Dipartimento di Biologia, Ecologia e Scienze della Terra - Tesi di dottorato

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Questa collezione raccoglie le Tesi di Dottorato afferenti al Dipartimento Dipartimento di Biologia, Ecologia e Scienze della Terra dell'Università della Calabria.

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Author: search.filters.author.Facciolo, Rosa MariaSubject: search.filters.subject.Disturbo dello spettro autistico. Chetosi. Microbiota intestinale. Probiotici. BTBR

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    Aspetti neurocomportamentali e possibili approcci terapeutici del Disturbo dello Spettro Autistico nel modello roditore BTBR T+Itpr3tf/J (BTBR)
    (Università della Calabria, 2024-04-29) Olivito, Ilaria; Angelone, Tommaso; Facciolo, Rosa Maria
    Autism Spectrum Disorder (ASD) is a complex neurodevelopmental syndrome characterized by a diverse range of clinical manifestations, encompassing social deficits and repetitive stereotypical behaviors. These symptoms often coexist with psychiatric and medical comorbidities, adding intricacy to the pathological profile of the disorder. The pervasive prevalence and enduring symptoms across the lifespan underscore the significant public health impact of ASD. However, the underlying pathophysiological mechanisms remain poorly understood, and there is a current lack of specific targeted medications. Given the intricate and heterogeneous nature of the symptomatology associated with this syndrome, the adoption of a multifaceted approach emerges as a valuable strategy to deepen the comprehension of its pathophysiology and advance more effective therapeutic interventions. Within these strategic considerations, inducing a ketogenic metabolic state presents a promising avenue, capable of mitigating abnormal behaviors while concurrently ameliorating psychological and sociological aspects across various neurological conditions. This approach operates through diverse molecular pathways, including the modulation of the gut microbiota, identified as a pivotal center for brain regulation. In the context of addressing these challenges, the current doctoral project aims to significantly contribute to the comprehension of ASD's pathophysiology. This is achieved through a comprehensive exploration of behavioral aspects, molecular dynamics, the association with the gut microbiota, and potential therapeutic strategies. Noteworthy is the adopted methodological approach, which involves analyzing the effects of ketosis in the BTBR rodent model of autism, encompassing both in vivo and in vitro assessments. This analysis includes evaluations of behavioral performance, key molecular mechanisms, and integration with the assessment of the gut microbiota. Results from an initial in vivo study demonstrated that the adoption of a ketogenic diet (KD) notably mitigated social deficit (p=0.002), repetitive behaviors (p<0.001), and memory impairments (p=0.001) in BTBR mice. These behavioral enhancements were associated with reduced levels of tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β, and IL-6 in the plasma (p=0.007; p<0.001, and p=0.023, respectively), prefrontal cortex (PFC; p=0.006; p=0.04, and p=0.03), and hippocampus (HIP; p=0.02; p=0.09, and p=0.03). Furthermore, the KD mitigated oxidative stress, evidenced by modifications in lipid peroxidation levels (TBARS) and superoxide dismutase (SOD) activity in the brain areas of BTBR mice. Of particular interest, the KD positively influenced beneficial microbiota (Akkermansia and Blautia) and normalized aberrant levels of Lactobacillus in the feces of BTBR mice, underlining its neurophysiological impact through the modulation of the gut microbiota. The correlation between gut microbiota modulation and behavioral changes is substantiated by a meticulous analysis of the effects of five Lactobacillus strains in a study conducted during the planned abroad period within the doctoral project. This specific investigation unveiled a differential impact of the strains L. salivarius - LS7892, L. gasseri - LG6410, L. plantarum - LP14D, L. reuteri - LR92, and L. camelliae - LC LMG 24277 on social behavior, motor activity, and anxiety in BTBR mice. Particularly noteworthy, LS7892 emerged as a potential probiotic for ASD treatment among the examined strains. Following in vitro investigations revealed alterations in the cytoskeletal and synaptic organization in PFC and HIP neurons of BTBR, linked to fluctuations in Brain-Derived Neurotrophic Factor (BDNF) expression levels. The induction of a ketogenic state exhibited a beneficial modulation of the neural network, stabilizing compromised connections, and significantly increasing BDNF levels (p<0.001). In conclusion, the outcomes of this doctoral project underscore the significant relevance of the ketogenic approach and the modulation of the gut microbiota in the context of ASD. This research contributes to a more profound understanding of the pathophysiological foundations, offering innovative perspectives for the development of personalized and targeted therapeutic approaches.