Biology subjects

Tyan, J.

Publications and source records attributed to Tyan, J..

4 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↗

bioRxiv2025

The entorhinal spatial map integrates visual identity information of landmarks

The location and identity of landmarks provide spatial and nonspatial information of an environment, respectively, to guide spatial navigation. While the medial entorhinal cortex (MEC) is essential for representing spatial information, it is unclear whether it also encodes landmark identity. Here, we conducted two-photon calcium imaging of the MEC when mice navigated in multiple virtual environments, and discovered a general ability of the MEC to encode landmark identity through cue cells, which responded to individual landmarks during virtual navigation. Cue cells represented landmark identity by exhibiting more distinct activity patterns between visually disparate landmarks than identical ones. The representation was modulated by the spatial shift of cue cell activity relative to landmark location. Moreover, the identity encoding by the same cue cell population changed between different environments but was maintained within the same environment despite increased experience. In contrast, landmark location encoding by cue cells was regulated by experience, suggesting different mechanisms underlying the encodings of landmark identity and location. Finally, compared to cue cells, grid cells weakly encoded landmark identity but more robustly encoded landmark location. Thus, the MEC integrates both spatial and nonspatial information during navigation, but potentially through different circuit mechanisms.

neuroscience↗

bioRxiv2023

A consistent map in the medial entorhinal cortex supports spatial memory

The medial entorhinal cortex (MEC) is hypothesized to function as a cognitive map for memory-guided navigation. How this map develops during learning and influences memory remains unclear. By imaging MEC calcium dynamics while mice successfully learned a novel virtual environment over ten days, we discovered that the dynamics gradually became more spatially consistent and then stabilized. Additionally, grid cells in the MEC not only exhibited improved spatial tuning consistency, but also maintained stable phase relationships, suggesting a network mechanism involving synaptic plasticity and rigid recurrent connectivity to shape grid cell activity during learning. Increased c-Fos expression in the MEC in novel environments further supports the induction of synaptic plasticity. Unsuccessful learning lacked these activity features, indicating that a consistent map is specific for effective spatial memory. Finally, optogenetically disrupting spatial consistency of the map impaired memory-guided navigation in a well-learned environment. Thus, we demonstrate that the establishment of a spatially consistent MEC map across learning both correlates with, and is necessary for, successful spatial memory.

neuroscience↗