Biology subjects

Guzman, S. J.

Publications and source records attributed to Guzman, S. J..

5 recordsLinked to original sources

bioRxiv2026

In-vivo MRI of noradrenergic and dopaminergic nuclei predicts future cognition and Alzheimers disease progression

Noradrenergic and dopaminergic nuclei modulate cognition, and post-mortem data indicate they are affected early in the neurodegenerative cascade of Alzheimers disease. We derived in-vivo locus coeruleus (LC) and substantia nigra-ventral tegmental area (SN-VTA) MRI integrity measures from 739 ADNI participants, examined MRI-histology correspondence in individuals with both in-vivo imaging and post-mortem data, and tested whether these measures reflect early MRI-indexed degeneration predicting later cognitive decline. LC and SN-VTA contrast predicted cognitive and behavioral function 10 years later, despite only weak associations with current function. LC- and SN-VTA-associated brain-wide atrophy patterns aligned with PET-derived norepinephrine-transporter and dopamine-receptor maps, respectively. A one-standard-deviation decrease in baseline LC contrast was associated with 84% higher five-year odds of MCI-to-AD progression, and predictive effects of the catecholaminergic nuclei were mediated by their corresponding atrophy patterns. The SN-VTA pattern was associated with less amyloid PET-related memory decline. Together, these findings establish LC and SN-VTA MRI contrast as markers of early neurodegeneration that forecast cognitive decline years before clinical onset.

neuroscience↗

bioRxiv2026

SCN1A haploinsufficiency disrupts neural progenitor networks and accelerates neurogenesis in human Dravet syndrome forebrain assembloids

Dravet syndrome is a severe childhood neurological disorder caused mostly due to mutations in the sodium channel gene SCN1A. Although the disorder is widely attributed to dysfunction of inhibitory neurons, growing evidence suggests that disease mechanisms may begin much earlier during brain development. To investigate the developmental consequences of SCN1A haploinsufficiency, we generated patient-derived dorsal-ventral forebrain assembloids that model key features of human corticogenesis. We found that SCN1A was expressed in ventricular zone neural progenitors and that its reduced expression was associated with impaired growth, disrupted ventricular zone organization, and progressive depletion of progenitor populations. We further demonstrated reduced progenitor proliferation and self-renewal, accelerated cell-cycle exit, and premature neuronal differentiation, leading to increased production of excitatory neurons and enhanced network excitability. Single cell transcriptomic analyses revealed reduced cycling radial glial cells, accelerated progenitor maturation, and dysregulation of gap junction and calcium signaling pathways. Following these findings, we examined progenitor calcium activity and found that SCN1A haploinsufficiency disrupted coordinated functional network organization, resulting in reduced recurrent connectivity and fragmentation of functional cellular assemblies. These abnormalities occurred despite preserved intrinsic electrophysiological properties of individual progenitors, indicating a defect in population-level coordination rather than single cell electrophysiology. Together, our findings identify disrupted progenitor communication as an early developmental consequence of SCN1A haploinsufficiency and suggest that abnormalities within neural progenitor populations contribute to altered corticogenesis, excitatory neurogenesis, and circuit hyperexcitability in Dravet syndrome. This work expands current disease models beyond interneuron dysfunction and highlights the developing ventricular zone as a potential therapeutic target.

neuroscience↗

bioRxiv2026

The Venification of the Artery: Insights from Single-Cell Transcriptomics of a Porcine Arteriovenous Fistula Model

