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.
Drinking in adolescence is common, but the consequences of excessive drinking during adolescence are not well understood. This NADIA research component continues studies on adolescent binge drinking models that cause increases in adult brain neuroimmune gene express, loss of adult cholinergic neuron markers and altered cognition. This proposal will do mechanistic studies using anti-inflammatory and cholinergic signaling strategies to block binge drinking pathology and will add brain connectivity studies to better understand how adolescent alcohol alters adult brain function.
Showing the most recent 10 out of 54 publications
