Synaptic changes in the hippocampus of adolescent female rodents associated with resilience to anxiety and suppression of food restriction-evoked hyperactivity in an animal model for anorexia nervosa

Abstract

Anorexia nervosa is a mental illness that emerges primarily during early adolescence, with mortality rate that is 200 times higher than that of suicide. The illness is characterized by intense fear of gaining weight, heightened anxiety, obstinate food restriction, often accompanied by excessive exercise, in spite of mounting hunger. The illness affects females nine times more often than males, suggesting an endocrine role in its etiology. Its relapse rate exceeds 25%, yet there are no accepted pharmacological treatments to prevent this. Here, I summarize studies from this laboratory that have used adolescent female rodents in activity-based anorexia (ABA), an animal model of anorexia nervosa, with the goal of identifying neurobiological underpinnings of this disease. We put forth a hypothesis that a GABAergic mechanism within the hippocampus is central to regulating an individual’s anxiety which, in turn, strongly influences the individual’s resilience/vulnerability to ABA. In particular, we propose that ionotropic GABAA receptors containing the subunits alpha4 and delta, are at play for exerting shunting inhibition upon hippocampal pyramidal neurons that become more excitable during ABA. Since these receptors confer insensitivity to benzodiazepines, this pharmacological profile of ABA fits with lack of report indicating efficacy of benzodiazepines in reducing the anxiety experienced by individuals with anorexia nervosa. The idea that the GABAergic system of the hippocampus regulates resilience/vulnerability to anorexia nervosa complements current opinions about the important roles of the prefrontal cortex, amygdala, striatum, gustatory pathways and feeding centers of the hypothalamus and of the neuromodulators, serotonin and dopamine, in the etiology of the disease.

NR2A- and NR2B-NMDA receptors and drebrin within postsynaptic spines of the hippocampus correlate with hunger-evoked exercise

“…The rise of pre- and postsynaptic NMDARs could facilitate LTP (long-term potentiation), learning, and memory, often associated more with the rise of NR2A-NMDARs than of NR2B-NMDARs (Liu et al 2004; Massey et al 2004). Supporting this prediction, other cohorts of adolescent female rats that underwent identical ABA and food-restriction-alone treatments exhibited faster acquisition of spatial memory, relative to the CON animals, after recovering from ABA for a week (Aoki et al 2016; Chowdhury et al 2014b). Consistent with this idea, individuals diagnosed with AN are often characterized to be perfectionists, high achievers, and goal-oriented (Kaye et al 2009; Bachner-Melman et al 2007; Sundquist et al 2016; Dura and Bornstein 1989; Beals 2004).…”

“…When these two environmental factors are applied simultaneously, a rat's voluntary wheel running increases dramatically (Aoki et al 2016). This food-restriction-evoked hyperactivity, termed activity-based anorexia (ABA), has been used as an animal model for AN (Guisinger 2003; Casper et al 2008; Gutierrez 2013).…”

Single injection of ketamine during mid‐adolescence promotes long‐lasting resilience to activity‐based anorexia of female mice by increasing food intake and attenuating hyperactivity as well as anxiety‐like behavior

“…The dorsal and ventral hippocampus of adolescent females that have undergone ABA exhibit significant morphological and molecular changes (Aoki, Chowdhury, Wable, & Chen, 2017). Ventral hippocampus is crucial for regulating anxiety responses (Bannerman et al, 2003;Jimenez et al, 2018).…”

α4βδ‐GABAA receptors in dorsal hippocampal CA1 of adolescent female rats traffic to the plasma membrane of dendritic spines following voluntary exercise and contribute to protection of animals from activity‐based anorexia through localization at excitatory synapses

“…Previous work from this lab showed that an animal model of anorexia nervosa, called activity‐based anorexia (ABA), also evokes increased expression of α4βδ‐GABA A Rs at excitatory synapses of stratum radiatum of the dorsal hippocampus of adolescent female rats (Aoki et al, ) and mice (Wable et al, ). ABA is an animal model that captures three hallmarks of anorexia nervosa: elevated anxiety (Wable et al, ), excessive exercise, and voluntary food restriction (reviewed in Aoki et al, ). ABA is induced in animals by combining restricted food access with free access to a running wheel.…”