Abstract
Adolescence is a critical period for brain development and adverse experiences like social isolation (SI) can lead to long-term affective disorders. This project investigates the impact of adolescent SI on adult psychopathology by identifying behavioral and molecular markers of vulnerability and resilience to SI-induced anxiety, depression, and stress-related disorders. Neurobiological mechanisms involved (HPA axis, BDNF, dynorphin) will be investigated by RNA-seq and genetic/epigenetic analyses. We hypothesize that SI increases susceptibility to affective disorders via neuroendocrine and neurofunctional dysregulation. The therapeutic potential of psilocybin, a psychedelic compound with promising antidepressant effects, will be evaluated in this model. We expect it to significantly reduce negative affective symptoms, particularly in SI-exposed rats, and to exert stronger therapeutic effects in these subjects. Molecular analyses will help uncover the underlying mechanisms of its action.
Results achieved
This project investigated the impact of social isolation during adolescence on the risk of developing affective disorders in adulthood, with the possibility to suggest innovative therapeutic tools for isolation-triggered psychopathologies. Using rat models of anxiety, depression and stress, the study evaluated the consequences of social isolation during adolescence on the neuronal mechanisms underlying psychiatric disorders. The project provided mechanistic insights into psilocybin effects on psychiatric-related behaviors and generated a preclinical rationale supporting its potential therapeutic use to treat isolation-triggered psychopathology at adulthood. The feasibility and translational relevance of this project, which has social as well as scientific implications, were endured by the expertise of the research team. In collaboration with the Department of Pharmacological and Biomolecular Sciences, University of Milan (Fabio Fumagalli) and Pharmacology Unit, Centre for Neuroscience, University of Camerino (Roberto Ciccocioppo), the main aim of this project was to investigate the impact of social isolation during adolescence on subsequent development of psychiatric-like conditions using rat models of psychiatric disorders. In doing so, it sought to contribute to the advancement of a highly impactful and clinically relevant line of research that, to date, remains relatively underexplored. We have studied the consequences of social isolation during adolescence on neuronal plasticity mechanisms involved in the manifestation of psychiatric-like conditions at adulthood and to determine the factors conferring vulnerability or resilience to the development of pathological conditions triggered by the social isolation during adolescence. This objective was fully met by elucidating critical biochemical and molecular changes induced by social isolation in brain regions relevant to psychiatric-like conditions, identifying alterations in intracellular signaling pathways, neurotrophic factors, and molecular markers associated with synaptic function and neuroplasticity. Particularly, we found changes in response to social isolation, which relate to the neurotrophin BDNF and the dynorphinergic system providing novel preclinical evidence to support the dysregulation of such systems in isolation-triggered psychopathology. Moreover, we tested the potential therapeutic effect of psilocybin on psychiatric-like conditions during adulthood. This objective was also successfully achieved by using pharmacological and mechanistic approaches, which have shown the involvement of specific molecular mechanisms mediating the beneficial effects of psilocybin. Our results contributed to a better understanding of how psilocybin may modulate isolation-triggered psychopathology at the molecular level. Overall, the experimental work carried out during the project successfully fulfilled our objectives and produced novel preclinical information on the mechanisms regulating the response to social isolation and the psilocybin treatment by using a validated preclinical model of psychiatric -like conditions. Taken together, these outcomes demonstrate that we have completed the main project objectives, showing our effort in the attempt to understand the mechanisms underlying the isolation-triggered psychopathology and the potential treatment with psilocybin. Several scientific articles arising from the project have already been published in peer-reviewed international journal. These publications document the main experimental findings of the project and confirm the successful achievement of its scientific objectives. In addition, further publications are expected in the short term. In fact, the project has generated a substantial body of experimental data supporting the involvement of the neurotrophin BDNF as well as the dynorphinergic and glutamatergic systems under isolated conditions and following the treatment with psilocybin glutamatergic neurotransmission in mediating. These findings provide a strong basis for additional mechanistic publications. The project was implemented in full accordance with the approved work plan and MUR requirements. All scientific objectives were achieved, and the activities were carried out within the planned timeframe and budget. The project contributed significantly to advancing knowledge on the therapeutic potential and mechanisms of action of psilocybin under isolated conditions. In addition to its scientific outcomes, the project promoted Open Science practices, gender equality, generational renewal, and knowledge dissemination, in line with the cross-cutting priorities of the PNRR. Overall, the project represents a successful example of high-quality, responsible, and impactful researchDettagli del progetto
Responsabile scientifico: Patrizia Romualdi
Strutture Unibo coinvolte:
Dipartimento di Farmacia e Biotecnologie
Coordinatore:
Università degli Studi di MILANO(Italy)
Contributo totale Unibo: Euro (EUR) 72.000,00
Durata del progetto in mesi: 24
Data di inizio
16/10/2023
Data di fine:
28/02/2026
