Biology subjects

Duff, K.

Publications and source records attributed to Duff, K..

6 recordsLinked to original sources

bioRxiv2026

High frame rate in vivo two-photon microscopy to quantify murine cerebrospinal fluid flow heterogeneity

Cerebrospinal fluid (CSF) flows through perivascular spaces (PVSs) surrounding brain vasculature, and impaired flow has been linked to neurodegenerative diseases such as Alzheimer's. However, the mechanisms driving CSF flow and its oscillatory dynamics remain poorly understood. Using high frame rate two-photon imaging (up to 113 Hz), we show that CSF flow is spatially heterogeneous and highly pulsatile, quantified using a regional CSF pulsatility index (PI). Reduced-order simulations with realistic domain length and Windkessel boundary conditions show that arterial pulsations generate peak CSF velocities but contribute negligibly to net transport. PI varies non-monotonically in space and substantially with downstream hydraulic resistance and compliance, indicating that CSF pulsatility is an emergent property of the hydraulic network rather than simply a consequence of local arterial wall motion. Measurements and simulations of the phase between arterial wall motion and CSF velocity further constrain proposed CSF driving mechanisms. Finally, we perform mouse-specific simulations to estimate average and peak wall shear stresses which support the potential role of pulsatile CSF flow in perivascular mechanotransduction. Together, these results establish CSF pulsatility as a measurable signature of network-scale CSF dynamics.

neuroscience↗

bioRxiv2025

Temporal Interference Stimulation Enhances Neural Regeneration

Neural regeneration therapies aim to treat neurodegeneration by promoting the proliferation and maturation of exogenous or endogenous neural progenitor cells (NPCs). However, their efficacy has been limited. Deep brain stimulation (DBS) via implanted electrodes has been shown to promote neurogenesis. However, its invasiveness precludes deployment in research and widespread clinical use. Temporal interference (TI) has emerged as a strategy for non-invasive, high-precision DBS using multiple kHz-range electric fields, with a frequency difference within the range of neural activity. Here, we validate the potential of TI stimulation for neural regeneration augmentation. We demonstrate that TI stimulation with a theta-band frequency difference enhances the maturation of embryonic neural progenitor cells in vitro. We then demonstrate that theta-band TI stimulation targeting the hippocampus enhances endogenous hippocampal neurogenesis in an in vivo mouse model of Alzheimers disease. By uncovering frequency-specific control of stem cell fate, we propose a clinically relevant regeneration strategy which avoids pharmacological or genetic manipulation. Our results demonstrate focal, non-invasive augmentation of deep-brain neural regeneration. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=197 SRC="FIGDIR/small/670811v1_ufig1.gif" ALT="Figure 1"> View larger version (49K): org.highwire.dtl.DTLVardef@984165org.highwire.dtl.DTLVardef@1ed8bbdorg.highwire.dtl.DTLVardef@715057org.highwire.dtl.DTLVardef@151882f_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2025

Scalable human neuronal models of tauopathy producing endogenous seed-competent 4R tau

The accumulation of pathological four-repeat (4R) tau is central to several frontotemporal dementia (FTD) subtypes, but human neuronal models amenable to high-throughput screening of 4R tau-targeting therapies remain very limited. To address this, we developed iPSC-derived i3Neuron (i3N) lines expressing >75% 4R tau, driven by FTD splice-shifting mutations (S305N or S305N/IVS10+3). These neurons develop hyperphosphorylated tau and demonstrate somatodendritic mis-localization. Unlike other stem cell models of tauopathy, these i3N neurons develop endogenous seed-competent tau and present pFTAA-positive tau assemblies after 28 days in culture. For scalable screening, we CRISPR-engineered a HiBiT luminescence tag at the endogenous MAPT locus into the S305N/IVS10+3 iPSC line, enabling precise quantification of tau levels and pharmacological responses. The model responded predictably to compounds affecting tau clearance, demonstrating its suitability for drug discovery. Overall, this i3N platform recapitulates key features of 4R tauopathy and provides a robust system to identify therapeutic modulators of pathological tau.

