When the Brain Coordinates Life-Risk Behavior: A Rewarding Anorexia

Understanding how brain supports adapted (and adaptive) decisions when individuals deal with challenge of the environment (stressor) is critical as adapted decision-making (goal-directed behavior) is supposed to protect from disturbances including unexpected death. How does the brain can then trigger chronic consumption of drugs or persistent food restriction (anorexia) until the point of death? In the neurosciences field, most of studies report correlations between behavioral disturbances in the face of environmental challenges and deregulations of neural circuits. Even if causal relationship is less described, exploring these correlations in simpler animal models makes possible the study of molecular and behavioral phenotypes in isolation and has revealed the conservation of specific molecular mechanisms in humans. For instance, involvement of serotonergic system in eating behavior remains crucial as current investigations, consistent with several decades (79 years from 1940 to 2019) of studies, reveals the conservation of specific molecular underpinnings of eating behaviors in animals and humans with eating disorders, suggesting the robustness of identified effects. In this context, studies describe commonalities between restrictive food intake and addiction, as in the nucleus accumbens - a critical structure of the brain’s reward system - activation of addictive signaling under the control of serotonin (5-HT, 5-hydroxytryptamine) 4 receptors (5-Ht₄Rs) mediates reduction in motivation for food in food-deprived mice, and ties anorexia and motor hyperactivity; Two hallmarks of anorexia nervosa. Accordingly, the brain prevents the transition from transient to persistent hypophagia (anorexia) with a network governing goal-directed behavior against depressive-like behavior, under the control of 5-Ht₄Rs localized in the medial prefrontal cortex. Food restriction at the onset following stress appears as an adapted behavior for managing stressors (as mediated by specific molecular changes related to depression resistance), but in the face of chronic stress, loss-of-control of the mPFC could imbalance the activity of the NAc and triggers persistent anorexia.

Keywords:Addiction; Anorexia; Stress; Food intake; Locomotion; Animal models; Brain; Nucleus accumbens; Medial prefrontal cortex; Serotonin 4 receptors

Abbreviations: cAMP: Cyclic Adenosine Monophosphate; CART: Cocaine- and Amphetamine-Regulated Transcript; KO: Knockout; mPFC: Medial Prefrontal Cortex; Nac: Nucleus Accumbens; Pka: Protein Kinase A; 5-Ht: 5-Hydroxytryptamine Or Serotonin; 5-Htrs: Serotonin Receptors; 5-Ht₄rs: Serotonin 4 Receptors; Sirna: Small Interference RNA