Biology subjects

Wong, A. S.

Publications and source records attributed to Wong, A. S..

5 recordsLinked to original sources

bioRxiv2024

Diminished social memory and hippocampal correlates of social interactions in chronic social defeat stress susceptibility

BackgroundThe susceptibility to chronic stress has been associated with depression, a mood disorder which highly implicates the hippocampus. Hippocampal contribution to stress susceptibility has been supported by findings in mice following chronic social defeat stress (CSDS). However, little is known of the role of hippocampal activity in determining the development of stress susceptibility. MethodsWe used the UCLA miniscope to longitudinally measure the activity of dorsal CA1 hippocampal neurons across CSDS. Apart from examining the representation of social information by these neurons, we also compared social memory in mice that were susceptible or resilient to CSDS. ResultsWe observed more stable dCA1 correlates of social interaction and social memory in CSDS resilience. Such changes were absent in CSDS susceptible mice and accompanied by greater social memory impairments. ConclusionsCSDS susceptibility may be supported by hippocampal social cognitive processes, reflected in diminished hippocampal representations of social information and a greater impairment in social memory.

neuroscience↗

bioRxiv2024

Social valence dictates sex differences in identity recognition

Social valence is the directional emotional significance affiliated with social experiences. Maladaptive processing of negative social valence (NSV) has been linked to mood disorder susceptibility, which is more prevalent in women. To determine whether there are sex differences in NSV processing, we developed social valence tasks where the identity recognition of conspecifics with distinct valences served as the readout. Male mice demonstrated identity recognition regardless of social valence. Conversely, female mice did not show identity recognition following the NSV task. In vivo calcium imaging of the dorsal CA1 further revealed sex differences in NSV processing with reduced hippocampal representation of social information in female mice. These results suggest the imprecise encoding of NSV may contribute to the heightened vulnerability to social stress-related mood disorders in women.

neuroscience↗

bioRxiv2023

Isolating Small Extracellular Vesicles from Small Volumes of Blood Plasma using size exclusion chromatography and density gradient ultracentrifugation: A Comparative Study

Small extracellular vesicles (sEVs) are heterogeneous biological vesicles released by cells under both physiological and pathological conditions. Due to their potential as valuable diagnostic and prognostic biomarkers in human blood, there is a pressing need to develop effective methods for isolating high-purity sEVs from the complex milieu of blood plasma, which contains abundant plasma proteins and lipoproteins. Size exclusion chromatography (SEC) and density gradient ultracentrifugation (DGUC) are two commonly employed isolation techniques that have shown promise in addressing this challenge. In this study, we aimed to determine the optimal combination and sequence of SEC and DGUC for isolating sEVs from small plasma volumes, in order to enhance both the efficiency and purity of the resulting isolates. To achieve this, we compared sEV isolation using two combinations: SEC-DGUC and DGUC-SEC, from unit volumes of 500 l plasma. Both protocols successfully isolated high-purity sEVs; however, the SEC-DGUC combination yielded higher sEV protein and RNA content. We further characterized the isolated sEVs obtained from the SEC-DGUC protocol using flow cytometry and mass spectrometry to assess their quality and purity. In conclusion, the optimized SEC-DGUC protocol is efficient, highly reproducible, and well-suited for isolating high-purity sEVs from small blood volumes.

bioengineering↗

bioRxiv2020

High-Throughput 5' UTR Engineering for Enhanced Protein Production in Non-Viral Gene Therapies

Despite significant clinical progress in cell and gene therapies, maximizing protein expression in order to enhance potency remains a major challenge. One approach to increase protein expression is by optimizing translation through the engineering of 5 untranslated regions (5 UTRs). Here, we developed a high-throughput strategy to design, screen, and optimize novel 5UTRs that enhance protein expression from a strong human cytomegalovirus (CMV) promoter. We first identified naturally occurring 5 UTRs with high translation efficiencies and used this information with in silico genetic algorithms to generate synthetic 5 UTRs. A total of [~]12,000 5 UTRs were then screened using a recombinase-mediated integration strategy that greatly enhances the sensitivity of high-throughput screens by eliminating copy number and position effects that limit lentiviral approaches. Using this approach, we identified three synthetic 5 UTRs that outperformed commonly used non-viral gene therapy plasmids in expressing protein payloads. Furthermore, combinatorial assembly of these 5 UTRs enabled even higher protein expression than obtained with each individual 5 UTR. In summary, we demonstrate that high-throughput screening of 5 UTR libraries with recombinase-mediated integration can identify genetic elements that enhance protein expression, which should have numerous applications for engineered cell and gene therapies.

synthetic biology↗

bioRxiv2018

Negative memory engrams in the hippocampus enhance the susceptibility to chronic social defeat stress

The hippocampus has been highly implicated in depression symptoms. Recent findings suggest that the expression and susceptibility of depression symptoms are related to the enhanced functioning of the hippocampus. We reasoned that hippocampal engrams, which represent ensembles of neurons with increased activity after memory formation, could underlie some contributions of the hippocampus to depression symptoms. Using the chronic social defeat stress (CSDS) model, we examined social defeat-related hippocampal engrams in mice that are either susceptible or resilient to the stressor. TetTag mice were used to label social defeat-related hippocampal ensembles by LacZ. Engram cells correspond to ensembles that were reactivated by the same stressor.\n\nCompared to resilient and non-stressed control mice, we found that in both the dorsal and ventral hippocampal CA1 regions, susceptible mice exhibited a higher reactivation of social defeat-related LacZ-labeled cells (i.e. engram cells). The density of CA1 engram cells correlated with the level of social avoidance. Using DREADD to reactivate social defeat-related but not neutral contextual stimuli-related CA1 engram cells decreased social interaction. Increased engram cells in susceptible mice were region specific and could not be found in the dentate gyrus. Susceptible mice exhibited more negative stimuli-, but not neutral stimuli-, related CA1 engram cells than resilient mice in the dorsal hippocampus. Finally, chronic, but not a short and subthreshold, social defeat protocol was necessary to increase CA1 engram cell density. Together, our findings reveal that the susceptibility to CSDS is regulated by hippocampal CA1 engrams for negative memory. Hippocampal engrams for negative memory may underlie the vulnerability and expression of cognitive symptoms in depression.\n\nSignificance statementWe provided evidence that negative memory hippocampal engrams contribute to the susceptibility to developing depression-related behavior after chronic social defeat stress. The activation of positive memory engrams have been shown to alleviate depression-related behaviors, while our findings reveal the pathological roles of negative memory engrams that could lead to those behaviors. Increased negative memory engrams could be a downstream effect of the reported high hippocampal activity in animal models and patients with depression. Unlike affective symptoms, we know much less about the cellular mechanisms of the cognitive symptoms of depression. Given the crucial roles of hippocampal engrams in memory formation, enhanced reactivation of negative memory engrams could be an important cellular mechanism that underlies the cognitive symptoms of depression.

animal behavior and cognition↗