Activity-Based Anorexia Dynamically Dysregulates the Glutamatergic Synapse in the Nucleus Accumbens of Female Adolescent Rats

Abstract

Intense physical activity and dieting are core symptoms of anorexia nervosa (AN). Their combination evolves into compulsivity, leading the patient into an out-of-control spiral. AN patients exhibit an altered activation of nucleus accumbens (NAc), revealing a dysfunctional mesocorticolimbic reward circuitry in AN. Since evidence exists that a dysregulation of the glutamate system in the NAc influences reward and taking advantage of the activity-based anorexia (ABA) rat model, which closely mimics the hallmarks of AN, we investigated the involvement of the glutamatergic signaling in the NAc in this experimental model. We here demonstrate that food restriction causes hyperactive and compulsive behavior in rodents, inducing an escalation of physical activity, which results in dramatic weight loss. Analysis of the glutamate system revealed that, in the acute phase of the pathology, ABA rats increased the membrane expression of GluA1 AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor subunits together with its scaffolding protein SAP97. Recovery of body weight reduced GluN2A/2B balance together with the expression of their specific scaffolding proteins, thus suggesting persistent maladaptive neurotransmission. Taken together, AMPA and NMDA (N-methyl-D-aspartate) receptor subunit reorganization may play a role in the motivational mechanisms underlying AN.

Is the Activity-Based Anorexia Model a Reliable Method of Presenting Peripheral Clinical Features of Anorexia Nervosa?

“…And those patients do not adequately respond to homeostatic body signals such as appetite regulating peptides that should trigger weight restoration [ 46 ]. The central aspects related to AN etiopathogenesis (for a review see, Skowron et al 2020) [ 11 ] are beyond the scope of this article; however, it should be noted that research using animal models, including the ABA model, has contributed immensely to the understanding of potential brain mechanisms that many underlie the causes and consequences of aberrant eating behaviors [ 48 , 49 , 50 ].…”

The Role of Glial Cells in Regulating Feeding Behavior: Potential Relevance to Anorexia Nervosa

“…However, since mGluR5 expression is not restricted to astrocytes but also found in neurons [ 49 ], it remains to be clarified whether these observations are specific to astrocytes although several hints suggest that glutamatergic gliotransmission plays a role in food intake control. Additionally, changes in glutamatergic signaling in an experimental ABA animal model were found: The expression of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunits GluA1, which mediates together with other subunits synaptic transmission, is enhanced in the nucleus accumbens potentially due to a disturbed mesocorticolimbic reward circuitry [ 50 ]. A recently published study using the same model showed that the increase in running wheel behavior correlates negatively with GLT-1 levels in the hippocampus indicating GLT-1 enhancement may counteract the severity of AN [ 51 ].…”

Cortical reorganization of the glutamate synapse in the activity‐based anorexia rat model: Impact on cognition

“…Evidence exists, in both AN patients and animal models, that maladaptive reorganization of the mesocorticolimbic structures may represent the neurobiological underpinning of the motivational mechanisms underlying AN phenotype (Foldi et al, 2017; Frank et al, 2018; Ho et al, 2016). In this scenario, it is possible to hypothesize that dysfunctions of glutamate homeostasis, which has been proposed as a signal of altered processing of food reward (Mottarlini et al, 2020; Murray & Holton, 2021; Ohrmann et al, 2004), may contribute to the anorexic phenotype. This possibility is supported by a recent pilot study at 7 Tesla, in which Godlewska and coworkers found that glutamate levels were diminished in the occipital cortex of AN patients, anterior cingulate cortex, and putamen, whereas the ratio of glutamine to glutamate was significantly increased, suggesting a hypoglutamatergic transmission in AN (Godlewska et al, 2017).…”