Gut transit and gut microbiome changes occur prior to the onset of motor impairment in a mouse model of Machado-Joseph disease

Zvyagina, V.; Kuriakose, A.; Simo, I.; Kam, J. Y.; Chakraborty, P.; Robinson, K. J.; Potapenko, A.; Watchon, M.; Paulsen, I. T.; Gamage, H. K. A. H.; Laird, A. S.

doi:10.1101/2025.04.30.651362

bioRxiv · 10.1101/2025.04.30.651362

Gut transit and gut microbiome changes occur prior to the onset of motor impairment in a mouse model of Machado-Joseph disease

Zvyagina, V.·Kuriakose, A.·Simo, I.·Kam, J. Y.·Chakraborty, P.·Robinson, K. J.·Potapenko, A.·Watchon, M.·Paulsen, I. T.·Gamage, H. K. A. H.·Laird, A. S.

View original source ↗Export metadata ↓

Abstract

We previously identified microbial shifts prior to the onset of motor and neurological symptoms within a mouse model of the fatal neurodegenerative disease Machado-Joseph disease (MJD). Here, we aimed to explore possible mechanisms contributing to these changes within the microbiome-gut-brain axis, and whether it preceded or followed central neurodegeneration. Here, we report that pre-symptomatic male MJD mice present with significantly different microbiome communities as early as 5-weeks-old. Furthermore, we show that male MJD mice have faster total gut transit times by 9-weeks-old, prior to signs of impaired motor function by 11-weeks-old. To elucidate whether these microbial and colonic functional changes are due to the presence of pathological and morphological changes in the gut, we quantified the formation of ataxin-3 protein aggregates within the gut and examined morphological changes within the gut of pre- and early symptomatic MJD mice relative to proteinopathy in the brain. Interestingly, we observed ataxin-3 aggregates within the brains of pre-symptomatic MJD mice, with significantly more aggregates present in MJD than WT mice from 7-weeks-of-age, an earlier timepoint than previously reported, coinciding with changes within the microbiome. However, we observed no ataxin-3 protein aggregates and no changes in enteric neuron populations or morphology within the gut. Analysis of endocrine factors involved in gut motility and inflammatory markers within the small intestine of 13-week-old males revealed increased expression of genes encoding cholecystokinin (Cck), ghrelin (Ghrl), heme oxygenase (Ho1), interleukin-1 beta (Il1b), and decreased inducible nitric oxide synthase (Nos2). Together, we demonstrate for the first time that colonic dysfunction occurs after gut microbiome changes, but prior to the onset of motor impairments in male MJD mice. Our work suggests that whilst proteinopathy or morphological changes within the gut may not be involved in these changes, inflammation and related endocrine changes could have a role in the interplay between the gut and brain during MJD development, warranting further investigation.

Source connections

Published article ↗

Explore related subjects

neuroscience Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Zvyagina, V., Kuriakose, A., Simo, I., Kam, J. Y., Chakraborty, P., Robinson, K. J., Potapenko, A., Watchon, M., Paulsen, I. T., Gamage, H. K. A. H., Laird, A. S.. 2025-05-01. Gut transit and gut microbiome changes occur prior to the onset of motor impairment in a mouse model of Machado-Joseph disease. https://doi.org/10.1101/2025.04.30.651362

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Attention Across Scales: From Individual Variation to Social Hierarchies and Brain Networks in Semi-Free-Ranging Macaques

Attention is a fundamental brain function supporting perception, decision-making, and social behavior, and its dysfunction profoundly impairs daily life. It is both dynamic and stable, varying across observations and individuals, changing across the lifespan, and being shaped by social and environmental experience. Yet capturing this complexity remains a central challenge in neuroscience. Here, we integrated longitudinal behavioral assessments of semi-free-ranging macaques living in naturalistic social groups with resting-state fMRI. We quantified performance across days, ages, and social hierarchies and related it to intrinsic brain organization. Distinct attentional phenotypes emerged, including individuals with reduced attentional control. Performance followed an inverted-U lifespan trajectory, improving from childhood to adulthood before declining. Social status modulated attentional performance. Critically, nonlinear lifespan trajectories and associations with individual attentional differences were most clearly expressed in frontoparietal connectivity. Together, these findings reveal how sustained attention is organized across scales, providing a biological framework for its individual diversity, social modulation, and neural basis.

neuroscience↗

bioRxiv2026

Decoding natural scenes from patterned optogenetic responses in mouse visual cortex

A central challenge in developing visual cortical prostheses is to determine how visual stimuli should be transformed into effective patterns of cortical stimulation. Although advances in stimulation technologies, including optogenetics, provide increasingly precise control over cortical activity, it remains unclear whether artificially evoked activity can reproduce the information content of naturally evoked visual representations. Here we establish a quantitative framework for evaluating visual encoding strategies by decoding cortical responses evoked by natural vision and patterned optogenetic stimulation. We developed a novel dual-modal paradigm in awake mice to bridge the gap between endogenous photostimulation and artificial network driving. By co-expressing the high-performance calcium indicator GCaMP6s and the red-shifted, ultra-sensitive opsin rsChRmine-oScarlet in the primary visual cortex (V1), we successfully translated dynamic natural movie frames into patterned, spatiotemporal optogenetic stimulation. Quantitative comparisons of macro-scale dynamics demonstrated that this patterned optogenetic injection evokes cortical states highly comparable and representationally aligned with those driven by actual visual photostimulation. To systematically evaluate the fidelity of these responses, we developed STAR, a deep learning model featuring spatial and temporal attention mechanisms, and successfully reconstructed the frames of natural movies from V1 signals under both experimental modalities. Collectively, our results demonstrate that complex sensory information can be both naturally encoded and synthetically injected into V1 circuits with high decoding fidelity. This work provides an empirical and computational proof-of-concept for intelligent, closed-loop biomimetic encoders, establishing a robust framework for next-generation cortical visual neuroprostheses and bidirectional brain-machine interfaces.

neuroscience↗

bioRxiv2026

Why Is Spontaneous Blink Timing Informative? An Adaptive Scheduling Perspective

Spontaneous eye blinks have long been linked to cognitive processing, yet how task demands shape blink timing and its relationship to behavioral performance remains unclear. We examined spontaneous blink behavior in 576 adults performing two variants of the Continuous Performance Task (CPT). Blink occurrence and timing were most strongly modulated by the experimental condition in the more demanding CPT-AX task, whereas their association with response time was stronger in the CPT-X task, where more consistent blink timing predicted faster responses. This dissociation suggests that task structure changes not only blink behavior but also the behavioral relevance of blink timing. These findings are consistent with an adaptive scheduling account of spontaneous blinking and provide a conceptual framework for understanding when and why blink timing contains chronometric information about ongoing cognition.

neuroscience↗