Biology subjects

Man, H.

Publications and source records attributed to Man, H..

8 recordsLinked to original sources

bioRxiv2026

Human-specific multicopy gene FRMPD2 promotes synapse formation via recruitment of neuroligin 1

FRMPD2 is a human-specific multi-copy gene with higher mRNA expression in brain tissue, but its role in synapse formation and neurodevelopment remains unknown. We find that FRMPD2 is a neuron-specific protein with a high expression level in human brains compared to rodent brains. FRMPD2 overexpression in rat neurons stimulates synaptogenesis, leading to increased synaptic activities. Importantly, our results show that FRMPD2 via its PDZ domains recruits and enhances neuroligin-1 protein levels at the postsynaptic sites, and via its FERM domain interacts with the F-actin network in the spine. Increased expression of FRMPD2 also promotes spine formation and maturation, a foundational process for synapse formation. In developing embryonic mouse brains expressing higher FRMPD2 protein levels, we observed delayed neuronal migration, presumably promoting a protracted timeline for cortical lamination as a feature in human brain development. Behaviorally, mice with FRMPD2 overexpression in the brain demonstrate enhanced spatial memory retention. These findings indicate an important function for FRMPD2 in neuronal connectivity, brain development, and cognitive function.

neuroscience↗

bioRxiv2026

Subthreshold membrane depolarization powerfully engages intracellular calcium dynamics in the brain

Membrane voltage (Vm) regulates spike timing and intracellular signaling. While Vm is extensively modulated by behavior, it is unclear how subthreshold Vm dynamics engage intracellular signaling in the awake mammalian brain. We developed a bicistronic viral vector to express genetically encoded and color compatible voltage and calcium (Ca2+) indicators in the same neuron, and simultaneously recorded cellular Vm and Ca2+ dynamics in awake mice. We report that prolonged subthreshold Vm depolarization is closely accompanied by prominent large amplitude Ca2+ elevation, whereas isolated spikes are coupled with weak Ca2+ rise. Additionally, individual spikes differentially engage intracellular Ca2+ dynamics depending on post-spiking Vm depolarization, consistent with a prominent role of slow Vm depolarization in regulating cellular signaling. While brief intracranial electrical stimulation consistently leads to Vm depolarization and Ca2+ increase, longer stimulation disrupts Vm and Ca2+ coupling, highlighting a tightly regulated cellular mechanism that relays slow Vm depolarization to intracellular signaling.

neuroscience↗

bioRxiv2024

AutoMorFi: Automated Whole-image Morphometry in Fiji/ImageJ for Diverse Image Analysis Needs

Running on the highly popular and accessible ImageJ/Fiji platform for biological image analysis, we have established AutoMorFi as a streamlined interface for automated whole-image morphometric analysis that generates at least 47 measurements per cell or object in under 1 minute. We performed multiple validated cluster and principal component analyses on nonredundant morphometric parameters derived from AutoMorFi for various cell types, objects, and organisms. We used images of rodent macrophages, human postmortem brain tissues from multiple sclerosis (MS) and Alzheimers disease (AD) patients, iPSC/animal models for Downs syndrome and autism spectrum disorder (ASD), and organisms such as sea anemone and corals. AutoMorFis adaptability extends across diverse imaging modalities including brightfield, confocal, or widefield fluorescence microscopy as well as underwater photography. Due to its unlimited and unbiased sampling across any image and high potential for modification and customization, using AutoMorFi has led to the discovery of new distinguishing features in previously studied cell types and organisms as well as the development of rapid diagnostic approaches. AutoMorFi represents a transformative tool that will accelerate morphometric analysis and offer broad relevance in biological studies.

cell biology↗

bioRxiv2024

Sexually dimorphic phenotypes and the role of androgen receptors in UBE3A-dependent autism spectrum disorder

Autism spectrum disorders (ASDs) are characterized by social, communication, and behavioral challenges. UBE3A is one of the most common ASD genes. ASDs display a remarkable sex difference with a 4:1 male to female prevalence ratio; however, the underlying mechanism remains largely unknown. Using the UBE3A-overexpressing mouse model for ASD, we studied sex differences at behavioral, genetic, and molecular levels. We found that male mice with extra copies of Ube3A exhibited greater impairments in social interaction, repetitive self-grooming behavior, memory, and pain sensitivity, whereas female mice with UBE3A overexpression displayed greater olfactory defects. Social communication was impaired in both sexes, with males making more calls and females preferring complex syllables. At the molecular level, androgen receptor (AR) levels were reduced in both sexes due to enhanced degradation mediated by UBE3A. However, AR reduction significantly dysregulated AR target genes only in male, not female, UBE3A-overexpressing mice. Importantly, restoring AR levels in the brain effectively normalized the expression of AR target genes, and rescued the deficits in social preference, grooming behavior, and memory in male UBE3A-overexpressing mice, without affecting females. These findings suggest that AR and its signaling cascade play an essential role in mediating the sexually dimorphic changes in UBE3A-dependent ASD.

