Frontolimbic circuitry, behavioral flexibility, and adolescent alcohol history

Project Summary/Abstract
High risk, binge-level drinking accounts for most alcohol-related harm. Binge drinking often begins in
adolescence when the brain is particularly vulnerable to alcohol insult, resulting in persistently atypical
neurocognitive function. For example, we found that a history of adolescent binge drinking in adult people and
adolescent intermittent ethanol (AIE) exposure in adult rats associates with less behavioral flexibility, which
describes an individual’s ability to adjust their behavior to changing environmental circumstances. These
behavioral effects are associated with altered resting-state functional connectivity among prefrontal and
subcortical control circuits. Mechanistic links between adolescent alcohol exposure and reduced behavioral
flexibility remain unclear, but several lines of evidence suggest a shift in the balance between excitation and
inhibition [excitatory/inhibitory (E/I) balance], towards hyperexcitability in the prefrontal cortex (PFC) together
with a weakening of top-down output from the PFC. Indeed, this proposal stems from our preliminary data in
humans and rats that AIE and/or current binge drinking alters metrics of E/I balance measured via magnetic
resonance spectroscopy (MRS) and EEG in humans and neurochemical and electrophysiological measures in
rats. Thus, we will test the hypothesis that adolescent binge alcohol promotes a shift in the balance between
excitatory and inhibitory (E/I) signaling within control circuits that has the net effect of reducing PFC output,
which in turn mediates more habitual action selection and greater vulnerability to alcohol insult in adulthood.
We further hypothesize that these AIE-induced E/I balance shifts are associated with altered functional
connectivity (humans) and neurochemistry (rats) of control hubs, including the dorsolateral PFC (or analogous
rodent prelimbic cortex) and anterior insula. To test this hypothesis, we will study rat and human subjects with
or without a history of adolescent and/or current binge drinking (or binge exposure in rats) and assess
behavioral flexibility in tasks that require adaptation to changes in response contingency. In human subjects,
we will use MRS and EEG techniques to assess indices of E/I balance, and MRI to measure functional
connectivity. In addition, we will measure whether changes in these measures mediate the effects of
transcranial alternating current stimulation (tACS) of PFC on behavioral flexibility. In rats, we will use
neurochemical and electrophysiological approaches to assess indices of E/I balance, and manipulate them via
chemogenetic tools. This work may ultimately identify therapeutic targets differentiated by adolescent alcohol
history and thus improve AUD treatment efficacy. Additionally, we propose a set of complementary studies that
will extend this work and build on collaborations across the Alcohol Research Center. This explicitly
translational approach allows the human and rodent findings to mutually inform each other and advances the
translation of basic science to clinical application.

Grant Number: 5P60AA011605-29
NIH Institute/Center: NIH
Principal Investigator: Charlotte Boettiger