Biology subjects

Chang, S.-y.

Publications and source records attributed to Chang, S.-y..

4 recordsLinked to original sources

bioRxiv2026

WTR: A Toolkit for Functional Anterograde Transsynaptic Circuit Mapping

The brain coordinates animal physiology and behavior via neuronal circuits. To understand and simulate brain functions, it is essential to delineate the synaptic connectivity between neurons. Transsynaptic tracers serve as powerful tools for such purposes. In response to the demand for anterograde tracers for circuit mapping and functional interrogation, we developed WTR, a fusion protein of mammalian codon-optimized WGA, TEV-protease cleavage sequence, and Recombinase. WTR expressed via AAV vectors in cell-type-specific starter neurons reaches their postsynaptic neurons and releases Cre/Flpo upon exposure to TEV-protease expressed in downstream neurons. Accompanied by Cre/Flpo-dependent expression of EGFP, GCaMP7s, or ChR2, the toolkit enables labeling, recording, or manipulation of downstream neurons. We utilized WTR to characterize downstream neurons of either glutamatergic or GABAergic neurons in the preoptic area of anterior hypothalamus for their differential actions in thermoregulation or stress responses, respectively. These results establish WTR as a versatile platform for functional anterograde circuit mapping.

neuroscience↗

bioRxiv2025

Therapeutic assessment of a novel mitochondrial complex I inhibitor in in vitro and in vivo models of Alzheimer's disease

Despite recent approval of monoclonal antibodies that reduce amyloid (A{beta}) accumulation, the development of disease-modifying strategies targeting the underlying mechanisms of Alzheimers disease (AD) is urgently needed. We demonstrate that mitochondrial complex I (mtCI) represents a druggable target, where its weak inhibition activates neuroprotective signaling, benefiting AD mouse models with A{beta} and p-Tau pathologies. Rational design and structure-activity relationship studies yielded novel mtCI inhibitors profiled in a drug discovery funnel designed to address their safety, selectivity, and efficacy. The new lead compound C458 is highly protective against A{beta} toxicity, has favorable pharmacokinetics, and has minimal off-target effects. C458 exhibited excellent brain penetrance, activating neuroprotective pathways with a single dose. Preclinical studies in APP/PS1 mice were conducted via functional tests, metabolic assessment, in vivo 31P- NMR spectroscopy, blood cytokine panels, ex vivo electrophysiology, and Western blotting. Chronic oral administration improved long-term potentiation, reduced oxidative stress and inflammation, and enhanced mitochondrial biogenesis, antioxidant signaling, and cellular energetics. These studies provide further evidence that the restoration of mitochondrial function and brain energetics in response to mild energetic stress represents a promising disease- modifying strategy for AD.

neuroscience↗

bioRxiv2025

Exploring GPCR-mediated optogenetic modulation of seizure network in a pig model of Temporal Lobe Epilepsy

RationaleOptogenetics offers unmatched cellular specificity and control over cellular activity. Various opsins have been tested in animal models of epilepsy, each contributing to our understanding of seizure circuit dynamics. However, inhibitory optogenetic tools based on microbial rhodopsins have low light sensitivity and, thus, are less suitable for applications involving larger brains. We evaluated eOPN3, a red-shifted, highly sensitive inhibitory G-protein coupled receptor opsin in a porcine seizure model using integrated electro-optical sensing and modulation. The results demonstrated the feasibility of eOPN3 circuit modulation in a large animal epilepsy model. MethodsMRI-guided stereotactic surgery was used to deliver 20-60 {micro}L of AAV-eOPN3 (AAV5-/AAV9-CaMKII-eOPN3-mScarlet) into the hippocampus (HPC) of three Gottingen minipigs. Each hemisphere received either an active or a control viral vector (AAV5/9-CaMKII-mScarlet) with gadolinium to visualize the injection sites and diffusion volume via post-operative MRI. Two to three months post-injection, bilateral deep brain stimulation electrodes integrated with optic fibers were stereotactically implanted into the anterior nucleus of the thalamus (ANT) and HPC to assess: 1) opsin expression using fiber photometry, 2) optogenetic modulation of stimulation evoked response potentials (SERPs), 3) induction and propagation of seizure-like activity via intrahippocampal kainic acid (KA) injection, and 4) optogenetic modulation of KA-induced seizure activity. After the electrophysiology recording, brains were harvested for histological analysis to evaluate injection target precision, eOPN3 expression, and estimate eOPN3-modulated volume. ResultseOPN3 expression was confirmed during surgery via fiber photometry. ANT electrical stimulation elicited robust SERPs in the HPCs, which were attenuated by HPC light illumination. HPC stimulation similarly induced SERPs in the ipsilateral ANT and the contralateral HPC. The HPC stimulation-induced SERPs were significantly reduced by illuminating the site of the recording areas, the ipsilateral ANT and the contralateral HPC, demonstrating the optogenetic inhibition of the synaptic release from the HPC. KA injection into the HPC induced 20-30 Hz seizure-like activity. The ANT and HPC light illumination suppressed the localized KA-induced seizure activity in the early stage. However, after the generalization of KA-induced seizures, the ANT-HPC illumination lost efficacy for the control of seizures. Histological analysis confirmed eOPN3 expression in the HPC, ANT and other Papez circuit nodes. ConclusionOur pilot study highlights that eOPN3-mediated inhibition alters SERP and the latency and spread of KA-induced seizure-like activity. We developed a platform incorporating pre- and postoperative MRI for precise viral vector delivery, real-time fiber photometry for quantifying opsin expression, and integrated electro-optical sensing and stimulation to assess optogenetic efficacy in a large animal model. The large animal model provides a solid foundation for future translational research to develop electro-optical devices and cellular therapies for human epilepsy.

neuroscience↗

bioRxiv2023

Vagus nerve stimulation using an endovascular electrode array

Vagus nerve stimulation (VNS), which involves a surgical procedure to place electrodes directly on the vagus nerve (VN), is approved clinically for the treatment of epilepsy, depression, and to facilitate rehabilitation in stroke. VNS at surgically implanted electrodes is often limited by activation of motor nerve fibers near and within the VN that cause neck muscle contraction. In this study we investigated endovascular VNS that may allow activation of the VN at locations where the motor nerve fibers are not localized. We used endovascular electrodes within the nearby internal jugular vein (IJV) to electrically stimulate the VN while recording VN compound action potentials and neck muscle motor evoked potentials in an acute intraoperative swine experiment. We show that the stimulation electrode position within the IJV is critical for efficient activation of the VN. We also demonstrate use of fluoroscopy (cone beam CT mode) and ultrasound to determine the position of the endovascular stimulation electrode with respect to the VN and IJV. At the most effective endovascular stimulation locations tested, thresholds for VN activation were several times higher than direct stimulation of the nerve using a cuff electrode; however, this work demonstrates the feasibility of VNS with endovascular electrodes and provides tools to optimize endovascular electrode positions for VNS. The ability to stimulate the VN with endovascular electrodes creates the possibility to stimulate at VN locations that would be otherwise too invasive and at VN locations where structures such as motor nerve fibers do not exist.

neuroscience↗