Neuroplastic mechanisms in addictive processes: focus on cognition during adolescence

Adolescence is a period of heightened vulnerability to external stimuli as the brain undergoes dynamic changes to reach complete maturation. Adolescence is a sensitive window for the development of addiction-relevant brain circuits, and a critical age-of-onset for psychiatric disorders that involves alterations in the reward neurocircuitry and display compulsive behaviors, such as anorexia nervosa (AN). Patients suffering from AN display altered neural activity, morphological, and functional connectivity in the cortico-limbic circuit that may result in deep cognitive impairments. To provide a molecular mechanism, we employed the activity-based anorexia (ABA) rat model, which combines the caloric restriction and physical exercise. In the prefrontal cortex (Pfc) and Hippocampus (Hip), we evaluated structural remodeling together with molecular alterations that may subserve behavioral dysfunctions at the acute phase (body weight loss and hyperactivity) and following a week of body weight recovery. Structural analyses performed after ABA induction in both Pfc and Hip revealed reduced dendritic spine density and mushroom-shaped spines, together with an increased number of filopodia. Such morphological changes are paralleled by alterations of markers of cytoskeletal stability, such as n-cadherin, neuroligin-1 and PSD95, of critical components of the glutamatergic synapse, i.e. AMPA and NMDA receptors and of neuroinflammation showing elevated TNFalpha. Notably, ABA rats exhibited cognitive deficits, as measured by the temporal and the spatial order object recognition tests. 7 days of recovery restored body weight, yet morphological, structural, and cognitive deficits persisted. Interestingly, microglia shifted toward a pro-phagocytic phenotype in the Hip only after recovery. This reorganization of the Pfc and Hip structural architecture, caused by the induction of the AN phenotype during adolescence, highlights a potential mechanism to explain the observed cognitive deficits. Moreover, such changes may unmask latent vulnerabilities and disrupt physiological maturation of pivotal neurocognitive circuits, that may be critical for AN persistence.