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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. Unders

Much progress has been made during the past 30 years with respect to elucidating the neural and endocrine pathways by which bodily needs for water and energy are brought to conscious awareness through the generation of thirst and hunger. One way that circulating hormones influence thirst and hunger is by acting on neurones within sensory circumventricular organs (CVOs). This is possible because the subfornical organ and organum vasculosum of the lamina terminalis (OVLT), the sensory CVOs in the forebrain, and the area postrema in the hindbrain lack a normal blood-brain barrier such that neurones within them are exposed to blood-borne agents. The neural signals generated by hormonal action in these sensory CVOs are relayed to several sites in the cerebral cortex to stimulate or inhibit thirst or hunger. The subfornical organ and OVLT respond to circulating angiotensin II, relaxin and hypertonicity to drive thirst-related neural pathways, whereas circulating amylin, leptin and possibly glucagon-like peptide-1 act at the area postrema to influence neural pathways inhibiting food intake. As a result of investigations using functional brain imaging techniques, the insula and anterior cingulate cortex, as well as several other cortical sites, have been implicated in the conscious perception of thirst and hunger in humans. Viral tracing techniques show that the anterior cingulate cortex and insula receive neural inputs from thirst-related neurones in the subfornical organ and OVLT, with hunger-related neurones in the area postrema having polysynaptic efferent connections to these cortical regions. For thirst, initially, the median preoptic nucleus and, subsequently, the thalamic paraventricular nucleus and lateral hypothalamus have been identified as likely sites of synaptic links in pathways from the subfornical organ and OVLT to the cortex. The challenge remains to identify the links in the neural pathways that relay signals originating in sensory CVOs to cortical sites