Biology subjects

Chen, P.-S.

Publications and source records attributed to Chen, P.-S..

4 recordsLinked to original sources

bioRxiv2026

Systemic AAV delivery of a calcium indicator in marmosets: functional validation in visual area MT

Functional optical imaging in nonhuman primates provides an important complement to electrophysiological approaches in neuroscience research, but its broader use has been limited by challenges in achieving large-scale, homogeneous expression of genetically encoded reporters, and imaging accessibility in species with gyrencephalic brains with sulci and fissures (e.g., rhesus macaques). Specifically, conventional local intracortical viral injections are invasive and often produce spatially restricted or heterogeneous expression, constraining population-level analyses. Here, we show that systemic intravenous delivery of an adeno-associated virus (AAV) capsid engineered for enhanced blood-brain barrier crossing, AAV.CAP-B10, supports robust and widespread expression of a calcium indicator CAaMP8s in the common marmoset. Intravenous delivery in two marmosets resulted in widespread cortical expression. Using a large cranial window over extrastriate visual area MT (and its satellite areas), we performed widefield single-photon imaging and two-photon cellular-resolution imaging in awake,behaving marmosets to functionally validate activity in this well studied primate visual-motion sensitive cortical area. Population level responses to visual motion and spatial organization measured with widefield imaging, as well as single-cell level motion direction tuning measured with two-photon imaging, were consistent with canonical properties of MT reported in previous electrophysiological studies. Quantitative analyses of lightsheet imaging after whole hemisphere brain clearing further confirmed the broad expression of GCaMP in both cortical and subcortical areas. Together, these results indicate that systemic delivery using AAV.CAP-B10 provides a minimally invasive approach for robust multi-scale functional optical imaging in awake, behaving marmosets.

neuroscience↗

bioRxiv2025

Area MT carries acceleration information in a quickly and directly decodable representation

We sought to better understand the neural representation of visual motion acceleration. A straightforward estimation of acceleration would involve calculating the rate of change of velocity, which itself would be calculated from change in position over time. As it is well-established that neurons in area MT encode velocity, the brain could thus indirectly estimate acceleration by calculating the change in MTs velocity representations. An alternate mechanism, however, could operate more rapidly and directly. In this case, the brain could exploit interactions between MTs standard motion encoding and idiosyncratic temporal dynamics of neural responses. Such direct decoding would thus exploit nonlinearities usually ignored in studies of MT coding. We tested between these two theories by measuring from ensembles of MT neurons while two male awake fixating macaques viewed linearly accelerating motion stimuli. Direct decoding of acceleration from MT was possible on faster time scales, and could be done with higher fidelity, than indirect decoding. Distinct motion acceleration information could thus be efficiently read out from rich and heterogeneous MT ensemble responses, regardless of the mechanisms that give rise to various forms of motion tuning that it exhibits. A similar analysis of activity in the medial superior temporal area (MST) did not suggest this later stage of motion processing has a more refined acceleration representation. Together, these results suggest that the brain may opportunistically exploit nonlinear idiosyncrasies of neural responses to efficiently extract behaviorally relevant information on fast time scales, instead of performing explicit calculation of some variables. Significance StatementThis study aims to understand if linear acceleration information of visual motion is extracted and represented in primate visual motion areas MT and MST. By combining large-scale multi-area neuronal recordings, population-level analyses, and a rich set of moving stimuli, we showed that linear acceleration can be decoded from MT activity. Specifically, our results demonstrate that (1) motion acceleration is encoded in MT, and can be directly and quickly decoded from MT ensemble activity, and (2) area MST, despite being a later stage of motion processing, does not refine acceleration representations. These findings call for revisiting how brain areas might efficiently extract behaviorally relevant information from the environment and highlight the importance of temporal dynamics in visual motion processing.

neuroscience↗

bioRxiv2025

MicroRNA-21-3p regulation of NOX4 and VEGFA contributes to hemorrhage in cerebral cavernous malformations