neuroscience↗

bioRxiv2022

The autism spectrum disorder risk gene NEXMIF alters hippocampal CA1 cellular and network dynamics

Perturbations in autism spectrum disorder (ASD) risk genes disrupt neural circuit dynamics and ultimately lead to behavioral abnormalities. To understand how ASD-implicated genes influence network computation during behavior, we performed in vivo calcium imaging from hundreds of individual hippocampal CA1 neurons simultaneously in freely locomoting mice with total knockout of NEXMIF. NEXMIF is an ASD risk gene most highly expressed in the hippocampus, and NEXMIF knockout in mice creates a range of behavioral deficits, including impaired hippocampal-dependent memory. We found that NEXMIF knockout does not alter the overall excitability of individual neurons but exaggerates movement-mediated neuronal responses. At the network level, NEXMIF knockout creates over-synchronization of the CA1 circuit, quantified by pairwise correlation and network closeness centrality. These neuronal effects observed upon NEXMIF knockout highlight the network consequences of perturbations in ASD-implicated genes, which have broad implications for cognitive performance and other ASD-related behavioral disruptions.

neuroscience↗

bioRxiv2021

Large-scale voltage imaging in the brain using targeted illumination

Recent improvements in genetically encoded voltage indicators enabled optical imaging of action potentials and subthreshold membrane voltage dynamics from single neurons in the mammalian brain. To perform high speed voltage imaging, widefield microscopy remains an essential tool for recording activity from many neurons simultaneously over a large anatomical area. However, the lack of optical sectioning makes widefield microscopy more prone to background signal contamination, and thus far voltage imaging using fully genetically encoded voltage indicators remains limited to simultaneous sampling of a few cells over a restricted field-of-view. We here demonstrate a strategy for large scale voltage imaging using the fully genetically encoded voltage indicator SomArchon and targeted illumination. We implemented a simple, low-cost digital micromirror device based targeted illumination strategy to restrict illumination to the cells of interest, and systematically quantified the improvement of this microscopy design theoretically and experimentally with SomArchon expressing neurons in single layer cell cultures and in the brains of awake mice. We found that targeted illumination, in comparison to widefield illumination, increased SomArchon signal contrast and reduced background cross-contamination in the brain. Such improvement permitted the reduction of illumination intensity, and thus reduced fluorescence photobleaching and prolonged imaging duration. When coupled with a high-speed, large area sCMOS camera, we routinely imaged tens of spiking neurons simultaneously over minutes in the brain. Thus, the widefield microscopy design with an integrated targeted illumination system described here offers a simple solution for voltage imaging analysis of large neuron populations in behaving animals.

neuroscience↗

bioRxiv2020

RTP801 Is A Key Modulator For Motor Learning

RTP801/REDD1 is a stress-regulated protein whose upregulation is necessary and sufficient to trigger neuronal death in in vitro and in vivo models of Parkinsons and Huntingtons diseases and is up regulated in compromised neurons in human postmortem brains of both neurodegenerative disorders. Indeed, in both Parkinsons and Huntingtons disease mouse models, RTP801 knockdown alleviates motor-learning deficits. Here, we investigated the physiological role of RTP801 in neuronal plasticity. RTP801 is found in rat, mouse and human synapses. The absence of RTP801 enhanced excitatory synaptic transmission in both neuronal cultures and brain slices from RTP801 knock-out (KO) mice. Indeed, RTP801 KO mice showed improved motor learning, which correlated with lower spine density but increased basal filopodia and mushroom spines in the motor cortex layer V. This paralleled with higher levels of synaptosomal GluA1 and TrkB receptors in homogenates derived from KO mice motor cortex, proteins that are associated with synaptic strengthening. Altogether, these results indicate that RTP801 has an important role modulating neuronal plasticity in motor learning.

neuroscience↗

bioRxiv2020

Neural Stimulation in vitro and in vivo by Photoacoustic Nanotransducers

Neuromodulation is an invaluable approach for study of neural circuits and clinical treatment of neurological diseases. Here, we report semiconducting polymer nanoparticles based photoacoustic nanotransducers (PANs) for neural stimulation. Our PANs strongly absorb light in the near-infrared second window and generate localized acoustic waves. PANs can also be surface-modified to selectively bind onto neurons. PAN-mediated activation of primary neurons in vitro is achieved with ten 3-nanosecond laser pulses at 1030 nm over a 3 millisecond duration. In vivo neural modulation of mouse brain activities and motor activities is demonstrated by PANs directly injected into brain cortex. With millisecond-scale temporal resolution, sub-millimeter spatial resolution and negligible heat deposition, PAN stimulation is a new non-genetic method for precise control of neuronal activities, opening potentials in non-invasive brain modulation.

neuroscience↗