Exploring reward system responsivity in the nucleus accumbens across chronicity of binge eating in female rats.

OBJECTIVE: Research has highlighted the importance of reward-based processes in binge eating (BE). However, both increased and decreased activation have been observed in reward related brain regions for BE. Differences may be similar to addiction research, where the reward system is initially hyper-responsive at early stages of use, but becomes hypo-responsive with prolonged drug/alcohol use. This study was the first to examine differences in reward system responsivity at early versus chronic BE stages. METHOD: Using an animal model, Sprague-Dawley female rats were identified as BE prone (BEP) or BE resistant (BER) and randomly assigned to an early or chronic stage group. Neural activation (via Fos protein) was quantified in the nucleus accumbens core (NAC) and shell (NAS). RESULTS: Early stage BEP rats had the highest levels of Fos expression of all of the study groups. By contrast, chronic stage BEP rats exhibited decreased activation in the NAS and NAC that was similar to the activation in chronic stage BER rats. DISCUSSION: Findings are significant in suggesting hyper-neural activation to reward in the early stages of BE and decreased activation in later stages of BE. Additional studies are needed to elucidate how these differences may impact risk for and maintenance of BE.

Relating applied strain to the type and severity of structural damage in the rat median nerve using second harmonic generation microscopy.

INTRODUCTION: Stretch injuries in peripheral nerves can cause pain, paralysis, and loss of sensation. Although optimal treatment depends on the degree of injury, it is difficult to determine the severity of induced nerve damage. METHODS: The load-deformation curves of rat median nerves were generated from monotonic load-to-failure experiments to determine low, medium, and high strain levels. Additional excised median nerves were then elongated to induce damage at low (4%), medium (10% and 12%), and high (14% and 20%) tensile strains and the resulting structural damage was evaluated using second harmonic generation (SHG) imaging and light microscopy. RESULTS: No substantial structural changes occurred at 4% strain, but higher strain values resulted in disruption of the normal collagen architecture. CONCLUSIONS: The results demonstrate a spectrum of structural damage that can be monitored using SHG, a non-destructive imaging modality, and that the pattern of damage may correspond to functional deficit.

The effects of puberty and ovarian hormone removal on developmental trajectories of palatable food and chow intake in female rats.

OBJECTIVE: Palatable food (PF) intake is significantly greater in females than males and increases during adolescence. Previous data suggest that puberty and ovarian hormones may contribute to these sex and developmental differences, but few studies have examined this possibility. The aim of the current study was to address these gaps by examining trajectories of PF and chow intake during pre-puberty, puberty, and adulthood in intact female rats (Study 1) as well as in those receiving pre-pubertal ovariectomies (P-OVX) (Study 2). METHOD: We examined our study aims using archival data from 66 intact Sprague-Dawley female rats (Study 1) and 77 P-OVX and 79 intact Sprague-Dawley female rats (Study 2). PF and chow intake were measured using a free-choice, intermittent exposure paradigm in which rats were exposed to both food types starting in pre-puberty and continuing into adulthood. RESULTS: Mixed linear models revealed a specific effect of puberty on PF intake in both studies. PF intake increased substantially during puberty in all rats, but increases were particularly pronounced in P-OVX rats in Study 2. By contrast, chow intake increased significantly during pre-puberty (rather than puberty) in both studies, and these increases were relatively unaffected by P-OVX. DISCUSSION: Findings confirm a specific effect of puberty and ovarian hormone removal on PF intake in female rats. Differential trajectories of PF versus chow intake highlight potential reward-based processes in pubertal and ovarian hormone effects on PF intake in females.

The Disruptive Effects of Estrogen Removal before Puberty on Risk for Binge Eating in Female Rats.

Recent research suggests that estrogen is protective against binge eating in adult females, and that pubertal estrogen may be critical for these effects. Nonetheless, to date, no study has examined the role of pubertal estrogen in adult binge eating phenotypes in females, potentially due to difficulties experimentally manipulating estrogen in humans to examine causal effects. We used a novel animal model to examine whether estrogen removal prior to puberty (via pre-pubertal ovariectomy (P-OVX)) increases rates of binge eating prone (BEP) phenotypes in adulthood in females. A total of 77 P-OVX and 79 intact rats were followed from pre-puberty into adulthood and phenotyped for BEP status in adulthood. Results showed significantly increased rates (~2-8x higher) of adult BEP phenotypes in P-OVX as compared to intact rats. Findings confirm that estrogen removal substantially increases later risk for binge eating in females, potentially by disrupting typical adolescent brain development.

Reduced Medial Prefrontal Control of Palatable Food Consumption Is Associated With Binge Eating Proneness in Female Rats.

Binge eating is the core, maladaptive eating behavior that cuts across several major types of eating disorders. Binge eating is associated with a significant loss of control over palatable food (PF) intake, and deficits in behavioral control mechanisms, subserved by the prefrontal cortex (PFC), may underlie binge eating. Few studies, to date, have examined whether the PFC is directly involved in the expression of binge eating. As such, the present study investigated the functional role of the medial PFC (mPFC) in PF consumption, using an individual differences rat model of binge eating proneness. Here, we tested the hypothesis that binge eating proneness (i.e., high levels of PF consumption) is associated with reduced mPFC-mediated behavioral control over PF intake. In experiment 1, we quantified PF-induced Fos expression in both excitatory and inhibitory neurons within the mPFC in binge eating prone (BEP) and binge eating resistant (BER) female rats. In experiment 2, we pharmacologically inactivated the mPFC of BEP and BER female rats, just prior to PF exposure, and subsequently quantified PF intake and scores of feeding behavior. While most Fos-expressing neurons of the mPFC in both BEPs and BERs were of the excitatory phenotype, fewer excitatory neurons were engaged by PF in BEPs than in BERs. Moreover, pharmacological inactivation of the mPFC led to a significant increase in PF intake in both BEPs and BERs, but the rise in PF consumption was stronger in BEPs than in BERs. Thus, these data suggest that lower, PF-induced excitatory tone in the mPFC of BEP rats may lead to a weaker, mPFC-mediated behavioral "brake" over excessive PF intake.

