Coexistence of anhedonia and sensation-seeking with context-dependent gut dysbiosis in a prodromal transgenic mouse model of Parkinson’s disease

Abstract Accumulating evidence indicates that gut microbiota plays a role in the progression of Parkinson’s disease (PD). Microbiota-based treatments for prodromal PD, which is accompanied by a wide range of neuropsychiatric symptoms, are being considered a potential early intervention but are still under-investigated. This study examined the association between symptoms of affective and motivational impairments and gut dysbiosis in a transgenic mouse model (line G2-3) that overexpresses A53T mutant α-synuclein, a key protein involved in the disease pathology. By introducing biologically meaningful variations, such as genotype-based social grouping, efforts have been made to strengthen validity of the results and their translational relevance. Behavioral assessment was conducted on 6-month-old mice (the premotor stage) using Open Field, Elevated Plus Maze, Sucrose Preference and Tail Suspension tests. Fecal microbiota of mice was analyzed using 16S rRNA gene sequencing. Obtained data revealed a strong behavioral phenotype in transgenic mice expressed as co-occurrence of consummatory anhedonia and sensation-seeking/risk-taking behavior, without significant motivational deficits and with variable gut dysbiosis: mixed-genotype housing, among others, prominently favored Bacteroidaceae/ Bacteroides , as observed in PD patients, while single-genotype housing increased Dubosiella , a key bacteria in gut-originated PD model, along with the enrichment of Bifidobacterium pseudolongum , a well-known health-promoting bacterium. Overall, using a mouse model with adequate construct validity, this study identifies challenges in novel strategies that consider gut microbiota as an early diagnostic and therapeutic target for PD; it highlights the potential of the examined transgenic strain in studying low hedonic tone- and sensation-seeking-associated PD prodrome, building the basis for personalized medicine.