In rats, no sex difference found in reward-guided associative learning, but females were more sensitive to probabilistic punishment (but less sensitive when punishment could be avoided with certainty)

Sex differences in reward- and punishment-guided actions. Tara G. Chowdhury et al. bioRxiv, Mar 18 2019. https://doi.org/10.1101/581546

ABSTRACT: Differences in the prevalence and presentation of psychiatric illnesses in men and women suggest that neurobiological sex differences confer vulnerability or resilience in these disorders. Rodent behavioral models are critical for understanding the mechanisms of these differences. Reward processing and punishment avoidance are fundamental dimensions of the symptoms of psychiatric disorders. Here we explored sex differences along these dimensions using multiple and distinct behavioral paradigms. We found no sex difference in reward-guided associative learning but a faster punishment-avoidance learning in females. After learning, females were more sensitive than males to probabilistic punishment but less sensitive when punishment could be avoided with certainty. No sex differences were found in reward-guided cognitive flexibility. Thus, sex differences in goal-directed behaviors emerged selectively when there was an aversive context. These differences were critically sensitive to whether the punishment was certain or unpredictable. Our findings with these new paradigms provide conceptual and practical tools for investigating brain mechanisms that account for sex differences in susceptibility to anxiety and impulsivity. They may also provide insight for understanding the evolution of sex-specific optimal behavioral strategies in dynamic environments.





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INTRODUCTION

Men and women show different rates of diagnosis, symptomology, and treatment responsivity in most brain disorders. For instance, men are more commonly diagnosed with schizophrenia, four times more likely to suffer from attention-deficit/hyperactivity disorder (ADHD) (Rowland, Lesesne, & Abramowitz, 2002), and twice as likely to be currently abusing illicit drugs (Abuse, 2013). On the other hand, major depressive disorder (MDD) and anxiety disorders are more common in women (Cyranowski, Frank, Young, & Shear, 2000). These patterns suggest that biological sex differences may underlie the disparities in vulnerability to these illnesses.

Reward-seeking and punishment-avoidance behaviors are fundamental to motivation, and are critical components of the pathophysiology of most psychiatric illnesses. For example, studies have shown that patients with depressive disorders (Pizzagalli et al., 2009), schizophrenia (Juckel, 2016; Kirsch, Ronshausen, Mier, & Gallhofer, 2007; Schlagenhauf et al., 2008), as well as ADHD (Scheres, Milham, Knutson, & Castellanos, 2007; Strohle et al., 2008) have modified brain responses to reward. In particular, major depression is associated with both a hyposensitivity to rewarding stimuli and hypersensitivity to punishment, and associated imaging findings are correlated with increasing frequency of depressive episodes (Kumar et al., 2018). Importantly, disorders where reward and aversive responding are differently affected also show different incidences and symptom profiles in women versus men. For example, in anxiety disorders there is an increased avoidance of aversive stimuli that is more pronounced in women (Sheynin et al., 2014). Similarly, in MDD, men are more likely to exhibit symptoms of aggression, substance abuse, and risky behavior, while females report higher rates of sleep disturbance, stress, and anhedonia (L. A. Martin, Neighbors, & Griffith, 2013). Similarly, it appears that sex influences substance abuse patterns, with women more likely than men to cite stress as the reason for initiating or relapsing drug use (Becker, McClellan, & Reed, 2017).

Finally, in ADHD, females diagnosed with the disorder more frequently experience comorbid anxiety and depression. These findings suggest that distinct responses to punishment may explain some of the observed sex differences in both the prevalence and expression of mental disorders.

Animal models are critical for understanding the behavioral neuroscience of sex differences, allowing assessment of motivated behaviors relevant to psychiatric disorders. Animal behavioral models, however, have been primarily developed and characterized with only male subjects. Additionally, these models often assess reward and punishment contingencies in separate tasks and constructs. In naturalistic environments, appetitive and aversive contexts and outcomes are often intertwined, and the ability to accurately assess and respond to these conflicting situations is critical for optimal decision-making. Females have been shown to respond differently than males to punishing stimuli (Denti & Epstein, 1972; Gruene, Flick, Stefano, Shea, & Shansky, 2015; Orsini, Willis, Gilbert, Bizon, & Setlow, 2016; Voulo & Parsons, 2017) as well as stress (Bangasser & Valentino, 2014; McEwen, 2014); however, little is known about how sex differences translate to tasks that involve both reward and punishment in the same behavioral series. Here, we investigate sex differences in multiple rodent behavioral tasks involving motivated behaviors (defined as behaviors where actions are guided by action-outcome contingencies) that integrate reward-seeking and punishment avoidance.

In the first task, the Punishment Risk Task (PRT), a rewarded action was associated with an escalating probability of punishment (Park & Moghaddam, 2017). Thus, action-reward contingency was certain but different blocks in the same behavioral series were associated with varying probability of receiving a shock after action execution. This task assesses behavior in response to unpredictability and perception of potential threats, which is relevant to human models of anxiety (Cornwell, Garrido, Overstreet, Pine, & Grillon, 2017). Human sex differences in prevalence and expression of anxiety-related behaviors suggest that males and females may respond differently to anxiety-provoking situations. This task, therefore, allowed us to compare motivated actions in male and female rats within a context of anxiety.

A second novel task, the Approach Avoid Task (AAT) measured actions to seek reward or avoid punishment during the same behavioral session. Rats were given simultaneous access to two distinct actions (lever-press or nose-poke), and two discriminative stimuli (a light or tone cue) signaled the trial type, either approach, in which a specific action was reinforced with a pellet, or avoidance, in which the other action prevented onset of a foot-shock. This task is relevant to symptoms of brain disorders such as anxiety, substance abuse, and MDD, which are associated with differences in processing of rewarding and punishing contexts (Dombrovski, Szanto, Clark, Reynolds, & Siegle, 2013; McCabe, Woffindale, Harmer, & Cowen, 2012). In addition to comparing learning and performance of male and female rats in this task, we conducted two experiments to gauge the impact of traditional models of anxiety in the context of this paradigm. These included measuring (1) the dose-response effect of a pharmacological model of anxiety (anxiogenic drug FG7142) on performance of the AAT and (2) elevated plus maze (EPM) performance of animals that had undergone training on the AAT compared to naïve animals.

Finally, we characterized sex differences in reward-motivated tasks that required behavioral inhibition and flexibility. Most disorders with higher prevalence in men than women (autism, ADHD, schizophrenia) involve impaired behavioral inhibition and flexibility. In addition, male predisposition to compulsive behavior may contribute to the higher rates of substance abuse and dependence in men [20]. To investigate these constructs, we used two operant tests of cognitive flexibility: reversal learning and extradimensional shifting. Both tasks required subjects to update behavior in response to changing rules.