Biology subjects

Tung, T.-H.

Publications and source records attributed to Tung, T.-H..

3 recordsLinked to original sources

bioRxiv2025

Fus depleted oligodendrocytes reduce neuronal damage and attenuate AD progression in the AppNL-G-F mouse

AbstractOligodendrocytes (OL) and myelin abnormalities have emerged as important contributors to the pathogenesis of Alzheimers Disease (AD). OL maintain neuronal health through myelin axon interactions and by supplying neurotrophic and metabolic support. To gain insight on how OL and myelin may improve neuronal deficits associated with AD, we have generated a novel mouse model (AD/cKO) by crossing the AppNL-G-F mouse which carries three human AD mutations in the mouse App gene with the FusOLcKO, which has thicker myelin associated with greater cholesterol biosynthesis. The spatial working memory deficits manifested by the aged AD mouse were fully rescued by the FusOLcKO. This outcome was associated with reduced neuronal oxidative damage, preserved presynaptic structures at the plaque niches and a shift in microglia state at the niches in both hippocampus and cortex. In contrast, plaque burden and microglia density were decreased in the hippocampus but not in cortex, uncoupling the neuronal and microglia effects from the amyloid burden. Single cell transcriptomics of AD/cKO hippocampal OL revealed upregulation of energy metabolism and antioxidant genes, suggesting a role of OL enhanced energy metabolism in protecting neurons and affecting microglia state in AD pathology.

neuroscience↗

bioRxiv2025

Aging diminishes interlaminar functional connectivity in the mouse cortical V1 and CA1 hippocampal regions

Aging disrupts brain network integration and is a significant risk factor for cognitive decline and neurological diseases, yet the circuit-level mechanisms underlying these changes remain unclear. Most previous studies have utilized cross-sectional or acute approaches, limiting insights into the longitudinal dynamics of the neural network. In this study, we chronically recorded laminar electrophysiological activity in both the primary visual cortex (V1) and hippocampal CA1 region of young (2-month-old) and aged (13-month-old) mice over 16 weeks. This approach allowed us to directly assess how aging modulates functional connectivity within hierarchically connected cortical and hippocampal circuits. We found that single-unit spiking activity and the signal-to-noise ratio were largely preserved in aged versus young mice, suggesting intact neuronal firing properties. However, aged mice showed global reductions in local field potential (LFP) power and a selective decrease in coherence across delta, alpha-beta, and gamma frequency bands within and between cortical layers and V1-CA1 pathways, while phase amplitude coupling remained unaffected. Interestingly, population level excitatory activity in CA1 was increased in aged animals. These findings indicate that aging selectively impairs network-level synchrony and temporal coordination in specific frequency bands and regions, with minimal loss of single-neuron function. Our results highlight the necessity of longitudinal, multi-region measurements to uncover the multi-scale vulnerabilities of the aging brain. Understanding the depth- and region-dependent circuit changes will guide strategies to preserve cortical-hippocampal communication and cognitive function in aging, as well as enhance neural interface technologies for older populations. NEW & NOTEWORTHYAging non-uniformly degrades cortico-hippocampal networks, leading to region- and frequency-specific breakdowns in coordinated activity. While single-neuron activity remains preserved, disruptions in frequency-selective synchrony (delta and alpha-beta) were observed in aged mice, indicating impaired V1-CA1 communication as a marker of aging rather than neuronal degeneration. By separating single-neuron activity and large-scale dynamics, we reveal that aging alters communication between sensory and memory systems, underscoring the need for longitudinal approaches to capture age-related impairments in laminar connectivity.

neuroscience↗

bioRxiv2025

Hypermyelination Improves Strength and Detection of Neuronal Activity in the CA1 Hippocampus and Facilitates Neuroprotection in FusOLcKO Mice

1.0.Loss of oligodendrocytes (OLs) and myelin impairs cortical neuronal firing and network stability, whereas enhancement of oligodendrogenesis improves electrophysiological stability in cortex and, to a lesser extent, hippocampus. OLs exhibit regional heterogeneity, especially in their ability to synthesize cholesterol, a critical driver of myelin wrapping and ensheathment of axons. Conditional depletion of the Fused in sarcoma (Fus) gene in OLs, referred to as FusOLcKO, increases cholesterol biosynthesis, myelin thickness, and tissue cholesterol content. We examine whether this hypermyelination alters extracellular recordings across the layers of visual cortex and the underlying hippocampal CA1 over 16 weeks. In FusOLcKO mice, visually-evoked single-unit detectability and firing rate in CA1 increased relative to wild-type littermates, whereas cortical recordings showed no improvement. At the population level, FusOLcKO cortex exhibited reduced firing rates and lower functional connectivity, indicating altered network dynamics. Post-mortem histology revealed higher neuron density in recorded cortex and greater excitatory synapse density in CA1 of FusOLcKO mice suggesting region-specific neuroprotection and synaptic strengthening. These results demonstrate that cholesterol-driven hypermyelination enhances chronic hippocampal recordings while disrupting cortical network communication. Our study highlights myelins region-dependent roles in supporting single-cell reliability, tuning population dynamics, and maintaining circuit integrity under chronic perturbation. 2.0. SIGNIFICANCE STATEMENTMyelin critically regulates neural circuit function via conduction and metabolic support. Here, we show that cholesterol-driven hypermyelination in FusOLcKO mice augments single-unit detection and firing in hippocampal CA1 but reduces population firing and interlaminar connectivity within the cortex. These findings reveal a dual role for myelin: it can both safeguard specific circuit activity and perturb large-scale cortical communication. Understanding these dynamics is essential for designing myelin-targeted therapies in neurodegenerative disorders.

neuroscience↗