Biology subjects

Mudlaff, F.

Publications and source records attributed to Mudlaff, F..

4 recordsLinked to original sources

bioRxiv2026

Behavior-Dependent Immediate Early Gene Activation in the Mouse Cerebellum

The cerebellum supports a wide range of motor and non-motor behaviors, yet the specific cerebellar regions and neuronal populations underlying this functional diversity remain poorly understood. Here, we mapped patterns of immediate early gene activation in the cerebellar cortex during the accelerating rotarod task, an established form of cerebellum-dependent motor learning. Using the immediate early gene c-Fos to identify cells active during the task, we found significantly greater activation throughout the vermis and in crus I of the hemispheres, specifically within the molecular and granule cell layers, compared to naive controls. However, a second control group, which was exposed to the rotarod apparatus but not placed on the rotating rod, revealed similar patterns of c-Fos expression, suggesting that novelty contributed substantially to the observed activation. To separate this potential novelty signal from the motor component of the task, mice were habituated to the apparatus prior to testing. This habituation resulted in an overall decrease in c-Fos expression across cerebellar lobules, with significant motor activity-related differences found in the anterior vermis. Finally, to determine how learning influences c-Fos expression patterns, mice were subjected to a multi-day motor learning paradigm in which genetic tagging of c-Fos-expressing neurons was performed on day 1, followed by c-Fos immunostaining on day 5. We found that, in mice that had learned the task, there was no significant increase in c-Fos signal above naive controls, indicating that rotarod task performance no longer recruited the same level of cerebellar cortical activity, consistent with a potentially reduced role for the cerebellar cortex once the task is well learned. Overall, these findings reveal distinct patterns of activation associated with novelty, motor behaviour, and learning, providing a framework for linking behavior to regional cerebellar function.

neuroscience↗

bioRxiv2024

Heterogeneity in slow synaptic transmission diversifies Purkinje cell timing

The cerebellum plays an important role in diverse brain functions, ranging from motor learning to cognition. Recent studies have suggested that molecular and cellular heterogeneity within cerebellar lobules contributes to functional differences across the cerebellum. However, the specific relationship between molecular and cellular heterogeneity and diverse functional outputs of different regions of the cerebellum remains unclear. Here, we describe a previously unappreciated form of synaptic heterogeneity at parallel fiber synapses to Purkinje cells. In contrast to uniform fast synaptic transmission, we found that the properties of slow synaptic transmission varied by up to three-fold across different lobules of the mouse cerebellum, resulting in surprising heterogeneity. Depending on the location of a Purkinje cell, the time of peak of slow synaptic currents varied by hundreds of milliseconds. The duration and decay-time of these currents also spanned hundreds of milliseconds, based on lobule. We found that, as a consequence of the heterogeneous synaptic dynamics, the same brief stimulus was transformed into prolonged firing patterns over a range of timescales that depended on Purkinje cell location

neuroscience↗

bioRxiv2023

Dnmt3a1 regulates hippocampus-dependent memory via the downstream target Nrp1

Epigenetic factors are well established players in memory formation. Specifically, DNA methylation is necessary for the formation of long-term memory in multiple brain regions including the hippocampus. Despite the demonstrated role for DNA methyltransferases (Dnmts) in memory formation, it is unclear whether individual Dnmts have unique or redundant functions in long-term memory formation. Furthermore, the downstream processes controlled by Dnmts during memory consolidation have not been investigated. In this study, we demonstrated that Dnmt3a1, the predominant Dnmt in the adult brain, is required for long-term spatial object recognition and contextual fear memory. Using RNA-sequencing, we identified an activity-regulated Dnmt3a1-dependent genomic program in which several genes were associated with functional and structural plasticity. Furthermore, we found that some of the identified genes are selectively dependent on Dnmt3a1, but not its isoform Dnmt3a2. Specifically, we identified Neuropilin 1 (Nrp1) as a downstream target of Dnmt3a1 and further demonstrated the involvement of Nrp1 in hippocampus-dependent memory formation. Importantly, we found that Dnmt3a1 regulates hippocampus-dependent memory via Nrp1. In contrast, Nrp1 overexpression did not rescue memory impairments triggered by reduced Dnmt3a2 levels. Taken together, our study uncovered a Dnmt3a-isoform-specific mechanism in memory formation, identified a novel regulator of memory, and further highlighted the complex and highly regulated functions of distinct epigenetic regulators in brain function.

neuroscience↗

bioRxiv2020

Modeling human age-associated increase in Gadd45γ expression leads to spatial recognition memory impairments in young adult mice

Aging is associated with the progressive decay of cognitive function. Hippocampus-dependent processes, such as the formation of spatial memory, are particularly vulnerable to aging. Currently, the molecular mechanisms responsible for age-dependent cognitive decline are largely unknown. Here, we investigated the expression and function of the growth arrest DNA damage gamma (Gadd45{gamma}) during aging and cognition. We report that Gadd45{gamma} expression is increased in the hippocampus of aged humans and that Gadd45{gamma} overexpression in the young adult mouse hippocampus compromises cognition. Moreover, Gadd45{gamma} overexpression in hippocampal neurons disrupted CREB signaling and the expression of well-established activity-regulated genes. This work shows that Gadd45{gamma} expression is tightly controlled in the hippocampus and its disruption may be a mechanism contributing to age-related cognitive impairments observed in humans.

neuroscience↗