Biology subjects

Newbold, E.

Publications and source records attributed to Newbold, E..

3 recordsLinked to original sources

bioRxiv2026

Enhanced glymphatic CSF tracer influx during α2-adrenergic agonist anesthesia is independent of tracer injection duration

The glymphatic system mediates brain-wide cerebrospinal fluid (CSF) transport and is highly sensitive to brain state. Experimental studies show that 2-adrenergic agonist- based anesthesia enhances glymphatic CSF influx, whereas isoflurane markedly suppresses it. However, it has been suggested that the reduced tracer influx observed during isoflurane anesthesia may reflect rapid clearance of tracer from the basal cisterns rather than genuine inhibition of glymphatic transport. To address this question, we compared conventional short-duration cisterna magna tracer injections with prolonged low-rate infusion while maintaining identical total tracer dose and anesthesia duration. Across both paradigms, ketamine/dexmedetomidine anesthesia consistently produced substantially greater perivascular CSF influx than isoflurane. In contrast, tracer accumulation in blood and cervical lymph nodes remained largely unchanged between conditions. These findings demonstrate that suppression of glymphatic influx during isoflurane anesthesia is independent of tracer injection duration and support the conclusion that 2-adrenergic agonist-based anesthesia promotes glymphatic transport through mechanisms linked to sleep-like brain states.

neuroscience↗

bioRxiv2025

Mechanical Ventilation Suppresses Glymphatic Function in Parallel with Delirium-Like Symptoms in Mice

Delirium is a common and serious complication in critically ill patients, arising from multiple overlapping risk factors. Its pathogenesis remains poorly understood because it reflects the combined effects of interacting clinical insults, and because appropriate experimental models for mechanistic studies have been lacking. Delirium most commonly develops in patients undergoing major surgery or requiring intensive care, where inhalational anesthesia, opioid sedation, and mechanical ventilation are common clinical exposures. Here, we tested the hypothesis that these clinically relevant interventions are sufficient to induce delirium-like behavior in healthy young wild-type mice by disrupting cerebrospinal fluid (CSF) glymphatic transport. The analysis showed that inhalational anesthesia combined with mechanical ventilation increased intracranial pressure (ICP) and induced a sustained suppression and rerouting of glymphatic waste clearance, resulting in impaired waste clearance, and acute cytokine accumulation. These findings identify disruption of brain fluid dynamics as a potential mechanism contributing to delirium in perioperative and intensive care settings. Equally important, this model represents a distinct experimental platform that combines clinically relevant mechanical ventilation, inhalational anesthesia, and opioid analgesia to produce delirium-like behavioral abnormalities in otherwise healthy mice. It therefore provides a powerful tool for future mechanistic studies of delirium pathogenesis.

neuroscience↗

bioRxiv2025

In vivo selection and glymphatic delivery of AAV5 capsids engineered to target human glial progenitor cells

To establish a means of efficiently transducing human glial progenitor cells (hGPCs) in vivo with therapeutic transgenes, we targeted PDGFRA-driven Cre-recombinase expressing hGPCs in human glial chimeric mice with a library of capsid-modified, recombination-reported adeno-associated viruses (AAVs). PCR screening for gliotropic viral capsid sequences, filtered against visceral organs, identified a set of AAV5-based vectors that preferentially infected human GPCs and/or their derived astrocytes and oligodendrocytes in vivo, with minimal systemic infection. To maximize the intracerebral distribution of these viruses while minimizing their dosing and extracerebral spread, we paired their intracisternal delivery with systemic hypertonicity. This method exploited intracerebral glymphatic flow to bypass the blood-brain barrier, delivering AAV directly into the brain parenchyma. Glymphatic delivery of capsid-modified AAV5s, evolved on human GPCs in vivo, thus enables efficient, brain-wide transgene delivery to human glia and their progenitors in the adult brain, with minimal off-target transduction.

neuroscience↗