Activity‐based anorexia disrupts systemic oxidative state and induces cortical mitochondrial fission in adolescent female rats

Hurley, Matthew M.; Murlanova, Kateryna; Macias, Lindsey K.; Sabir, Aliasgher I.; O'Brien, S; Bhasin, Harshit; Tamashiro, Kellie L.K.; Pletnikov, Mikhail V.; Moran, Timothy H.

doi:10.1002/eat.23453

Cited by 9 publications

(7 citation statements)

References 22 publications

(23 reference statements)

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“…We have previously shown that pathological weight loss does not occur in all rats exposed to ABA conditions, and in fact a subpopulation of rats remains resistant to weight loss when exposed to the same experimental conditions (Milton et al, 2018). These susceptible and resistant subpopulations have been replicated in other studies investigating the neurobiology of AN in ABA rats (Hurley, Murlanova, et al, 2021) and mice (Beeler et al, 2020), supporting the use of the ABA model for examining predictors of pathological weight loss.…”

Section: Introductionmentioning

confidence: 55%

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

Milton

Patton

O’Keeffe

et al. 2022

Intl J Eating Disorders

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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.

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Section: Introductionmentioning

confidence: 55%

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

Milton

Patton

O’Keeffe

et al. 2022

Intl J Eating Disorders

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“…These studies demonstrate that, like in patients with AN, ABA rodents have decreased brain volume that is reversed by re-feeding [ 11 – 14 , 15 •]. Weight loss is also associated with increased markers of oxidative stress in the prefrontal cortex that is reversed by weight restoration [ 16 ]. The ABA model provided new insights into the impact of AN on the brain by identifying reductions in astrocyte number and proliferation in the cerebral cortex without a change in neuronal number [ 15 •].…”

Section: Aba Paradigm: Classical Approachesmentioning

confidence: 99%

Rethinking the Approach to Preclinical Models of Anorexia Nervosa

François

Zeltser

2022

Curr Psychiatry Rep

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Purpose of Review The goal of this review is to describe how emerging technological developments in pre-clinical animal research can be harnessed to accelerate research in anorexia nervosa (AN). Recent Findings The activity-based anorexia (ABA) paradigm, the best characterized animal model of AN, combines restricted feeding, excessive exercise, and weight loss. A growing body of evidence supports the idea that pathophysiological weight loss in this model is due to cognitive inflexibility, a clinical feature of AN. Targeted manipulations that recapitulate brain changes reported in AN — hyperdopaminergia or hyperactivity of cortical inputs to the nucleus accumbens — exacerbate weight loss in the ABA paradigm, providing the first evidence of causality. Summary The power of preclinical research lies in the ability to assess the consequences of targeted manipulations of neuronal circuits that have been implicated in clinical research. Additional paradigms are needed to capture other features of AN that are not seen in ABA.

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“…We have previously shown that pathological weight loss does not occur in all rats exposed to ABA conditions, and in fact a subpopulation of adolescent female Sprague-Dawley rats remain resistant to weight loss, even when exposed to the same experimental conditions [41]. These susceptible and resistant subpopulations have been replicated in other studies investigating the neurobiology of AN in ABA rats [42] and mice [43], supporting the use of the ABA model for examining behavioural and immune phenotypes that predispose animals to pathological weight loss.…”

Section: Introductionmentioning

confidence: 61%

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

Milton

Patton

O’Keeffe

et al. 2021

Preprint

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Anorexia nervosa (AN) has high rates of mortality and low rates of recovery, with outcomes that worsen with illness duration. Improved early intervention strategies are required and identifying risk factors that contribute to the development of AN is critical to their implementation. The development of AN often follows a pre-existing diagnosis of anxiety disorders and obsessive-compulsive disorder and substantial genetic overlap between these conditions suggest common underlying features may predict vulnerability to AN. Moreover, patients with AN have increased levels of circulating proinflammatory cytokines, which may be involved in susceptibility to pathological weight loss considering that children with immune dysfunction have a higher risk of subsequent AN diagnoses. Here, we used the activity-based anorexia (ABA) model to examine whether baseline levels of locomotion, anxiety-like behaviour, compulsive behaviour, and circulating immune markers predict the subsequent development of pathological weight loss in adolescent female rats. While none of these primary features were shown to differentiate rats that went on to be susceptible or resistant to weight loss in ABA, increased locomotion and anxiety-like behaviour were both associated with the extent of weight loss in susceptible but not resistant animals. Intriguingly, behaviour related to poor decision-making in a situation of conflict was shown to predict vulnerability to ABA. Future research using the ABA model to uncover early predictors of AN should focus on translationally relevant assays of decision-making and cognitive behaviour, dysfunction of which may not only predispose animals to ABA but may also represent an endophenotype linking anorectic, anxiety-like and compulsive behaviour.

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Activity‐based anorexia disrupts systemic oxidative state and induces cortical mitochondrial fission in adolescent female rats

Cited by 9 publications

References 22 publications

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

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

Rethinking the Approach to Preclinical Models of Anorexia Nervosa

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

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