No abstract

Impairments in choosing optimally between immediate and delayed rewards are associated with numerous psychiatric disorders. Such ‘intertemporal’ choice is influenced by genetic and experiential factors; however, the contributions of biological sex are understudied and data to date are largely inconclusive. Rats were used to determine how sex and gonadal hormones influence choices between small, immediate and large, delayed rewards. Females showed markedly greater preference than males for small, immediate over large, delayed rewards (greater impulsive choice). This difference was neither due to differences in food motivation or reward magnitude perception, nor was it affected by estrous cycle. Ovariectomies did not affect choice in females, whereas orchiectomies increased impulsive choice in males. These data show that male rats exhibit less impulsive choice than females and that this difference is at least partly maintained by testicular hormones. These differences in impulsive choice could be linked to gender differences across multiple neuropsychiatric conditions.

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The ability to decide advantageously among options that vary in both their risks and rewards is critical for survival and well-being. Previous work shows that some forms of risky decision making are robustly modulated by monoamine signaling, but it is less clear how monoamine signaling modulates decision making under risk of explicit punishment. The goal of these experiments was to determine how this form of decision making is modulated by dopamine, serotonin, and norepinephrine signaling, using a task in which rats choose between small, “safe” food rewards and large food rewards associated with variable risks of punishment. Preference for the large, risky reward (risk taking) was reduced by administration of a D2/3 dopamine receptor agonist (bromocriptine) and a selective D2 agonist (sumanirole). The selective D3 agonist PD128907 appeared to attenuate reward discrimination abilities, but did not affect risk taking per se. In contrast, drugs targeting serotonergic and noradrenergic signaling had few if any effects on choice behavior. These data suggest that in contrast to other forms of risky decision making, decision making under risk of punishment is selectively modulated by dopamine signaling, predominantly through D2 receptors.

Individuals who use cocaine exhibit maladaptive decision-making, overweighting rewards, and underweighting potential risks. We previously showed that chronic cocaine self-administration in young adult male rats causes long-lasting increases in risk taking. The present study expanded upon these findings to determine whether effects of cocaine on risk taking depend on the route of cocaine administration and extend to females. To address the former question, rats in Experiment 1 were trained on the Risky Decisionmaking Task (RDT), received passively administered cocaine, and were retested in the RDT. Surprisingly, passive cocaine had no effect on risk taking. Experiment 2 determined whether cocaine self-administration increases risk taking in females in a manner comparable to males. Males and females were trained in the RDT, underwent cocaine self-administration, and were retested in the RDT. Unexpectedly, cocaine selfadministration had no effect on risk taking in either sex. Because Experiments 1 and 2 involved cocaine exposure at a considerably older age than in previous work, Experiments 3 and 4 determined if cocaine effects on risk taking depend on the age of exposure. Rats began cocaine self-administration at postnatal (PN) day 77 (Experiment 3) or passive cocaine injections starting on PN day 63 (Experiment 4) and were tested in the RDT 3 weeks after cocaine cessation. In these experiments, cocaine increased risk taking in both sexes. These results reveal a limited time window during young adulthood of vulnerability to the effects of chronic cocaine on risk taking.

Decision making is a complex cognitive process that recruits a distributed network of brain regions, including the basolateral amygdala (BLA) and nucleus accumbens shell (NAcSh). Recent work suggests that communication between these structures, as well as activity of cells expressing dopamine D2 receptors (D2R) in the NAcSh, are necessary for some forms of decision making; however, the contributions of this circuit and cell population during decision making under risk of punishment are unknown. The current experiments addressed this question using circuit- and cell type-specific optogenetic approaches in rats during a decision-making task involving risk of punishment. In Experiment 1, Long-Evans rats received intra-BLA injections of halorhodopsin or mCherry (control) and in Experiment 2, D2-Cre transgenic rats received intra-NAcSh injections of Cre-dependent halorhodopsin or mCherry. Optic fibers were implanted in the NAcSh in both experiments. Following training in the decision-making task, BLA→NAcSh or D2R-expressing neurons were optogenetically inhibited during different phases of the decision process. Inhibition of the BLA→NAcSh during deliberation (the time between trial initiation and choice) increased preference for the large, risky reward (increased risk taking). Similarly, inhibition during delivery of the large, punished reward increased risk taking, but only in males. Inhibition of D2R-expressing neurons in the NAcSh during deliberation increased risk taking. In contrast, inhibition of these neurons during delivery of the small, safe reward decreased risk taking. These findings extend our knowledge of the neural dynamics of risk taking, revealing sex-dependent circuit recruitment and dissociable activity of selective cell populations during decision making.Significance Statement:Until recently, the ability to dissect the neural substrates of decision making involving risk of punishment (risk taking) in a circuit- and cell-specific manner has been limited by the tools available for use in rats. Here, we leveraged the temporal precision of optogenetics, together with transgenic rats, to probe contributions of a specific circuit and cell population to different phases of risk-based decision making. Our findings reveal BLA→NAcSh is involved in evaluation of punished rewards in a sex-dependent manner. Further, NAcSh D2R-expressing neurons make unique contributions to risk taking that vary across the decision-making process. These findings advance our understanding of the neural principles of decision making and provide insight into how risk taking may become compromised in neuropsychiatric diseases.

No abstract

Decision making is a complex cognitive process that recruits a distributed network of brain regions, including the basolateral amygdala (BLA) and nucleus accumbens shell (NAcSh). Recent work suggests that communication between these structures, as well as activity of cells expressing dopamine D2 receptors (D2R) in the NAcSh, are necessary for some forms of decision making; however, the contributions of this circuit and cell population during decision making under risk of punishment are unknown. The current experiments addressed this question using circuit- and cell type-specific optogenetic approaches in rats during a decision-making task involving risk of punishment. In Experiment 1, Long-Evans rats received intra-BLA injections of halorhodopsin or mCherry (control) and in Experiment 2, D2-Cre transgenic rats received intra-NAcSh injections of Cre-dependent halorhodopsin or mCherry. Optic fibers were implanted in the NAcSh in both experiments. Following training in the decision-making task, BLA projections to the NAcSh or D2R-expressing neurons were optogenetically inhibited during different phases of the decision process. Inhibition of the BLA projections to the NAcSh during deliberation (the time between trial initiation and choice) increased choice of the large, risky reward (increased risk taking). Similarly, inhibition during delivery of the large, punished reward increased risk taking, but only in males. Inhibition of D2R-expressing neurons in the NAcSh during deliberation increased risk taking. In contrast, inhibition of these neurons during delivery of the small, safe reward decreased risk taking. These findings extend our knowledge of the neural dynamics of risk taking, revealing sex-dependent circuit recruitment and dissociable activity of selective cell populations during decision making.