C. Reed1, E. Walker-Ziegler1, S. Aldrich1, J. Erk1, S.H. Mitchell1, T.J. Phillips1,2

A relationship between low initial cognitive flexibility and subsequent high ethanol intake has been demonstrated in non-human primates (NHPs) by members of the Portland Alcohol Research Center (PARC). We designed an operant set-shifting task for mice that parallels that used in NHPs to examine this relationship in mouse lines selectively bred for high and low ethanol preference (HP, LP). This task incorporates a series of fixed rule sets beginning with simple discrimination (SD), followed by intra- and extra-dimensional shifts (ID and ED respectively), and reversal of each ruleset. In two studies, we manipulated mode of responding (lever or nosepoke), method for obtaining the reward (dipper or sipper), and reward type (saccharin or sucrose solution). The number of days to complete training criteria of 30 operant responses in a 30-minute session for saccharin/nosepoke and sucrose/lever testing conditions did not differ between the HP and LP lines. There were no line differences in the number of days to complete the SD rule when the signal light location was fixed. In the final testing week of the sucrose/lever study, there was a significant line difference, only in females, with HP mice reaching a higher rule set than LP mice. However, a majority (97%) of mice were unable to move beyond following the signal light when it was variably presented above the nosepoke/lever (rule 3 out of 7). NHPs are able to complete complex operant set-shifting tasks that are challenging to model in mice.

1Department of Behavioral Neuroscience and the Portland Alcohol Research Center, Oregon Health & Science University, 2VA Portland Health Care System, Portland, OR 97239, USA

Funding Support: NIH/NIAAA P60AA010760 (USA) and Department of Veterans Affairs Senior Research Career Scientist Award 15F-RCS-010 (USA).

Erika Cortez ^1,2 and Kristin M Scaplen ^1,2,3

Alcohol use disorder (AUD) is a chronic relapsing disorder that manifests as problematic patterns of alcohol use. At the core of AUD’s behavioral manifestations is alcohol’s profound effect on the brain. Alcohol engages and ultimately subordinates memory circuits resulting in enduring preferences, habitual behaviors, and persistent cravings. Insight to the circuit mechanisms that underlie how alcohol-associated memories are encoded, maintained, and expressed is critical to understanding why these memories are remarkably resistant to change. However, understanding the circuit basis of
reward-related learning and addiction has been challenging. Efforts are often hindered by the neuronal heterogeneity that exists within dopamine (DA) sub-regions, as well as the lack of spatial and temporal resolution to distinguish neuronal subpopulations or isolate individual neurons. Drosophila melanogaster is a powerful model organism to address these challenges because they offer a rich genetic toolkit that permits dissection of heterogenous circuits with precise temporal and spatial resolution. Importantly, Drosophila form persistent alcohol reward memories, which impel them to
overcome aversive stimuli in pursuit of alcohol-associated cues. Previous work identified discrete circuits that underlie alcohol reward memories and their temporal requirements. In Drosophila alcohol reward memory requires the mushroom body (MB), a region essential for learning and memory as well DA modulation of the MB which shifts from an entire population during acquisition to two discrete DA subsets known to process memories with opposing valences. However, it remains unclear the mechanisms by which these memories are consolidated. The Dorsal Paired Medial neurons (DPM), which innervate the MB have an established role in sleep regulation and memory consolidation. Using neurogenetic tools available in Drosophila we investigated the role of DPM neurons in alcohol reward memories and other alcohol associated behaviors. Further, we report postsynaptic targets of DPM using the genetic anterograde transsynaptic tracing tool, trans-Tango. Preliminary data suggest that DPM is required for the consolidation of alcohol reward memories but not acquisition or retrieval and is synaptically connected with neurons previously identified to be important for the consolidation of alcohol reward memories. These findings provide insight to the circuit mechanisms underlying the consolidation of alcohol associated memories and why they are so resistant to change.

1 Department of Psychology, Bryant University, Smithfield, RI, 02917

2 Center for Health and Behavioral Sciences, Bryant University, Smithfield, RI 02917

3 Department of Neuroscience, Brown University, Providence, RI, 02912