Coexistence of anhedonia and sensation-seeking traits with variable gut dysbiosis in a prodromal transgenic mouse model of Parkinson's disease

Background: Preclinical findings suggest that overexpression of alpha-synuclein, a key protein involved in the pathology of Parkinson's disease (PD), can lead to dysbiosis, but its role in disease symptoms remains unclear. This study investigated whether overexpression of human mutant A53T alpha-synuclein in the transgenic/congenic JAX006823 strain is related to hedonic, motivational and emotional difficulties, as frequent prodromal symptoms of the PD, and gut dysbiosis. Methods: By introducing biologically meaningful variations, efforts have been made to strengthen validity of the findings. Transgenic (Tg) and non-transgenic male mice were housed in mixed- and single-genotype housing (MGH, SGH) after weanling, improving external validity. C57BL/6J male mice, used in backcrossing, were included to show the role of the control group in internal validity. Behavioral assessment was conducted on 6-month-old mice using Open Field, Elevated Plus Maze, Sucrose Preference and Tail Suspension tests. Fecal microbiota was analyzed using 16S rRNA gene sequencing. Results: Tg mice displayed consummatory anhedonia and anxiolytic/sensation-seeking-like behavior in both MGH and SGH conditions, without significant motivational deficits and consistent dysbiosis. Altered taxa included: Prevotellaceae, Bacteroidaceae/Bacteroides, Lactobacillus, Limosilactobacillus and A2 in MGH; Coriobacteriia/Coriobacteriales and Dubosiella in SGH; increased abundance of Bacteroides and Lachnospiraceae species in TgMGH and Bifidobacterium pseudolongum in TgSGH. Hypohedonia and abundant Lactobacillales/Lactobacillaceae/Ligilactobacillus emerged as characteristics of the transgenic/congenic strain. Conclusion: Alpha-synuclein overexpression in mice of the JAX006823 strain is associated with a robust premotor behavioral phenotype, but modifiable microbiota, identifying challenges in describing prodromal gut dysbiosis. Nevertheless, this transgenic/congenic strain is valuable in studying low hedonic tone-related disorders as prodromal features of alpha-synucleinopathies.