Prior Cocaine Use Alters the Normal Evolution of Information Coding in Striatal Ensembles during Value-Guided Decision-Making

Abstract

Substance use disorders (SUDs) are characterized by maladaptive behavior. The ability to properly adjust behavior according to changes in environmental contingencies necessitates the interlacing of existing memories with updated information. This can be achieved by assigning learning in different contexts to compartmentalized "states." Though not often framed this way, the maladaptive behavior observed in individuals with SUDs may result from a failure to properly encode states because of drug-induced neural alterations. Previous studies found that the dorsomedial striatum (DMS) is important for behavioral flexibility and state encoding, suggesting the DMS may be an important substrate for these effects. Here, we recorded DMS neural activity in cocaine-experienced male rats during a decision-making task where blocks of trials represented distinct states to probe whether the encoding of state and state-related information is affected by prior drug exposure. We found that DMS medium spiny neurons (MSNs) and fast-spiking interneurons (FSIs) encoded such information and that prior cocaine experience disrupted the evolution of representations both within trials and across recording sessions. Specifically, DMS MSNs and FSIs from cocaine-experienced rats demonstrated higher classification accuracy of trial-specific rules, defined by response direction and value, compared with those drawn from sucrose-experienced rats, and these overly strengthened trialtype representations were related to slower switching behavior and reaction times. These data show that prior cocaine experience paradoxically increases the encoding of state-specific information and rules in the DMS and suggest a model in which abnormally specific and persistent representation of rules throughout trials in DMS slows value-based decision-making in well trained subjects.

Perseverative behavior under uncertainty is enhanced by tryptophan depletion but diminished with subclinical obsessive–compulsive symptoms

“…Importantly, the OFC, a key area of dysfunction in OCD (Chamberlain et al 2008;Remijnse et al 2006), is implicated in representing states (Schuck et al 2016;Wilson et al 2014). In extension of this framework, it should be noted that SUD, where high stimulus stickiness has been observed (Kanen et al 2019), may be characterised by over-encoding of state-specific rules and information (Mueller et al 2020).…”

Behavioral Inflexibility from a Neuronal Population Perspective

“…In other words, trial-type information reflects the odor-reward contingencies in a task block. Statistical inference revealed that the decoding accuracies for MSN and FSI pseudo-ensembles from the cocaine group were significantly higher than those from the sucrose group in some trial phases, suggesting that prior cocaine use increases the amount of rewardrelated information being encoded by the pseudo-ensembles (Mueller et al, 2021).…”

“…Behavioral flexibility is typically assessed using reversal learning tasks, in which subjects learn to perform a specific action to receive a reward, then must alter their behavior when a different action is rewarded instead (Izquierdo et al, 2017). Impairments in such flexibility are observed in substance use disorder, characterized by persistent drug use despite negative outcomes (Mueller et al, 2021). Individuals with substance use disorders may choose to use drugs even when more rewarding alternatives are available especially in contexts that were previously associated with drug use.…”

“…To address this question, Mueller et al (2021) examined how prior cocaine use affected performance and dorsomedial striatum neuronal activity during a reversal learning task in rats. Rats with prior cocaine or sucrose self-administration experience were trained to perform an odor-guided choice task in which two of three instructional odors were associated with a big and a small reward, on the left and right fluid well, respectively.…”

“…To investigate the relationship between the neural and behavioral findings, Mueller et al (2021) further analyzed decoding misclassifications using confusion matrices and found that information represented by pseudo-ensembles from the sucrose group changed over time, from reward contingency to response information, resulting in faster reaction times. However, cocaine prevented this information change from occurring, ultimately blocking the optimization of decision-making in rats (Mueller et al, 2021).…”