Objective: The maturation of an autologous arteriovenous fistula (AVF) depends on the coordinated hemodynamic adaptation of the inflow artery and the outflow vein. While venous remodeling has been extensively studied, the mechanisms of arterial adaptation are poorly understood. We addressed this knowledge gap with the first temporal single-cell atlas of the porcine AVF model. Methods: Six Yorkshire pigs underwent bilateral femoro-femoral AVF creation for tissue harvest at 2 and 21 days postoperatively or sham operation to collect native vessels after 2 days. Arteries and veins were analyzed by droplet-based single-cell RNA sequencing, histology, and immunohistochemistry. Results: All fistulas were patent, with flows reaching 1185.0 +/- 170.6 mL/min despite mild to moderate neointima formation in the veins. Arteries and veins demonstrated >60% endothelial denudation and increased neovascularization. Arterial remodeling was characterized by a progressive increase in venous-like transcriptional features. Arteries presented a venous-like endothelial cell (EC) composition at 21 days postop and a temporal increase in venous-associated phenotypes of myofibroblasts and fibroblasts. In both vessels, the latter populations were the main bearers of mechanosensitive signatures at 2 days. Despite the temporal convergence in phenotypes, arteries and veins retained vessel-selective characteristics. Arterial ECs expressed high levels of nitric oxide synthase, whereas venous ECs were largely inflammatory. Arterial myofibroblasts and fibroblasts had higher expression of Notch signaling transducers (HEY2, HEYL) and cellular communication network factors (CCN3, CCN5), while Wnt signaling regulators (DKK2, SFRP4) and complement genes (C3, C7, CFD) were upregulated in veins. Anti-inflammatory macrophages increased in both vessels during remodeling, likely contributing to the maturation of the fistulas. Conclusion: These analyses challenge the traditional paradigm of exclusive vein arterialization and support a complementary process of arterial venification after anastomosis. Recognition of this underappreciated phenomenon may reshape our understanding of AVF biology and guide the discovery of both vascular-wide and vessel-selective anti-stenotic therapies.

bioinformatics↗

bioRxiv2025

Cerebral Organoids Uncover Mechanisms of Neural Activity Changes in Epileptogenesis

Neurological disorders often originate from progressive brain network dysfunctions that start years before symptoms appear. How these changes emerge in the developing human brain remains elusive due to a lack of tractable model systems. Here, we show a cerebral organoid model of Tuberous Sclerosis Complex (TSC) that recapitulates hallmarks of epileptogenesis in vitro. We compare extracellular recordings of TSC organoids with intraoperative electrocorticography from TSC patients to reveal striking functional similarities, including high-frequency oscillations - an electrical biomarker for epileptogenic tissue. In TSC, a human-specific interneuron sub-type derived from the caudal ganglionic eminence drives network hyper-synchronization through increased spontaneous firing and altered excitability. Inhibiting overproliferation of its progenitors via long-term epidermal growth factor receptor inhibition prevented the onset of this pathological phenotype at functional and morphological levels. Our work shows that organoids allow mechanistic analysis of emerging neural network phenotypes, enabling anti-epileptogenic drug testing in a human brain development model.

neuroscience↗

bioRxiv2019

Fast signaling and focal connectivity of PV+ interneurons ensure efficient patternseparation by lateral inhibition in a full-scale dentate gyrus network model

Pattern separation is a fundamental brain computation that converts small differences in synaptic input patterns into large differences in action potential (AP) output patterns. Pattern separation plays a key role in the dentate gyrus, enabling the efficient storage and recall of memories in downstream hippocampal CA3 networks. Several mechanisms for pattern separation have been proposed, including expansion of coding space, sparsification of neuronal activity, and simple thresholding mechanisms. Alternatively, a winner-takes-all mechanism, in which the most excited cells inhibit all less-excited cells by lateral inhibition, might be involved. Although such a mechanism is computationally powerful, it remains unclear whether it operates in biological networks. Here, we develop a full-scale network model of the dentate gyrus, comprised of granule cells (GCs) and parvalbumin+ (PV+) inhibitory interneurons, based on experimentally determined biophysical cellular properties and synaptic connectivity rules. Our results demonstrate that a biologically realistic principal neuron-interneuron (PN-IN) network model is a highly efficient pattern separator. Mechanistic dissection in the model revealed that a winner-takes-all mechanism by lateral inhibition plays a crucial role in pattern separation. Furthermore, both fast signaling properties of PV+ interneurons and focal GC-interneuron connectivity are essential for efficient pattern separation. Thus, PV+ interneurons are not only involved in basic microcircuit functions, but also contribute to higher-order computations in neuronal networks, such as pattern separation.

neuroscience↗