Dataset Information

In pursuit of biomarkers for predicting susceptibility to activity-based anorexia in adolescent female rats.

ABSTRACT:

Objective

Identifying risk factors that contribute to the development of anorexia nervosa (AN) is critical for the implementation of early intervention strategies. Anxiety, obsessive-compulsive behavior, and immune dysfunction may be involved in the development of AN; however, their direct influence on susceptibility to the condition remains unclear. Here, we used the activity-based anorexia (ABA) model to examine whether activity, anxiety-like behavior, compulsive behavior, and circulating immune markers predict the subsequent development of pathological weight loss.

Method

Female Sprague-Dawley rats (n = 44) underwent behavioral testing before exposure to ABA conditions after which they were separated into susceptible and resistant subpopulations. Blood was sampled before behavioral testing and after recovery from ABA to screen for proinflammatory cytokines.

Results

Rats that were vulnerable to pathological weight loss differed significantly from resistant rats on all key ABA parameters. While the primary measures of anxiety-like or compulsive behavior were not shown to predict vulnerability to ABA, increased locomotion and anxiety-like behavior were both associated with the extent of weight loss in susceptible but not resistant animals. Moreover, the change in expression of proinflammatory markers IL-4 and IL-6 evoked by ABA was associated with discrete vulnerability factors. Intriguingly, behavior related to risk assessment was shown to predict vulnerability to ABA.

Discussion

We did not find undisputable behavioral or immune predictors of susceptibility to pathological weight loss in the ABA rat model. Future research should examine the role of cognition in the development of ABA, dysfunction of which may represent an endophenotype linking anorectic, anxiety-like and compulsive behavior.

Public significance

Anorexia nervosa (AN) has among the highest mortality rates of all psychiatric disorders and treatment options remain limited in their efficacy. Understanding what types of risk factors contribute to the development of AN is essential for implementing early intervention strategies. This study describes how some of the most common psychological features of AN could be used to predict susceptibility to pathological weight loss in a well-established animal model.

SUBMITTER: Milton LK

PROVIDER: S-EPMC9311799 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Activity-based anorexia (ABA) is an animal model of anorexia nervosa, a mental illness with highest mortality and with onset that is most frequently during adolescence. We questioned whether vulnerability of adolescent mice to ABA differs between sexes and whether individual differences in resilience are causally linked to ?4??-GABAAR expression. C57BL6/J WT and ?4-KO adolescent male and female mice underwent ABA induction by combining wheel access with food restriction. ABA vulnerability was measured as the extent of food restriction-evoked hyperactivity on a running wheel and body weight losses. ?4??-GABAAR levels at plasma membranes of pyramidal cells in dorsal hippocampus were assessed by electron microscopic immunocytochemistry. Temporal patterns and extent of weight loss during ABA induction were similar between sexes. Both sexes also exhibited individual differences in ABA vulnerability. Correlation analyses revealed that, for both sexes, body weight changes precede and thus are likely to drive suppression of wheel running. However, the suppression was during the food-anticipatory hours for males, while for females, suppression was delayed by a day and during food-access hours. Correspondingly, only females adaptively increased food intake. ABA induced up-regulation of ?4??-GABAARs at plasma membranes of dorsal hippocampal pyramidal cells of females, and especially those females exhibiting resilience. Conversely, ?4-KO females exhibited greater food restriction-evoked hyperactivity than WT females. In contrast, ABA males did not up-regulate ?4??-GABAARs, did not exhibit genotype differences in vulnerability, and exhibited no correlation between plasmalemmal ?4??-GABAARs and ABA resilience. Thus, food restriction-evoked hyperactivity is driven by anxiety but can be suppressed through upregulation of hippocampal ?4??-GABAARs for females but not for males. This knowledge of sex-related differences in the underlying mechanisms of resilience to ABA indicates that drugs targeting ?4??-GABAARs may be helpful for treating stress-induced anxiety and anorexia nervosa of females but not males.