Preliminary evidence of sex differences in behavioral and neural responses to palatable food reward in rats

Highlights

• Females are at greater risk than males for binge eating and eating disorders.

• Female rats show a robust shift in place preference for palatable food, males do not.

• Palatable food elicits greater activation of neural reward circuitry in female rats.

• Enhanced responses to food reward may underlie female bias in binge eating.

Abstract

The female bias in eating disorder prevalence is the largest in all of psychiatry. Binge eating on palatable food (PF) is a core, maladaptive symptom that cuts across all major types of eating disorders and can be studied via animal models. Using an individual differences rat model of binge eating that identifies binge eating prone (BEP) and binge eating resistant (BER) phenotypes, we previously showed that, compared with males, females consume more PF and are more likely to be classified as BEP. One potential explanation for this sex difference is that PF is inherently more rewarding to females, leading to higher rates of binge eating. Here we tested the hypothesis that females have more robust behavioral and neural responses to PF reward than males. Adult male (N = 18) and female (N = 17) Sprague-Dawley rats were exposed to the Conditioned Place Preference paradigm using PF as the unconditioned stimulus. Select males (N = 9) and females (N = 9) were video-recorded during three of the PF-paired conditioning sessions to score feeding behavior. Following CPP, 13 male and 12 female rats were exposed to PF just prior to sacrifice to induce expression of the neural activation marker Fos, and Fos expression was quantified in mesocorticolimbic, hypothalamic, and amygdalar circuits. In the CPP paradigm, females displayed a more robust shift in preference for the chamber paired with PF compared with males, and behavioral analyses revealed that average duration of individual feeding bouts during pairing sessions was longer in females than in males. Fos expression was significantly higher in females vs. males in select regions of the mesocorticolimbic reward circuit, with no sex differences in hypothalamic or amygdalar regions. These results provide initial evidence that PF may be more rewarding to females than to males, possibly due to heightened responsiveness of neural substrates that mediate the hedonic and motivational responses to PF, which in part, may underlie sex differences in binge eating proneness.

Introduction

The female bias in eating disorder (ED) prevalence is the most robust sex difference in all of psychiatry, with women being up to ten times as likely as men to suffer from an ED [1], [2], [3], [4], [5]. A core maladaptive symptom that cuts across all major types of EDs (e.g., bulimia nervosa, binge eating disorder, anorexia nervosa binge/purge subtype) is binge eating, defined as the consumption of a large amount of food (typically palatable food, PF) in a short period of time and accompanied by lack of control over food intake [6]. Even in community-based samples, binge eating is 2–4 times more prevalent in females than in males (reviewed in [7]). Traditionally, most research on the etiology of EDs and binge eating has focused on psychosocial factors (i.e., drive for thinness, body dissatisfaction, low self-esteem [8], [9]), but there is increasing evidence that biological variables also play a role. While it is difficult to disentangle psychosocial from biological contributions to sex differences in binge eating in humans, preclinical animal models of binge eating offer promise for discovery of biological mechanisms because critical psychosocial risk factors for EDs are absent in these models.

While binge eating has been widely studied in several different rodent models (reviewed in [10]), only a handful of studies has considered sex as a biological variable. Nevertheless, these studies collectively provide strong evidence for a female bias in binge eating in rodents similar to that seen in humans. Female rodents consume more PF than males [11], [12], more rapidly escalate their PF consumption when provided intermittent access to PF [13], [14], and under several different conditions, are more likely than males to engage in binge eating-like episodes of PF consumption [11], [12], [15]. Using a rat model of individual differences in binge eating that identifies extreme binge eating prone (BEP) and binge eating resistant (BER) phenotypes, our group has also found that females are 2–6 times more likely than males to meet criteria for classification as BEP [11]. Thus, the neural circuits that drive PF consumption and binge eating must be different in females and males, but currently we have very little scientific understanding of these differences.

Converging lines of evidence point to sex differences in the processing of reward as one neural mechanism underlying sex differences in binge eating. PFs strongly activate the mesocorticolimbic reward circuit much to the same degree as do drugs of abuse [16], [17], and both pre-clinical and clinical research has demonstrated that females are more sensitive to drugs of abuse than males. In rodent models, female rats acquire drug self-administration more quickly [18] and work harder to obtain drugs than male rats [19]. Clinically, women self-report greater pleasure during drug consumption and succumb to addiction more rapidly as compared to men [20]. Collectively, these data suggest higher mesocorticolimbic reward circuit responsiveness to drugs of abuse in females, and they highlight a potential mechanism that may translate to sex differences in the neural response to PF reward as well. To date, two studies have reported that female rats are more motivated than males to work for sucrose (i.e., females have a higher breakpoint in a progressive ratio schedule of reinforcement [14], [21]), yet no studies in rodent models have directly investigated whether PF is more rewarding to females than to males, or whether neural activation patterns in response to PF differ between males and females.

The aim of the current study was therefore to determine whether behavioral and neural responses to PF reward differ in male and female rats as a first approach towards identifying mechanisms that may drive sex differences in binge eating [11]. First, we employed the conditioned place preference (CPP) paradigm, using PF as the unconditioned stimulus, to determine whether the inherent, rewarding properties of PF (i.e., the tendency to form a CPP for PF) differ between the two sexes. Second, we determined whether neural responsiveness to PF reward differs between males and females by quantifying the expression of the neural activation marker Fos in mesocorticolimbic, hypothalamic, and amygdalar brain regions [22], [23]. We hypothesized that females would show 1) a more robust place preference for PF, and 2) higher neural activation during PF intake, specifically within the mesocorticolimbic reward circuit. Such outcomes would suggest that females respond more strongly to the hedonic, rewarding properties of PF, and that sex differences in mesocorticolimbic responsiveness to PF may underlie the female bias in binge eating risk and prevalence.