Stress Facilitates the Development of Cognitive Dysfunction After Chronic Ethanol Exposure

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 (EtOH) and stress exposure on prefrontal cortex (PFC)‐dependent cognition. Methods Adult male C57BL/6J mice were trained to drink EtOH (15%, v/v) on a 1 h/d 1‐bottle schedule. Once stable, mice were exposed to cycles of chronic intermittent EtOH (CIE) or air‐control vapor exposure (Air), followed by test cycles of 1 h/d EtOH 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 4 experimental groups: control, Air/NS; EtOH‐dependent no stress, CIE/NS; nondependent stress, Air/FSS; or EtOH‐dependent stress, CIE/FSS. After 2 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 were collected for measurement of c‐Fos activity in PFC and locus coeruleus (LC). Results CIE/FSS mice escalated EtOH intake faster than CIE/NS and consumed more EtOH than Air/NS across all test cycles. After 2 cycles of CIE/FSS, mice showed impairments in contextual learning and extradimensional 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. Conclusions Together, these findings show that interactions between EtOH and stress exposure rapidly lead to disruptions in signaling across cognitive networks and impairments in PFC‐dependent cognitive function. We examined the combined effects of chronic ethanol and stress exposure on prefrontal cortex (PFC) dependent cognition and drinking. Mice were exposed to ethanol vapor, swim stress, both, or neither. Relative to controls, ethanol and stress exposed mice showed rapid escalation in ethanol consumption and decreased cognitive performance. Impaired mice also showed decreased c‐fos activity across PFC and locus coeruleus circuits.These findings show that interactions between ethanol and stress can disrupt activity in cognitive networks that support PFC‐dependent cognition.