Distinct region- and time-dependent functional cortical adaptations in C57BL/6J mice after short and prolonged alcohol drinking

Abstract

Alcohol (ethanol) use disorder is associated with changes in frontal cortical areas including the anterior cingulate (ACC) and orbitofrontal cortex that contribute to cognitive deficits, uncontrolled drinking, and relapse. Acute ethanol exposure reduces intrinsic excitability of lateral orbitofrontal cortex (lOFC) neurons, while chronic exposure and long-term drinking influence plasticity of intrinsic excitability and function of glutamatergic synapses. However, the time course that these adaptations occur across a history of ethanol drinking is unknown. The current study examined whether short- and long-term voluntary ethanol consumption using an intermittent access paradigm would alter the biophysical properties of deep-layer pyramidal neurons in ACC and lOFC neurons. Neuronal spiking varied in the ACC with an initial increase in evoked firing after one day of drinking followed by a decrease in firing in mice that consumed ethanol for 3 days. No difference in lOFC spike number was observed between water controls and 1-day ethanol drinking mice, but mice that consumed ethanol for 1-week or more showed a significant increase in evoked firing. Voluntary ethanol drinking also produced a total loss of ethanol inhibition of lOFC neurons. There was no effect of drinking on excitatory or inhibitory synaptic events in ACC or lOFC neurons across all time points in this model. Overall, these results demonstrate that voluntary drinking alters neuronal excitability in the ACC and lOFC in distinct ways and on a different time scale that may contribute to the impairment of prefrontal cortex-dependent behaviors observed in individuals with alcohol use disorder.

Significance Statement Adaptations in function of prefrontal cortex neurons caused by chronic ethanol exposure have been described previously, but the time course and region specificity that these changes occur is unknown. We find that voluntary ethanol drinking in mice produces distinct time-dependent changes in cellular excitability across two cortical subregions that varied by direction and duration. These drinking-induced changes in cellular excitability were specific to action potential firing, but not to function of excitatory or inhibitory synapses. Our findings highlight the importance and sensitivity of alterations in cellular firing of cortical neurons that occur early in a drinking history and persist during long-term ethanol consumption.