Biology subjects

Gauthier, D. W.

Publications and source records attributed to Gauthier, D. W..

4 recordsLinked to original sources

bioRxiv2026

Impaired formation and updating of internal predictive models in a rat model of Fragile X Syndrome

Predictive coding frameworks propose that perception emerges from a continuous comparison of incoming sensory signals with internally generated predictions, with mismatches between the two computed as prediction errors. Disruptions to the balance between these top-down predictions and bottom-up sensory signals are theorized to contribute to sensory abnormalities in neuropsychiatric conditions like autism spectrum disorders. However, disambiguating bottom-up from top-down contributions to sensory perception remains a difficult challenge, particularly in animal models. Here we develop a probabilistic oddball detection task in which rats must track local statistics within a trial to detect a deviant stimulus, as well as global statistics across trials to anticipate when a deviant will occur. This design enables formation of experimentally specified internal models of deviant expectation that can be quantitatively derived from behavior and manipulated independently of local stimulus statistics. We used this task to characterize sensory predictive behavior in a Fmr1 KO rat model of Fragile X Syndrome, the most common monogenic cause of autism. Male Fmr1 KO rats detected deviant stimuli at wildtype levels but exhibited reduced anticipation of deviant occurrence based on cross-trial statistics and failed to adapt their behavior when these statistics changed. Computational modeling revealed that these behavioral deficits reflected imprecise and unstable internal predictive models skewed towards sensory immediacy. These findings provide evidence for disrupted predictive processing in Fragile X Syndrome, consistent with active inference accounts of autism, and highlight the utility of this probabilistic oddball task design for interrogating predictive coding and perceptual impairments in neuropsychiatric conditions.

neuroscience↗

bioRxiv2026

Disrupted Developmental Trajectory of Ultrasonic Vocalizations in a Rat Model of Fragile X Syndrome

Communication deficits are a defining feature of autism spectrum disorder (ASD) and among the earliest detectable markers of atypical neurodevelopment. Yet how specific genetic ASD risk factors shape the developmental trajectory of vocal communication remains poorly understood. Fragile X syndrome (FXS) is the most common inherited cause of ASD, resulting from the transcriptional silencing of the FMR1 gene, and a majority of FXS individuals exhibit impaired language development and atypical vocal communication. Rodent ultrasonic vocalizations (USVs) produced during maternal isolation provide a tractable model for studying the developmental trajectory of early vocal communication in FXS. Here, we characterized isolation- induced USVs in Fmr1 knockout (KO) and littermate wildtype (WT) rats from postnatal days 3- 21 to determine whether Fmr1 mutation disrupts the acoustic structure, temporal organization, or sequential syntax of USVs across postnatal development. We found that Fmr1 KO rat pups exhibited reduced call number during the peak developmental window for isolation-induced calling (p6-p10), while acoustic structure and temporal organization were largely preserved. Network analysis of call transitions revealed that WT pups exhibited a progressive increase in syntactic complexity from p3-p10. However, this developmental trajectory was significantly altered and delayed in Fmr1 KO pups. Together, these findings demonstrate that Fmr1 mutation not only disrupts vocal production but the developmental expansion of syntactic flexibility in rats, highlighting USV syntax as a sensitive marker of atypical communicative development in FXS models.

neuroscience↗

bioRxiv2026

Stable, Variable, Encoding: Distinct Roles of SST, VIP, and EXC Neurons in Visual Novelty Processing

Detecting and processing novelty is critical for learning and survival, yet the stability and flexibility of novelty representations at the level of single neurons remain poorly understood. How novelty evoked responses persist across time, whether novel stimuli are encoded in a stimulus-specific or non-specific manner, and how encoding adapts under changing conditions remain largely unknown. Importantly, novelty responses involve both excitatory and inhibitory neurons, highlighting the need to understand how these cell types differentially contribute to stable and flexible cortical representations. We analyzed longitudinal calcium imaging dataset from mouse visual cortex, tracking excitatory (EXC), somatostatin-expressing (SST), and vasoactive intestinal peptide-expressing (VIP) neurons across six days of a change detection task incorporating contextual novelty, stimulus omissions, and absolute novelty. At the population level, novelty responses were stable across days. However, single-neuron analysis revealed marked instability in EXC and VIP neurons. SST neurons exhibited the highest single-cell stability across all conditions, suggesting a role in maintaining consistent sensory representations. VIP neurons displayed stable responses only to omissions. Regarding information content of novelty responses, we found that EXC neurons encoded both stimulus-specific and non-specific novelty while VIP neurons uniquely transitioned from non-specific to mixed encoding under absolute novelty, revealing previously unrecognized flexibility. These findings reveal distinct, cell-type-specific roles in novelty processing, with SST cells supporting stability and VIP cells adapting their coding to novelty type.

neuroscience↗

bioRxiv2025

Altered auditory feature discrimination in a rat model of Fragile X Syndrome

Atypical sensory processing, particularly in the auditory domain, is one of the most common and quality-of-life affecting symptoms seen in autism spectrum disorders (ASD). Fragile X Syndrome (FXS) is the leading inherited cause of ASD and a majority of FXS individuals present with auditory processing alterations. While auditory hypersensitivity is a common phenotype observed in FXS and Fmr1 KO rodent models, it is important to consider other auditory coding impairments that could contribute to sound processing difficulties and disrupted language comprehension in FXS. We have shown previously that a Fmr1 knockout (KO) rat model of FXS exhibits heightened sound sensitivity that coincided with abnormal perceptual integration of sound bandwidth, indicative of altered spectral processing. Frequency discrimination is a fundamental aspect of sound encoding that is important for a range of auditory processes, such as source segregation and speech comprehension, and disrupted frequency coding could thus contribute to a range of auditory issues in FXS and ASD. Here we explicitly characterized spectral processing deficits in male Fmr1 KO rats using an operant conditioning tone discrimination assay and in vivo electrophysiology recordings from the auditory cortex and inferior colliculus. We found that Fmr1 KO rats exhibited poorer frequency resolution, which corresponded with neuronal hyperactivity and broader frequency tuning in auditory cortical but not collicular neurons. Using an experimentally informed population model, we show that these cortical physiological differences can recapitulate the observed behavior discrimination deficits, with decoder performance being tightly linked to differences in cortical tuning width and signal-to-noise ratios. These findings suggest that cortical hyperexcitability may account for a range of auditory behavioral phenotypes in FXS, providing a potential locus for development of novel biomarkers and treatment strategies that could extend to other forms of ASD.

neuroscience↗