Chronic alcohol produces neuroadaptations to prime dorsal striatal learning

Abstract

Drug addictions including alcoholism are characterized by degradation of executive control over behavior and increased compulsive drug seeking. These profound behavioral changes are hypothesized to involve a shift in the regulation of behavior from prefrontal cortex to dorsal striatum (DLS). Studies in rodents have shown that ethanol disrupts cognitive processes mediated by the prefrontal cortex, but the potential effects of chronic ethanol on DLS-mediated cognition and learning are much less well understood. Here, we first examined the effects of chronic EtOH on DLS neuronal morphology, synaptic plasticity, and endocannabinoid-CB1R signaling. We next tested for ethanol-induced changes in striatal-related learning and DLS in vivo single-unit activity during learning. Mice exposed to chronic intermittent ethanol (CIE) vapor exhibited expansion of dendritic material in DLS neurons. Following CIE, DLS endocannabinoid CB1 receptor signaling was down-regulated, and CB1 receptordependent long-term depression at DLS synapses was absent. CIE mice showed facilitation of DLS-dependent pairwise visual discrimination and reversal learning, relative to air-exposed controls. CIE mice were also quicker to extinguish a stimulus-reward instrumental response and faster to reduce Pavlovian approach behavior under an omission schedule. In vivo single-unit recording during learning revealed that CIE mice had augmented DLS neuronal activity during correct responses. Collectively, these findings support a model in which chronic ethanol causes neuroadaptations in the DLS that prime for greater DLS control over learning. The shift to striatal dominance over behavior may be a critical step in the progression of alcoholism.lcoholism is a highly prevalent disorder with a massive and growing impact on public health (1). The course of alcoholism and other chronic drug addictions has been conceptualized as involving the progressive deterioration of executive control of behavior and the corresponding emergence of compulsive drug seeking (2, 3). At the neural systems level, this shift is associated with a "devolution" away from prefrontal cortical (PFC) regulation of behavior in favor of greater control by subcortical regions including the dorsal striatum (DS) (2, 4).Consistent with this scheme, alcohol-dependent individuals show impairments on PFC-mediated cognitive measures, such as impulse control and reversal learning (5, 6), but exaggerated neural responses in the DS when, for example, presented with alcohol-associated cues (7-9). Along similar lines, rodents chronically exposed to ethanol (EtOH) exhibit deficits in PFC-and hippocampal-mediated tasks, including spatial and reversal learning, set-shifting, and fear extinction, that in some cases are linked to cortical cell death (10-17).These observations are consistent with an EtOH-induced impairment in various PFC-related cognitive behaviors but do not address the possibility of concomitant changes in processes mediated by the DS. In this context, recent studies in rats have found that ch...

Neurobiological Interactions Between Stress and the Endocannabinoid System

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Chronic Intermittent Ethanol Exposure Enhances the Excitability and Synaptic Plasticity of Lateral Orbitofrontal Cortex Neurons and Induces a Tolerance to the Acute Inhibitory Actions of Ethanol

“…Although not yet completely understood, these dynamic changes in PFC/OFC neuronal function may contribute to the alterations in OFC-and PFC-based behaviors (eg, reversal learning and set-shifting) that are observed during post-WD periods similar to those examined in this study (Badanich et al, 2011;DePoy et al, 2013;Holmes et al, 2012;Kroener et al, 2012;Trantham-Davidson et al, 2014). Such changes, if present in alcohol-dependent humans, may contribute to cognitive and behavioral deficits associated with long-term alcohol abuse that underlie the inability of these individuals to exert cognitive control over their drinking in the face of adverse consequences.…”

16p11.2 Deletion mice display cognitive deficits in touchscreen learning and novelty recognition tasks

“…Pairwise visual discrimination and reversal were tested in the automated Bussey-Saksida touchscreen equipment for mice (Campden Instruments Ltd/Lafayette Instruments), using a procedure based on methods described previously (Brigman and Rothblat 2008;Bussey et al 2008Bussey et al , 2012Brigman et al 2013;DePoy et al 2013;Horner et al 2013;Oomen et al 2013;Silverman et al 2015). Since we had discovered that the Dolmetsch line of 16p11.2 +/2 is deaf, using the acoustic startle response and the auditory brainstem response tests (Yang et al 2015b), operant methods were modified to accommodate +/2 mice.…”