Detecting structural and inflammatory response after in vivo stretch injury in the rat median nerve via second harmonic generation.

BACKGROUND: Second Harmonic Generation (SHG) microscopy is a promising method for visualizing the collagenous structure of peripheral nerves. Assessing collagen continuity and damage after a stretch injury provides inferential insight into the level of axonal damage present. NEW METHODS: This study utilizes SHG microscopy after a calibrated in vivo stretch injury of rat median nerves to evaluate collagen continuity at several time points throughout the recovery process. Endoneurial collagen was qualitatively assessed in nerves that were subjected to low strain (LS) and high strain (HS) injuries using SHG microscopy, conventional histology, and immunohistochemistry. RESULTS: Following an in vivo stretch injury, both LS and HS damaged nerves exhibit signs of structural collagen damage in comparison with sham control nerves (SC). Furthermore, LS nerves exhibit signs of full regeneration while HS nerves exhibited signs of only partial regeneration with lasting damage and intra-neural scar formation. COMPARISON WITH EXISTING METHODS: SHG observations of structural changes and inflammatory response due to stretch injury were validated upon comparison with conventional histological methods CONCLUSIONS: We propose that SHG microscopy can be utilized to visualize significant structural artifacts in sectioned median nerves following in vivo stretch injury. Based on the findings in this study, we believe that the in vivo application of SHG microscopy should be further investigated as a means for real-time, intra-operative, quantitative assessment of nerve damage.

Perinatal testosterone contributes to mid-to-post pubertal sex differences in risk for binge eating in male and female rats.

Exposure to testosterone early in life may contribute to sex differences and pubertal changes in risk for eating pathology (i.e., females > males, after pubertal onset). Specifically, perinatal testosterone permanently alters brain structure/function and drives the masculinization of several sex-differentiated behaviors. However, the effects of perinatal testosterone are often not evident until puberty when increases in gonadal hormones activate the expression of sex typical behavior, including eating behaviors (e.g., chow intake; saccharin preference) in rodents. Despite perinatal testosterone's masculinizing effects on general feeding behavior, it remains unknown if perinatal testosterone exposure contributes to sex differences in pathological eating. The current study addressed this gap by examining whether perinatal testosterone exposure decreases risk for binge eating proneness after pubertal onset in male and female rats. Sprague-Dawley rats (n = 40 oil-treated control females; n = 39 testosterone-treated females; n = 40 oil-treated control males) were followed longitudinally across pre-to-early puberty, mid-to-late puberty, and adulthood. The binge eating prone (BEP)/binge eating resistant (BER) rodent model was used to identify individual differences in binge eating proneness across the dimensional spectrum. As expected, testosterone-treated females and control males showed masculinized (i.e., lower) risk for binge eating as compared to control females, but only after midpuberty. These animal data are significant in suggesting that perinatal testosterone exposure may protect against binge eating and underlie sex differences in binge eating prevalence during and after puberty. (PsycINFO Database Record

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

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.

Differential mesocorticolimbic responses to palatable food in binge eating prone and binge eating resistant female rats.

Binge eating is a key symptom of many eating disorders (e.g. binge eating disorder, bulimia nervosa, anorexia nervosa binge/purge type), yet the neurobiological underpinnings of binge eating are poorly understood. The mesocorticolimbic reward circuit, including the nucleus accumbens and the medial prefrontal cortex, is likely involved because this circuit mediates the hedonic value and incentive salience of palatable foods (PF). Here we tested the hypothesis that higher propensity for binge eating is associated with a heightened response (i.e., Fos induction) of the nucleus accumbens and medial prefrontal cortex to PF, using an animal model that identifies binge eating prone (BEP) and binge eating resistant (BER) rats. Forty adult female Sprague-Dawley rats were given intermittent access to PF (high fat pellets) 3×/week for 3 weeks. Based on a pattern of either consistently high or consistently low PF consumption across these feeding tests, 8 rats met criteria for categorization as BEP, and 11 rats met criteria for categorization as BER. One week after the final feeding test, BEP and BER rats were either exposed to PF in their home cages or were given no PF in their home cages for 1h prior to perfusion, leading to three experimental groups for the Fos analysis: BEPs given PF, BERs given PF, and a No PF control group. The total number of Fos-immunoreactive (Fos-ir) cells in the nucleus accumbens core and shell, and the cingulate, prelimbic, and infralimbic regions of the medial prefrontal cortex was estimated by stereological analysis. PF induced higher Fos expression in the nucleus accumbens shell and core and in the prelimbic and infralimbic cortex of BEP rats compared to No PF controls. Throughout the nucleus accumbens and medial prefrontal cortex, PF induced higher Fos expression in BEP than in BER rats, even after adjusting for differences in PF intake. Differences in the neural activation pattern between BEP and BER rats were more robust in prefrontal cortex than in nucleus accumbens. These data confirm that PF activates brain regions responsible for encoding the incentive salience and hedonic properties of PF, and suggest that binge eating proneness is associated with enhanced responses to PF in brain regions that exert executive control over food reward.