neuroscience↗

bioRxiv2024

Single MAPT knock-in mouse models of frontotemporal dementia for sharing with the neurodegenerative research community

We recently reported development of human MAPT knock-in mice that carry single or double pathogenic mutations of frontotemporal dementia. However, it takes more than 14 months for the line with the most aggressive phenotypes to exhibit tau pathology without forming high-order tau oligomers, along with concomitant abnormal behavior. We thus generated MAPT knock-in mice carrying triple mutations, among which the MAPTP301S;Int10+3;S320F line exhibited robust pathology starting earlier than 6 months. Tau accumulation took place mainly in the thalamus, hypothalamus, amygdala and entorhinal cortex, but less so in the hippocampus, leading to synaptic loss, atrophy and behavioral abnormalities. Crossbreeding MAPTP301S;Int10+3;S320F with App knock-in mice AppNL-G-F resulted in the manifestation of tau pathology in the hippocampus and cortex. These mutant mice will be valuable tools for understanding the mechanisms of frontotemporal dementia, Alzheimers disease and other tauopathies.

neuroscience↗

bioRxiv2020

Evidence for associations between Rey-Osterrieth Complex Figure test and motor skill learning in older adults

Age-related declines in motor learning may be related to poor visuospatial function. Thus, visuospatial testing could evaluate older adults potential for motor learning, which has implications for geriatric motor rehabilitation. To this end, the purpose of this study was to identify which visuospatial test is most predictive of motor learning within older adults. Forty-five nondemented older adults completed six standardized visuospatial tests, followed by three weekly practice sessions on a functional upper-extremity motor task. Participants were re-tested one month later on the trained task and another untrained upper-extremity motor task to evaluate the durability and generalizability of motor learning, respectively. Principal component analysis first reduced the dimensions of the visuospatial battery to two principal components for inclusion in a mixed-effects model that assessed one-month follow-up performance as a function of baseline performance and the principal components. Of the two components, only one was related to one-month follow-up. Factor loadings and post hoc analyses suggested that of the six visuospatial tests, the Rey-Osterrieth test (visual construction and memory) was related to one-month follow-up of the trained and untrained tasks. Thus, it may be plausible that older adults long-term motor learning capacity could be evaluated using the Rey-Osterrieth test, which would be feasible to administer prior to motor rehabilitation to indicate risk of non-responsiveness to therapy.

neuroscience↗

bioRxiv2020

Atrophy associated with tau pathology precedes overt cell death in a mouse model of progressive tauopathy

In the early stages of Alzheimers disease (AD), tau pathology first develops in the entorhinal cortex (EC), then spreads to the hippocampus and at later stages, to the neocortex. Pathology in the neocortex correlates with impaired cognitive performance. Overall, tau pathology correlates well with neurodegeneration but the spatial and temporal association between tau pathology and overt volume loss is unclear. Using in vivo magnetic resonance imaging (MRI) with tensor-based morphometry (TBM) we mapped the spatio-temporal pattern of structural changes in a mouse model of AD-like progressive tauopathy. A novel, co-registered in vivo MRI atlas identified particular regions in the medial temporal lobe (MTL) that had significant volume reduction. The medial entorhinal cortex (MEC) and pre-/para-subiculum (PPS) had the most significant atrophy at the early stage, but atrophy then spread into the hippocampus, most notably, the CA1, dentate gyrus (DG) and subiculum (Sub). TBM-related atrophy in the DG and Sub preceded overt cell loss that has been reported in ex vivo studies in the same mouse model. By unifying an ex vivo 3D reconstruction of tau pathology with the TBM-MRI results we mapped the progression of atrophy in the MTL with the corresponding spread of tau pathology. Our study shows that there is an association between the spread of tau pathology and TBM-related atrophy from the EC to the hippocampus, but atrophy in the DG and Sub preceded overt cell loss. One Sentence SummarySpread of tau pathology in a mouse model of Alzheimers disease assessed by MRI was associated with reduced brain tissue volume but not neuronal loss.

neuroscience↗