occur after similar ethanol treatment in adulthood. In an important parallel with human studies, we found increased expression of neuroimmune genes and reduced expression of ChAT and other cholinergic neuron markers in the post-mortem brains of alcoholic patients. This is consistent with adolescent alcohol exposure contributing to adult alcoholic neuropathology. This proposal will test multiple hypotheses: 1) that inhibiting AIE-induced neuroimmune signaling will protect against loss of adult neurogenesis and ChAT+ neurons, and reduce reversal learning deficits. 2) That reduced cholinergic signaling contributes to AIE-induced adult neuroimmune gene induction, reduced neurogenesis, reduced adult prefrontal cortical neuronal responses to ethanol, and reversal learning deficits. As well as investigating adolescent rat brain connectivity using resting-state functional Magnetic Resonance Imaging (rsfMRI) for direct comparisons to human studies testing hypothesis 3, i.e. that adolescent alcohol exposure alters neural connectivity in the adult brain through persistent increases in neuroimmune signaling and deficits in ChAT. It is expected that AIE will alter adult functional connectivity through pro-inflammatory gene induction and decreased cholinergic signaling. These studies will link key signaling mechanisms to AIE-induced adult neuropathology and lead to therapies.
StatusActive
Effective start/end date9/1/108/31/20

Funding

  • NIH National Institute on Alcohol Abuse and Alcoholism (NIAAA)

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Ethanol
Alcohols
Neurogenesis
Reversal Learning
Brain
Therapeutics
Alcoholics
Cholinergic Agents
Genes
Cholinergic Neurons
Choline O-Acetyltransferase
Alcoholism
Acetylcholine
Magnetic Resonance Imaging
Gene Expression
Neurons
Enzymes