Numerous studies have shown that the brain’s gut axis, that is the mutual communication between the central nervous system (CNS) and the enteric nervous system, is involved in the onset and progression of numerous pathologies. Intestinal dysbiosis has been shown to cause changes in both peripheral and central circadian pathways, which in turn are responsible for the proper activity of the glymphatic system in the brain. The glymphatic system is a waste disposal system that uses a perivascular tunnel system of astroglial cells to promote the elimination of soluble proteins and metabolites from the central nervous system. As a result, an alteration in circadian rhythmicity that affects the functionality of the glymphatic system can result in the accumulation of various neurotoxic products in different brain areas, suggesting its involvement in various pathologies and neurological disorders. Our hypothesis is that the impairment of both the circadian rhythms and the glymphatic system are the starting point for numerous neurodegenerative processes. This project aims to investigate how the impairment of the circadian system and consequently of the glymphatic system, as a result of peripheral inflammatory damage, have an impact on the initiation of neurodegenerative processes. At the experimental level, peripheral inflammation was induced using a mouse model of acute colitis through the administration of sodium dextran sulphate (DSS). As a result of this insult, modifications in the expression of the main genes constituting circadian rhythmicity, both peripheral and central, were evaluated. Moreover, the alteration of the glymphatic system has been studied evaluating the expression of the main astrocytic constituents involved in the transport of cerebrospinal fluid. In addition, through proton magnetic resonance spectroscopy (H-MRS) alterations in the levels of certain metabolites and neurotransmitters in specific brain areas were analyzed, based on their characteristic spectrum of response to MRI pulse sequences. The data obtained from our project could highlight the link between neurodegeneration and peripheral inflammatory processes, leading to strengthening the growing links between intestinal dysbiosis, alteration of the circadian rhythms and impairment of the glymphatic flow, in order to implement and direct the research of specific therapeutic approaches aimed at the treatment of various neurodegenerative diseases.
Numerosi studi hanno dimostrato che l’asse intestino cervello, ossia la mutua comunicazione tra il sistema nervoso centrale (SNC) e il sistema nervoso enterico, è coinvolto nell’insorgenza e nella progressione di numerose patologie. È stato dimostrato che la disbiosi intestinale è in grado di causare alterazioni nei pathway circadiani sia periferici che centrali, a loro volta sono responsabili della corretta attività del sistema glinfatico a livello cerebrale. Il sistema glinfatico rappresenta un sistema di smaltimento dei rifiuti che utilizza un sistema di tunnel perivascolari, formato da cellule astrogliali, per promuovere l’eliminazione delle proteine solubili e dei metaboliti dal sistema nervoso centrale. Di conseguenza, un’alterazione della ritmicità circadiana che si ripercuote sulla funzionalità del sistema glinfatico può comportare l’accumulo di vari prodotti neurotossici in diverse aree cerebrali, suggerendo il suo coinvolgimento in varie patologie e disturbi neurologici. La nostra ipotesi è che la compromissione sia dei ritmi circadiani che del sistema glinfatico siano il punto di partenza per numerosi processi neurodegenerativi. Il presente progetto si propone di indagare come la compromissione del sistema circadiano e conseguentemente del sistema glinfatico, in seguito ad un danno infiammatorio periferico, abbiano un impatto sull’innesco di processi neurodegenerativi. A livello sperimentale l’infiammazione periferica è stata indotta utilizzando un modello murino di colite acuta attraverso la somministrazione di destrano solfato di sodio (DSS). A seguito di tale insulto sono state valutate le modificazioni nell’espressione dei principali geni costituenti la ritmicità circadiana, sia a livello periferico che centrale. Inoltre è stata studiata l’alterazione del sistema glinfatico valutando l’espressione dei principali costituenti astrocitari coinvolti nel trasporto del fluido cerebrospinale. In aggiunta, attraverso la spettroscopia protonica di risonanza magnetica (H-MRS) sono state analizzate le alterazioni nei livelli di alcuni metaboliti e neurotrasmettitori in specifiche aree encefaliche, sulla base del loro caratteristico spettro di risposta a sequenze di impulsi di risonanza magnetica. I dati ottenuti dal nostro progetto potrebbero mettere in risalto il collegamento tra neurodegenerazione e processi infiammatori periferici, portando a rafforzare i crescenti collegamenti tra disbiosi intestinale, alterazione dei ritmi circadiani e compromissione del flusso glinfatico, al fine di implementare e indirizzare la ricerca di specifici approcci terapeutici volti al trattamento delle varie malattie neurodegenerative.
L’asse intestino-cervello: compromissione nella regolazione circadiana della funzionalità del sistema glinfatico come driver di neurodegenerazione
CONTI, FILIPPO
2021/2022
Abstract
Numerous studies have shown that the brain’s gut axis, that is the mutual communication between the central nervous system (CNS) and the enteric nervous system, is involved in the onset and progression of numerous pathologies. Intestinal dysbiosis has been shown to cause changes in both peripheral and central circadian pathways, which in turn are responsible for the proper activity of the glymphatic system in the brain. The glymphatic system is a waste disposal system that uses a perivascular tunnel system of astroglial cells to promote the elimination of soluble proteins and metabolites from the central nervous system. As a result, an alteration in circadian rhythmicity that affects the functionality of the glymphatic system can result in the accumulation of various neurotoxic products in different brain areas, suggesting its involvement in various pathologies and neurological disorders. Our hypothesis is that the impairment of both the circadian rhythms and the glymphatic system are the starting point for numerous neurodegenerative processes. This project aims to investigate how the impairment of the circadian system and consequently of the glymphatic system, as a result of peripheral inflammatory damage, have an impact on the initiation of neurodegenerative processes. At the experimental level, peripheral inflammation was induced using a mouse model of acute colitis through the administration of sodium dextran sulphate (DSS). As a result of this insult, modifications in the expression of the main genes constituting circadian rhythmicity, both peripheral and central, were evaluated. Moreover, the alteration of the glymphatic system has been studied evaluating the expression of the main astrocytic constituents involved in the transport of cerebrospinal fluid. In addition, through proton magnetic resonance spectroscopy (H-MRS) alterations in the levels of certain metabolites and neurotransmitters in specific brain areas were analyzed, based on their characteristic spectrum of response to MRI pulse sequences. The data obtained from our project could highlight the link between neurodegeneration and peripheral inflammatory processes, leading to strengthening the growing links between intestinal dysbiosis, alteration of the circadian rhythms and impairment of the glymphatic flow, in order to implement and direct the research of specific therapeutic approaches aimed at the treatment of various neurodegenerative diseases.È consentito all'utente scaricare e condividere i documenti disponibili a testo pieno in UNITESI UNIPV nel rispetto della licenza Creative Commons del tipo CC BY NC ND.
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https://hdl.handle.net/20.500.14239/15590