Differential transcriptome profile underlying risky choice in a rat gambling task.

Background and aims: Proper measurement of expected risk is important for making rational decisions, and maladaptive decision making may underlie various psychiatric disorders. However, differentially expressed genetic profiling involved in this process is still largely unknown. A rodent version of the gambling task (rGT) has been developed to measure decision-making by adopting the same principle of Iowa Gambling Task in humans. In the present study, we examined using next-generation sequencing (NGS) technique whether there are differences in gene expression profiles in the medial prefrontal cortex (mPFC) and the nucleus accumbens (NAc) when rats make different choices toward risk in rGT. Methods: Rats were trained in a touch screen chamber to learn the relationships between 4 different light signals on the window of the screen and accompanied reward outcomes or punishments set up with different magnitudes and probabilities. Once they showed a stabilized pattern of preference upon free choice, rats were classified into risk-averse or risk-seeking groups. After performing the rGT, rats were decapitated, the mPFC and the NAc was dissected out, and NGS was performed with the total RNA extracted. Results: We found that 477 and 36 genes were differentially expressed (approximately 75 and 83% out of them were downregulated) in the mPFC and the NAc, respectively, in risk-seeking compared to risk-averse rats. Among those, we suggested a few top ranked genes that may contribute to promoting risky choices. Discussion and conclusions: Our findings provide insights into transcriptional components underlying risky choices in rats.

Disruption of amphetamine sensitization by alteration of dendritic thin spines in the nucleus accumbens core.

Repeated injections of psychomotor stimulants like amphetamine (AMPH) to rodents can induce behavioral sensitization, which represents a long-lasting craving that is usually observed in human addicts. Behavioral sensitization is characteristically maintained for a long duration, accompanied by structural plasticity in some brain areas involved in reward circuitry. For example, it increased dendritic spine densities in the nucleus accumbens (NAcc), which is considered to reflect neurophysiological changes at this site, leading to addictive behaviors. The ezrin, radixin, and moesin (ERM) proteins regulate spine maturity by modifying their phosphorylation at the C-terminal region. We previously showed that ERM phosphorylation is reduced by AMPH in the NAcc core, suggesting that ERM-mediated spine changes at this site might be associated with AMPH sensitization. To test this hypothesis, we administered AMPH to rats according to a sensitization development schedule, with lentivirus encoding a phosphomimetic pseudo-active mutant of radixin (Rdx T564D) in the NAcc core, and examined dendritic spines at this site. We found that compared to acute AMPH, AMPH sensitization increased thin spine density with a similar ratio of filopodia-like to mature thin spines. However, with Rdx T564D, the density of thin spines increased, with augmented filopodia-like thin spines, resulting in no AMPH sensitization. These results indicate that Rdx T564D forces thin spines to immaturity and thereby inhibits AMPH sensitization, for which an increase in mature thin spines is normally necessary. These findings provide significant clues to our understanding of the role of dendritic spines in mediating the development of psychomotor stimulant addiction.

Impulsive Action and Impulsive Choice Are Differentially Expressed in Rats Depending on the Age at Exposure to a Gambling Task.

Impulsivity is considered an important feature associated with the development of numerous psychiatric disorders, including addictions. In the behavioral approach, impulsivity can be broadly divided into two distinct subtypes: impulsive action and choice. In the present study, we used a rodent version of the gambling task (rGT) to examine how impulsive action and impulsive choice are differentially influenced by difference in age at exposure (i.e., late adolescents/young adults vs. mature adults) to rGT. Rats were trained in a touch-screen chamber to learn the relationships between 4 light signals on the window of the screen and accompanying reward outcomes or punishments associated with different magnitudes and probabilities. Depending on their stabilized pattern of preference when allowed free choice, rats were categorized into risk-averse or risk-seeking group. While undergoing a series of experimental schemes, including extinction, re-acquisition, and acute cocaine injection, rats were re-tested for their premature response during inter-trial interval and choice preference toward the 4 different windows in rGT. Notably, rats exposed early, compared with those exposed late, to rGT showed increased impulsive action, particularly during re-acquisition period, in all sub-groups. In contrast, rats exposed late, compared with those exposed early, to rGT showed increased impulsive choice after acute cocaine injection, but these results were only obtained in a sub-group pre-categorized as high impulsive and risk-averse. These results suggest that different aspects of impulsivity can be differentially expressed during decision-making, and differentially influenced by the age at exposure to a gambling task.

Interaction between trait and housing condition produces differential decision-making toward risk choice in a rat gambling task.

Poor decision-making is a core problem in psychiatric disorders such as pathological gambling and substance abuse. Both trait and environmental factors are considerably important to affect decision-making. However, it has not yet been systematically shown how they interact to affect risk preference in animal models evaluating decision-making. Here, we trained rats, housed in pairs or in isolation, in a touch screen chamber to detect the association between four different light signals on the screen and accompanied reward and punishment outcomes arranged with different schedules. Then, the rats were allowed to freely choose from 4 different light signals. Once animals showed a stabilized pattern of preference (risk-averse or risk-seeking), they were injected with saline or cocaine (a single injection per day for 7 days) followed by 2 weeks of withdrawal. Then, their preference of choice was re-tested in the touch screen chamber while they were cocaine challenged. All rats significantly changed their preference toward more risky choices when they were exposed to and challenged with cocaine, except those in the risk-averse/isolated housing group. These results indicate that the pre-existing trait toward risk and the housing condition interact to affect the quality of decision-making, and cocaine may help to aggravate this process.