A history of low-dose ethanol alters behavioral strategy selection and ventral hippocampus function

Kathleen Grace Marion Bryant

doi:10.17918/00001566

More than half of adults within the U.S. have consumed alcohol within the past year, but do not meet criteria for alcohol use disorder (AUD). Chronic alcohol use at sub-diagnostic, casual drinking levels is common and can produce profound neurobiological and behavioral changes that impact reward learning and seeking. These alterations may further engender subsequent vulnerability to AUD. The ventral hippocampus (vHPC) is increasingly considered a critical contributor to reward learning and seeking. Glutamatergic neurons and synapses are particularly sensitive to low doses of ethanol, and the vHPC contains a high number of glutamatergic neurons. Indeed, the vHPC is one of the first regions to exhibit changes in neuronal activity and pyramidal neuron loss as a result of chronic ethanol exposure. Thus, the broad objective of my thesis work was to identify long-term effects of low-dose ethanol on reward seeking and vHPC function. My behavioral findings showed that a history of repeated, low-dose ethanol exposure did not globally promote inflexible reward seeking. However, low-dose ethanol exposure increased motivated sucrose seeking - as measured by progressive ratio (PR) responding - in male, but not female, mice. I also found that low-dose ethanol exposure altered behavioral strategy selection, and this was associated with differences in motivated behavior depending on differences in reinforcement schedule history. To investigate whether a history of low-dose ethanol exposure altered vHPC activity during motivated behavior, mice were implanted with an electrode array in the vHPC. Neural activity was recorded during performance of the PR task and analyzed surrounding key behavioral events. My results demonstrated that vHPC activity was suppressed following reward seeking behavior (lever press) in ethanol-naïve mice, whereas this suppression preceded the lever press in ethanol-exposed mice. This was specific to reward seeking, as I found no ethanol-induced differences in activity surrounding reward checking behavior (magazine entry). To determine whether inhibition of vHPC activity was sufficient to alter motivated reward seeking, vHPC activity was inhibited during discrete temporal epochs time locked to mouse behavior using closed-loop optogenetics. Brief vHPC inhibition increased breakpoints on the PR test in ethanol-naive-, but not ethanol-exposed, mice. Further, inhibition of vHPC reduced latencies to check for reward delivery in ethanol-naive-, but not ethanol-exposed, mice. These results suggest that a history of low-dose ethanol exposure dysregulates vHPC activity during reward seeking and fundamentally changes the role of vHPC activity in modulating motivated behavior. A greater understanding of the neurobiological and behavioral substrates impacted by low-dose ethanol exposure can help identify factors placing casual drinkers at risk for transition to AUD.

A history of low-dose ethanol alters behavioral strategy selection and ventral hippocampus function

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A history of low-dose ethanol alters behavioral strategy selection and ventral hippocampus function

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