Cocaine intake correlates with risk-taking behavior and affects estrous cycling in female Sprague-Dawley rats.

Navigating complex decisions and considering their relative risks and rewards is an important cognitive ability necessary for survival. However, use of and dependence on illicit drugs can result in long-lasting changes to this risk/reward calculus in individuals with substance use disorder. Recent work has shown that chronic exposure to cocaine causes long-lasting increases in risk taking in male and female rats, but there are still significant gaps in our understanding of the relationship between cocaine use and changes in risk taking. For example, it is unclear whether the magnitude of cocaine intake dictates the extent to which risk taking is altered. To address this, male and female Sprague-Dawley rats underwent cocaine (or sucrose) self-administration and, following a period of abstinence, were trained and tested in a rodent model of risky decision making. In this behavioral task, rats made discrete-trial choices between a lever associated with a small food reward (i.e., "safe" option) and a lever associated with a larger food reward accompanied by a variable risk of footshock delivery (i.e., "risky" option). Surprisingly, and in contrast to prior work in Long-Evans rats, there were no effects of cocaine self-administration on choice of the large, risky reward (i.e., risk taking) during abstinence in males or females. There was, however, a significant relationship between cocaine intake and risk taking in female rats, with greater intake associated with greater preference for the large, risky reward. Relative to their sucrose counterparts, female rats in the cocaine group also exhibited irregular estrous cycles, characterized by prolonged estrus and/or diestrus phases. Collectively, these data suggest that there may be strain differences in the effects of cocaine on risk taking and highlight the impact that chronic cocaine exposure has on hormonal cyclicity in females. Future work will focus on understanding the neural mechanisms underlying cocaine's intake-dependent effects on risk taking in females, and whether this is directly related to cocaine-induced alterations in neuroendocrine function.

Effects of fentanyl self-administration on risk-taking behavior in male rats.

RATIONALE: Individuals with opioid use disorder (OUD) exhibit impaired decision making and elevated risk-taking behavior. In contrast to the effects of natural and semi-synthetic opioids, however, the impact of synthetic opioids on decision making is still unknown. OBJECTIVES: The objective of the current study was to determine how chronic exposure to the synthetic opioid fentanyl alters risk-based decision making in adult male rats. METHODS: Male rats underwent 14 days of intravenous fentanyl or oral sucrose self-administration. After 3 weeks of abstinence, rats were tested in a decision-making task in which they chose between a small, safe food reward and a large food reward accompanied by variable risk of footshock punishment. Following testing in the decision-making task, rats were tested in control assays that assessed willingness to work for food and shock reactivity. Lastly, rats were tested on a probabilistic reversal learning task to evaluate enduring effects of fentanyl on behavioral flexibility. RESULTS: Relative to rats in the sucrose group, rats in the fentanyl group displayed greater choice of the large, risky reward (risk taking), an effect that was present as long as 7 weeks into abstinence. This increased risk taking was driven by enhanced sensitivity to the large rewards and diminished sensitivity to punishment. The fentanyl-induced elevation in risk taking was not accompanied by alterations in food motivation or shock reactivity or impairments in behavioral flexibility. CONCLUSIONS: Results from the current study reveal that the synthetic opioid fentanyl leads to long-lasting increases in risk taking in male rats. Future experiments will extend this work to females and identify neural mechanisms that underlie these drug-induced changes in risk taking.

Circuit and Cell-Specific Contributions to Decision Making Involving Risk of Explicit Punishment in Male and Female Rats.

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 (DA) 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-specific 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-specific 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 basolateral amygdala (BLA)→nucleus accumbens shell (NAcSh) is involved in evaluation of punished rewards in a sex-dependent manner. Further, NAcSh D2 receptor (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.

Age-Related Changes in Risky Decision Making and Associated Neural Circuitry in a Rat Model.

Altered decision making at advanced ages can have a significant impact on an individual's quality of life and the ability to maintain personal independence. Relative to young adults, older adults make less impulsive and less risky choices; although these changes in decision making could be considered beneficial, they can also lead to choices with potentially negative consequences (e.g., avoidance of medical procedures). Rodent models of decision making have been invaluable for dissecting cognitive and neurobiological mechanisms that contribute to age-related changes in decision making, but they have predominantly used costs related to timing or probability of reward delivery and have not considered other equally important costs, such as the risk of adverse consequences. The current study therefore used a rat model of decision making involving risk of explicit punishment to examine age-related changes in this form of choice behavior in male rats, and to identify potential cognitive and neurobiological mechanisms that contribute to these changes. Relative to young rats, aged rats displayed greater risk aversion, which was not attributable to reduced motivation for food, changes in shock sensitivity, or impaired cognitive flexibility. Functional MRI analyses revealed that, overall, functional connectivity was greater in aged rats compared with young rats, particularly among brain regions implicated in risky decision making such as basolateral amygdala, orbitofrontal cortex, and ventral tegmental area. Collectively, these findings are consistent with greater risk aversion found in older humans, and reveal age-related changes in brain connectivity.