ObjectiveMicroRNAs regulate the brain vascular integrity and are involved in the lesion development of cerebral cavernous malformations (CCM). This study examines the role of microRNA-21-3p in CCM-related cerebral hemorrhage and its underlying mechanisms. MethodsThe expression of miRNA-21-3p and its target genes of NADPH oxidase 4 (NOX4) and vascular endothelial growth factor A (VEGFA) in brain microvascular endothelial cells (BMECs) and pericytes were assessed in cavernous malformation lesions of 20 sporadic CCM patients by fluorescence in situ hybridization. The association of their expression with hemorrhage manifestation was evaluated. Cell proliferation, permeability, reactive oxygen species (ROS), migration, tubule formation, and the expression of NOX4 and VEGFA were assessed in CCM2 gene-depleted human BMECs and pericytes after miRNA-21-3p intervention. Cerebral hemorrhage, vascular permeability, vascular dilation, and angiogenesis after miRNA-21-3p intervention were evaluated in the ccm2 gene-knockdown zebrafish. ResultsDecreased miRNA-21-3p and increased NOX4 and VEGFA were shown in BMECs and pericytes of the CCM lesions compared to peri-lesion normal vessels from epilepsy patients, which were also correlated with the presence of cerebral hemorrhage in CCM patients. Increasing miRNA-21-3p attenuated cell proliferation, permeability, ROS expression, cell migration, and tubule formation by targeting NOX4 and VEGFA in CCM2 gene-depleted BMECs and pericytes. In vivo studies revealed that increasing miRNA-21-3p reduced cerebral hemorrhage, vascular permeability, vascular dilation, angiogenesis, and the overexpression of nox4 and vegfa in ccm2 gene-knockdown zebrafish. ConclusionMiRNA-21-3p can be a novel therapeutic target by regulating NOX4 and VEGFA, thereby stabilizing vascular integrity and reducing cerebral hemorrhage in CCM lesions.

neuroscience↗

bioRxiv2024

Challenging the Conventional Treatment Initiation Paradigm: Early Detection of Irreversible Cellular Damage in Cardiac Biopsies of Fabry Disease Before the Formation of Gb3 Inclusion Bodies

BackgroundFabry disease (FD) is a lysosomal storage disorder impacting multiple organs, including the heart. We investigated whether early-stage globotriaosylceramide (Gb3) accumulation, before occurrence of inclusion bodies, could cause significant stress and irreversible damages of the cardiomyocytes in FD patients. To assess the cellular stress and irreversible damage of cardiomyocytes in FD during early-stage Gb3 accumulation before the occurrence of typical pathology. MethodsImmunofluorescent (IF) staining or Western blotting were performed on fibroblasts from FD patients and myocardial biopsies from G3Stg/GLAko mice and FD patients. Notably, all biopsies exhibited detectable Gb3 accumulation under IF but lacked typical FD (Gb3 inclusion body) pathology. Staining targeted nuclear factor-{kappa}B (NF-{kappa}B), interleukin-18 (IL-18), phospho-p42/44 mitogen-activated protein kinase (MAPK), and inducible nitric oxide synthase (iNOS) as inflammatory and oxidative stress markers. Alpha-smooth muscle actin (-SMA) IF staining was conducted to detect myofibroblasts. ResultsFibroblasts from FD patients, in conjunction with cardiomyocytes from both G3Stg/GLAko mice and FD patients, exhibited significant accumulation of inflammatory markers such as NF-{kappa}B IL-18 and phospho-p42/44 MAPK, as well as the oxidative stress marker iNOS. Despite the absence of typical FD pathology, the presence of fibrosis was confirmed in myocardial biopsies from these patients through strong positive staining of -SMA. ConclusionsSignificant cellular stress and even irreversible damage may occur before the onset of typical pathological changes in cardiomyocytes of FD. Based on our findings, treatment should be initiated much earlier than we currently thought to prevent irreversible damage and improve the prognosis of FD patients.

pathology↗