BACKGROUND Chronic exposure to stress or alcohol can drive neuroadaptations that alter cognition. Alterations in cognition may contribute to alcohol use disorders by reducing cognitive control over drinking and maintenance of abstinence. Here we examined effects of combined ethanol and stress exposure on prefrontal cortex (PFC)-dependent cognition. METHODS Adult male C57BL/6J mice were trained to drink ethanol (15%, v/v) on a 1hr/day 1-bottle schedule. Once stable, mice were exposed to cycles of chronic intermittent ethanol (CIE) or air-control vapor exposure (Air), followed by test cycles of 1hr/day ethanol drinking. During test drinking mice received no-stress (NS) or 10 minutes of forced swim stress (FSS) 4 hours before each test. This schedule produced four experimental groups: control, Air/NS; ethanol-dependent no stress, CIE/NS; non-dependent stress, Air/FSS; or ethanol-dependent stress, CIE/FSS. After two cycles of CIE and FSS exposure we assessed PFC-dependent cognition using object/context recognition and attentional set-shifting. At the end of the study mice were perfused and brains collected for measurement of c-Fos activity in PFC and locus coeruleus (LC). RESULTS CIE/FSS mice escalated ethanol intake faster than CIE/NS and consumed more ethanol than Air/NS across all test cycles. After two cycles of CIE/FSS, mice showed impairments in contextual learning and extra-dimensional set shifting relative to other groups. In addition to cognitive dysfunction, CIE/FSS mice demonstrated widespread reductions in c-Fos activity within prelimbic and infralimbic PFC as well as LC. CONCLUSION Together, these findings show that interactions between ethanol and stress exposure rapidly lead to disruptions in signaling across cognitive networks and impairments in PFC-dependent cognitive function.

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Rodent premotor cortex (M2) integrates information from sensory and cognitive networks for action selection and planning during goal-directed decision making. M2 function is regulated by cortical inputs and ascending neuromodulators, including norepinephrine (NE) released from the locus coeruleus (LC). LC-NE has been shown to modulate the signal to noise ratio of neural representations in target regions prior to decision execution, to increase the salience of relevant stimuli. Using rats performing a two-alternative forced choice task after administration of an adrenergic antagonist (propranolol), we show that action planning in M2 is mediated by adrenergic signaling. Loss of adrenergic signaling results in failure to suppress irrelevant action plans in M2 that disrupts decoding of cue related information, delays decision times, and increases trial omissions, particularly in females. Furthermore, we identify a potential mechanism for the sex bias in behavioral and neural changes after propranolol administration via differential expression of receptors across sexes, particularly on local inhibitory neurons. Overall, we show a critical role for adrenergic signaling in M2 during decision making by suppressing irrelevant information to enable efficient action planning and decision execution.

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Cognitive control is key to regulating alcohol intake and preventing relapse. Behavioral inflexibility can prevent adaptive strategies such as mindfulness or other relapse-prevention behaviors. In a mouse model we investigated whether individual variability in behavioral flexibility (using attentional set-shifting task; ASST) predicts future alcohol intake. Adult male and female C57BL/6J mice were subjected to ASST using a bowl digging paradigm where mice identify a baited bowl based on compound odor and textural cues. This was completed prior to any alcohol exposure. Individual performance across mice varied within the group. We integrated several metrics, specifically ASST stage completed, trials to completion and errors performed to produce an individual performance index measure of behavioral flexibility. After, ASST mice were trained to drink ethanol (15%, v/v, 1hr/day) for 3-4 weeks until intake stabilized. Using this prospective approach, we identified an inverse relationship between behavioral flexibility and drinking - less flexible mice had a propensity to consume more alcohol. Similar relationships have been identified previously in non-human primates and rats. Our results show that the relationship between alcohol and cognitive flexibility is a robust trait that is conserved across species and can be used in mice to study neural substrates underlying these behaviors.

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