α4-GABAA receptors of hippocampal pyramidal neurons are associated with resilience against activity-based anorexia for adolescent female mice but not for males

Abstract

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 α4βδ-GABAR expression. C57BL6/J WT and α4-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. α4βδ-GABAR 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 α4βδ-GABARs at plasma membranes of dorsal hippocampal pyramidal cells of females, and especially those females exhibiting resilience. Conversely, α4-KO females exhibited greater food restriction-evoked hyperactivity than WT females. In contrast, ABA males did not up-regulate α4βδ-GABARs, did not exhibit genotype differences in vulnerability, and exhibited no correlation between plasmalemmal α4βδ-GABARs and ABA resilience. Thus, food restriction-evoked hyperactivity is driven by anxiety but can be suppressed through upregulation of hippocampal α4βδ-GABARs for females but not for males. This knowledge of sex-related differences in the underlying mechanisms of resilience to ABA indicates that drugs targeting α4βδ-GABARs may be helpful for treating stress-induced anxiety and anorexia nervosa of females but not males.

Hippocampal volumes in anorexia nervosa at different stages of the disorder

“…This observation suggests that hippocampal volume may be a sensitive marker of disorder-specific alterations, but, in contrast to what is observed in other psychiatric conditions, it does not seem to be a useful marker of neuroprogression in AN. Data on the rodent model of AN (Farinetti et al, 2020) are suggestive of early involvement of the hippocampus in starvation, in keeping with studies of the Center for Neural Science of the New York University (Aoki et al, 2018;Chen, Actor-Engel, & Aoki, 2018) that highlighted the crucial role of this brain area in modulating the ABA model-induced anxiety.…”

“…Data on the rodent model of AN (Farinetti et al, 2020) are suggestive of early involvement of the hippocampus in starvation, in keeping with studies of the Center for Neural Science of the New York University (Aoki et al, 2018; Chen, Actor‐Engel, & Aoki, 2018) that highlighted the crucial role of this brain area in modulating the ABA model‐induced anxiety.…”

Food restriction engages prefrontal corticostriatal cells and local microcircuitry to drive the decision to run vs conserve energy

“…Thus, C21 delivery specifically increases FAA running during FR, but has no effect on running in general, when food is freely available. DREADD-driven effects observed during FAA of FR2 were no longer present during FAA of FR3, 18 hrs after the last ligand delivery (vs CON; for distance: t(23) = 1.208, p = 0.239, unpaired t-test; for duration: t(23) = 1.097, p = 0.284, unpaired t-test).As previously reported(Chen YW, H Actor-Engel, et al 2018), running distance and duration decreased dramatically for all animals following transition from FAA hours to feeding time (7pm-9pm). Delivery of C21 on FR2 had no further effect on feeding time (7pm -9pm) running distance (t(19) = 0.508, p = 0.617, unpaired t-test) or duration (t(7.694) = 0.540, p = 0.604, Welch's t-test; Fig.2A), compared to CON subjects.…”

Animal Models for Anorexia Nervosa—A Systematic Review

“…The research group of Chen et al examined gender-specific vulnerability to ABA in mice (Chen et al, 2018 ). ABA led to an overall suppression of wheel running (compared to baseline) but there was a sex-specific effect: suppression of wheel running occurred during the food-anticipatory hours in males, while in females suppression was observed during food-access hours.…”

“…ABA led to an overall suppression of wheel running (compared to baseline) but there was a sex-specific effect: suppression of wheel running occurred during the food-anticipatory hours in males, while in females suppression was observed during food-access hours. Correspondingly, only females adaptively increased food intake (Chen et al, 2018 ). Another study reported that rats with the highest body weight loss had the lowest level of food-anticipatory activity (running in the wheel during the time period of 4 h before feeding) and that postprandial activities are more directly predictive of weight loss (Wu et al, 2014 ).…”