Biology subjects

Malone, T. J.

Publications and source records attributed to Malone, T. J..

3 recordsLinked to original sources

bioRxiv2025

Aberrant medial entorhinal cortex dynamics link tau pathology to spatial memory impairment

Tau pathology in the entorhinal cortex (EC) is associated with spatial memory decline in aging and early-stage Alzheimers disease, but its impact on EC computations during learning is not well understood. We performed longitudinal two-photon calcium imaging of layer 2 excitatory neurons in the medial EC (MEC) of PS19 tauopathy mice over 10 days of an operant spatial learning task. Male PS19 mice showed marked learning impairments accompanied by dysregulated MEC activity and unstable spatial coding. Their activity also showed weakened representations in cue-poor relative to cue-rich regions, correlated with attenuated speed modulation. These changes suggest that impaired path integration destabilizes MEC spatial maps, leading to impaired spatial memory. In contrast, female PS19 mice exhibited only mild behavioral and neural deficits despite a comparable tau burden, suggesting sex-specific resilience. Among MEC cell types, pyramidal cells accumulated more phosphorylated tau than stellate cells and displayed the most severe functional disruption, linking cellular tau load to circuit dysfunction. Finally, general linear models of MEC activity reliably predicted learning performance, highlighted particularly strong contributions from non-grid and pyramidal cells, and accurately classified PS19 versus wild-type mice. These findings identify aberrant MEC dynamics as a key circuit mechanism underlying tau-related spatial memory deficits and point to early diagnostic and circuit-targeted therapeutic strategies.

neuroscience↗

bioRxiv2025

Activation of the medial entorhinal cortex drives memory-guided navigation behavior

The cognitive map in the medial entorhinal cortex (MEC) is essential for spatial memory and exhibits experience-dependent changes. Yet, it remains unclear whether MEC activation is sufficient to bias the network toward memory-guided navigation, precluding a causal link between the MEC and spatial memory. To address this gap, we examined and optogenetically manipulated MEC activity as mice navigated a virtual track for a water reward based on memory. During learning, spatial activity in the pre-reward region showed the highest consistency along the track and closely paralleled improvements in reward-predictive behaviors. This elevated pre-reward consistency was widespread across MEC neurons, rather than confined to a particular cell type, indicating a network-level representation supporting reward prediction. Strikingly, optogenetic activation of MEC at non-reward locations biased reward-predictive behaviors toward stimulation sites, but only when stimulation patterns were spatially consistent. Consistent stimulation also induced anticipatory reward-seeking before stimulation onset and this behavior gradually developed with repeated stimulation, reflecting memory formation for stimulation locations. Moreover, in animals that failed to learn the track well, consistent pre-reward activation, alone or combined with landmark activation, significantly enhanced their reward prediction. Thus, spatially consistent MEC activation underlies memory-guided reward prediction, supporting a causal role for the MEC in spatial memory.

neuroscience↗

bioRxiv2024

Neuronal potassium channel activity triggers initiation of mRNA translation through binding of translation regulators

Neuronal activity stimulates mRNA translation crucial for learning and development. While FMRP (Fragile X Mental Retardation Protein) and CYFIP1 (Cytoplasmic FMR1 Interacting Protein 1) regulate translation, the mechanism linking translation to neuronal activity is not understood. We now find that translation is stimulated when FMRP and CYFIP1 translocate to the potassium channel Slack (KCNT1, Slo2.2). When Slack is activated, both factors are released from eIF4E (Eukaryotic Initiation Factor 4E), where they normally inhibit translation initiation. A constitutively active Slack mutation and pharmacological stimulation of the wild-type channel both increase binding of FMRP and CYFIP1 to the channel, enhancing the translation of a reporter for {beta}-actin mRNA in cell lines and the synthesis of {beta}-actin in neuronal dendrites. Slack activity-dependent translation is abolished when both FMRP and CYFIP1 expression are suppressed. The effects of Slack mutations on activity-dependent translation may explain the severe intellectual disability produced by these mutations in humans. HIGHLIGHTSO_LIActivation of Slack channels triggers translocation of the FMRP/CYFIP1 complex C_LIO_LISlack channel activation regulates translation initiation of a {beta}-actin reporter construct C_LIO_LIA Slack gain-of-function mutation increases translation of {beta}-actin reporter construct and endogenous cortical {beta}-actin C_LIO_LIFMRP and CYFIP1 are required for Slack activity-dependent translation C_LI IN BRIEFMalone et al. show that the activation of Slack channels triggers translocation of the FMRP/CYFIP1 complex from the translation initiation factor eIF4E to the channel. This translocation releases eIF4E and stimulates mRNA translation of a reporter for {beta}-actin and cortical {beta}-actin mRNA, elucidating the mechanism that connects neuronal activity with translational regulation.

neuroscience↗