MALADAPTIVE PLASTICITY IN ANOREXIA NERVOSA: EVIDENCE OF A PERIPHERY-TO-BRAIN CROSSTALK IN A PRECLINICAL MODEL
Tesi di Dottorato
Data di Pubblicazione:
2021
Citazione:
MALADAPTIVE PLASTICITY IN ANOREXIA NERVOSA: EVIDENCE OF A PERIPHERY-TO-BRAIN CROSSTALK IN A PRECLINICAL MODEL / F. Mottarlini ; tutor: F. Fumagalli; coordinator: G. D. Norata. Dipartimento di Scienze Farmacologiche e Biomolecolari, 2021 Dec 09. 34. ciclo, Anno Accademico 2021.
Abstract:
Anorexia Nervosa (AN) is a devastating psychiatric disorder affecting pubescent females ninefold more than males, in a period of life extremely vulnerable to external stimuli: the adolescence. AN begins with a self-induced restrictive diet to lose weight, below 85% of expected body mass index, that in combination with intense physical activity and aberrant body image concern, it progresses to an out-of-control spiral. In this condition, the positive experience of control on food intake and intense exercise is indeed extremely rewarding for the patient, reinforcing the dieting behavior. AN is associated with the highest mortality rate among the wide family of psychiatric disorders, and despite the knowledge about the clinical symptomatology, AN etiopathogenesis remains unclear, treatment is challenging and often hampered by high relapse. At the neurobiological level, patients suffering from AN display altered neural activity, morphological and functional connectivity in the fronto-striatal and thalamo-cortical circuits. In particular, hypoglutamatergic transmission and aberrant excitability of cortical and striatal regions observed in AN patients might underpin cognitive deficits that fuel the vicious cycle of dieting behavior. It has been suggested that the driving force of such abnormal behavior might be represented by an altered balance between reward and inhibition mechanisms in the brain, the first mainly mediated by the Nucleus Accumbens (NAc), and the latter being normally triggered by the medial prefrontal cortex (mPFC) that is immature and still growing during adolescence. Such dysfunctional mechanisms combined with alterations in the levels of appetite modulators, such as ghrelin and leptin, and dysregulations in peripheral organs and metabolic active tissues functionality may lead to a distorted response to salient stimuli, such as food, fueling the maintenance of the anorexic phenotype. AN is not only a brain disorder but it is rather a systemic disease that affects the whole body, particularly skeletal muscles and circulating hormones, suggesting the presence of a crosstalk between peripheral signals and brain functions.
Therefore, the main goal of this project is to investigate from a preclinical point of view the neurobiological mechanisms involved in the pathophysiology of AN. We pointed our attention to the possibility that the combination of food restriction with intense exercise, the hallmarks of AN, activates dysfunctional periphery-to-brain crosstalk that may drive for weight loss seeking inducing aberrant dieting behaviors, affecting reward processes and cognition, via altered neurometabolic pathways in specific areas of the brain, and in turn, promoting the long-lasting maintenance of AN disorder.
Therefore, with the aim to investigate the central and peripheral alterations in biological mechanisms that may support the anorexic condition and induce cognitive impairments, we employed the well-known animal model of AN, the activity-based anorexia (ABA) rat model, which recapitulates human AN by combining caloric restriction and physical exercise to induce self-induced body-weight loss. We have demonstrated that, under a paradigm of food restriction and free access to a mechanical activity wheel, adolescent female rats showed reduced food intake, reduced body weight and increased running activity on the wheel, thus developing the anorexic phenotype.
To dissect the neurobiological underpinnings of this condition and the cognitive-related dysfunctions during a critical developmental period, we performed structural, morphological and molecular studies on critical brain areas of the reward system, crucially involved in processing feeding information and in mediating high-level cognitive functions such as the N
Tipologia IRIS:
Tesi di dottorato
Elenco autori:
F. Mottarlini
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