The Utility of Animal Models for Studying the Metabo-Psychiatric Origins of Anorexia Nervosa

Abstract

Anorexia nervosa (AN) is a severe eating disorder that primarily affects young women and girls, and is characterized by abnormal restrictive feeding and a dangerously low body-mass index. AN has one of the highest mortality rates of any psychiatric disorder, and no approved pharmacological treatments exist. Current psychological and behavioral treatments are largely ineffective, and relapse is common. Relatively little basic research has examined biological mechanisms that underlie AN compared to other major neuropsychiatric disorders. A recent large-scale genome-wide association study (GWAS) revealed that the genetic architecture of AN has strong metabolic as well as psychiatric origins, suggesting that AN should be reconceptualized as a metabo-psychiatric disorder. Therefore, identifying the metabo-psychiatric mechanisms that contribute to AN may be essential for developing effective treatments. This review focuses on animal models for studying the metabo-psychiatric mechanisms that may contribute to AN, with a focus on the activity-based anorexia (ABA) paradigm. We also highlight recent work using modern circuit-dissecting neuroscience techniques to uncover metabolic mechanisms that regulate ABA, and encourage further work to ultimately identify novel treatment strategies for AN.

Long-lasting BDNF signaling alterations in the amygdala of adolescent female rats exposed to the activity-based anorexia model

“…As previously published, the ABA model, i.e., the combination of caloric restriction and physical exercise, induces a food-restriction-evoked hyperactivity thus generating a severe weight loss that, in turn, induces a cycle of self-motivating and compulsive habits promoting hyperactive behaviors despite the severe emaciation (Gutierrez, 2013 ; Spadini et al, 2021 ; Zhang and Dulawa, 2021 ). In fact, the body weight loss of ABA rodents was much greater than the body weight loss of animals exposed to food restriction only, which was also accompanied by an exponential increase in physical activity within 48 h from the beginning of the caloric restriction.…”

Reduced GABA transmission onto ventral tegmental area dopamine neurons underlies vulnerability for hyperactivity in a mouse model of Anorexia Nervosa

“…The ABA paradigm is a well-established rodent model of AN [23, 56] and the development of FAA is a hallmark and intriguing phenomenon. We hypothesized that FAA, and more generally hyperlocomotion, could occur because of an urge to exercise originating from alterations of VTA neuronal activity.…”

“…DA transmission in the ventral tegmental area (VTA) is involved in energy homeostasis by regulating both exercise and feeding behaviors [17][18][19][20][21][22]. The activity-based anorexia (ABA) model is typically used to better understand the neurobiology of AN and evaluate potential treatment targets (for review see [23,24]). Studies using the ABA model have shown that manipulation of dopamine transmission facilitates the development of behaviors that resemble AN symptoms, such as excessive exercise and weight loss, supporting the role of altered DA neuron activity in hyperactivity (for review see [25]).…”

Central extended amygdala neurons in the development of activity-based anorexia

“…Although functional alterations of brain regions associated with AN have been observed in human neuroimaging studies 31–33 , details of neural mechanisms that might cause AN are still being uncovered. Studies exploring these underlying neural processes often use the ABA animal model, which demonstrates three major characteristics leading to the development of anorexia: life-threatening decrease in body weight, reduced food intake, and increased physical activity 13,14,18,33 . The increased running wheel activity, in particular, has been established as a robust predictor for the susceptibility of ABA 25 .…”

“…These studies— combined with known amygdala hyperreactivity in human AN—support the plausibility that neural circuits involving EAc PKC-δ neurons contribute to mechanisms underlying AN development. Thus, the current study investigates how this particular subpopulation of neurons in the CeA and ovBNST may regulate the development AN using the currently best animal model of AN, activity-based anorexia (ABA), in which rodents develop life-threatening self-starvation and hyperactivity tendencies when exposed to a restricted feeding schedule in combination with ad libitum access to a running wheel 12–14 .…”