Circuit and cell-specific contributions to decision making involving risk of explicit punishment in male and female rats.

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 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.

Regulation of sex differences in risk-based decision making by gonadal hormones: Insights from rodent models.

Men and women differ in their ability to evaluate options that vary in their rewards and the risks that are associated with these outcomes. Most studies have shown that women are more risk averse than men and that gonadal hormones significantly contribute to this sex difference. Gonadal hormones can influence risk-based decision making (i.e., risk taking) by modulating the neurobiological substrates underlying this cognitive process. Indeed, estradiol, progesterone and testosterone modulate activity in the prefrontal cortex, amygdala and nucleus accumbens associated with reward and risk-related information. The use of animal models of decision making has advanced our understanding of the intersection between the behavioral, neural and hormonal mechanisms underlying sex differences in risk taking. This review will outline the current state of this literature, identify the current gaps in knowledge and suggest the neurobiological mechanisms by which hormones regulate risky decision making. Collectively, this knowledge can be used to understand the potential consequences of significant hormonal changes, whether endogenously or exogenously induced, on risk-based decision making as well as the neuroendocrinological basis of neuropsychiatric diseases that are characterized by impaired risk taking, such as substance use disorder and schizophrenia.

GABAB receptors in prelimbic cortex and basolateral amygdala differentially influence intertemporal decision making and decline with age.

The ability to decide adaptively between immediate vs. delayed gratification (intertemporal choice) is critical for well-being and is associated with a range of factors that influence quality of life. In contrast to young adults, many older adults show enhanced preference for delayed gratification; however, the neural mechanisms underlying this age difference in intertemporal choice are largely un-studied. Changes in signaling through GABAB receptors (GABABRs) mediate several age-associated differences in cognitive processes linked to intertemporal choice. The current study used a rat model to determine how GABABRs in two brain regions known to regulate intertemporal choice (prelimbic cortex; PrL and basolateral amygdala; BLA) contribute to age differences in this form of decision making in male rats. As in humans, aged rats showed enhanced preference for large, delayed over small, immediate rewards during performance in an intertemporal choice task in operant test chambers. Activation of PrL GABABRs via microinfusion of the agonist baclofen increased choice of large, delayed rewards in young adult rats but did not influence choice in aged rats. Conversely, infusion of baclofen into the BLA strongly reduced choice of large, delayed rewards in both young adult and aged rats. Aged rats further showed a significant reduction in expression of GABABR1 subunit isoforms in the prefrontal cortex, a discovery that is consonant with the null effect of intra-PrL baclofen on intertemporal choice in aged rats. In contrast, expression of GABABR subunits was generally conserved with age in the BLA. Jointly, these findings elucidate a role for GABABRs in intertemporal choice and identify fundamental features of brain maturation and aging that mediate an improved ability to delay gratification.

Regulation of risky decision making by gonadal hormones in males and females.

Psychiatric diseases characterized by dysregulated risky decision making are differentially represented in males and females. The factors that govern such sex differences, however, remain poorly understood. Using a task in which rats make discrete trial choices between a small, "safe" food reward and a large food reward accompanied by varying probabilities of footshock punishment, we recently showed that females are more risk averse than males. The objective of the current experiments was to test the extent to which these sex differences in risky decision making are mediated by gonadal hormones. Male and female rats were trained in the risky decision-making task, followed by ovariectomy (OVX), orchiectomy (ORX), or sham surgery. Rats were then retested in the task, under both baseline conditions and following administration of estradiol and/or testosterone. OVX increased choice of the large, risky reward (increased risky choice), an effect that was attenuated by estradiol administration. In contrast, ORX decreased risky choice, but testosterone administration was without effect in either ORX or sham males. Estradiol, however, decreased risky choice in both groups of males. Importantly, none of the effects of hormonal manipulation on risky choice were due to altered shock sensitivity or food motivation. These data show that gonadal hormones are required for maintaining sex-typical profiles of risk-taking behavior in both males and females, and that estradiol is sufficient to promote risk aversion in both sexes. The findings provide novel information about the mechanisms supporting sex differences in risk taking and may prove useful in understanding sex differences in the prevalence of psychiatric diseases associated with altered risk taking.

Testicular hormones mediate robust sex differences in impulsive choice in rats.

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.

Optogenetic dissection of basolateral amygdala contributions to intertemporal choice in young and aged rats.

Across species, aging is associated with an increased ability to choose delayed over immediate gratification. These experiments used young and aged rats to test the role of the basolateral amygdala (BLA) in intertemporal decision making. An optogenetic approach was used to inactivate the BLA in young and aged rats at discrete time points during choices between levers that yielded a small, immediate vs. a large, delayed food reward. BLA inactivation just prior to decisions attenuated impulsive choice in both young and aged rats. In contrast, inactivation during receipt of the small, immediate reward increased impulsive choice in young rats but had no effect in aged rats. BLA inactivation during the delay or intertrial interval had no effect at either age. These data demonstrate that the BLA plays multiple, temporally distinct roles during intertemporal choice, and show that the contribution of BLA to choice behavior changes across the lifespan.