Biology subjects

Yeung, C.

Publications and source records attributed to Yeung, C..

6 recordsLinked to original sources

bioRxiv2025

A dataset of differentiable biologically-derived single neuron models

Biological neural networks contain diverse cell types with heterogeneous electrophysiological properties. Artificial neural networks (ANNs) model computational aspects of biology but use homogeneous neurons, limiting realism. A key obstacle to building bio-inspired ANNs is the absence of a database of neuron models that both fit biological data and remain differentiable for gradient-based learning. We present such a database: over 1,000 differentiable single-neuron firing-rate models with accompanying PyTorch code for integration with machine learning. The models belong to the linear-nonlinear (LN) class, which, for ease of reference, we term Generalized Firing Rate (GFR) neurons. Each GFR neuron uses input and firing-rate history filters across multiple timescales, followed by a nonlinearity to generate firing rates. Models are fit to patch-clamp recordings from mouse and human central nervous system slices. Parameter clustering reflects electrophysiological diversity and partially aligns with transgenic lines. This resource will enable development of bio-inspired ANNs built from biologically grounded, differentiable single-neuron models. HighlightsO_LIResource of over 1,000 differentiable single-neuron models fit to mouse and human patch-clamp recordings C_LIO_LIOpen source PyTorch code and reproducible pipelines support model fitting, evaluation, and network integration C_LIO_LIFitted model parameters capture electrophysiological diversity, with parameter clusters partially aligning to inhibitory/excitatory types and Cre driver lines C_LI

neuroscience↗

bioRxiv2025

Deciphering the combinatorial expression pattern and genetic regulatory mechanisms of Beats and Sides in the olfactory circuits of Drosophila

Over the past decades, many critical molecular players have been uncovered to control distinct steps in olfactory circuit assembly in Drosophila. Among these, multi-member gene families of cell surface proteins are of interest because they can act as neuron-specific identification/recognition tags in combinations and contribute to circuit assembly in complex brains through their heterophilic or homophilic interactions. Recently, a multi-protein interactome has been described between the Beat and Side families of IgSF proteins. Here, we use the publicly available single-cell RNA-seq datasets and newly generated gene trap transgenic driver lines to probe the in vivo spatial expression pattern of the beat/side gene families in odorant receptor neurons (ORNs) and their synaptic target projection neurons (PNs). Our results revealed that each ORN and its synaptic target PN class expresses a class-specific combination of beat/side genes, hierarchically regulated by lineage-specific genetic programs. Though ORNs or PNs from closer lineages tend to possess more similar beat/side profiles, we also found many examples of divergence from this pattern among closely related ORNs and closely related PNs. To explore whether the class-specific combination of beats/sides defines ORN-PN matching specificity, we perturbed presynaptic beat-IIa and postsynaptic side-IV in two ORN-PN partners. However, disruption of Beat-IIa-Side-IV interaction did not produce any significant mistargeting in these two examined glomeruli. Though without affecting general glomerular targeting, knockdown of side in ORNs leads to the reduction of synaptic development. Interestingly, we found conserved expression patterns of beat/side orthologs across ORNs in ants and mosquitoes, indicating the shared regulatory strategies specifying the expression of these duplicated paralogs in insect evolution. Overall, this comprehensive analysis of expression patterns lays a foundation for in-depth functional investigations into how Beat/Side combinatorial expression contributes to the olfactory circuit assembly.

neuroscience↗

bioRxiv2023

Conserved atypical cadherin, Fat2, regulates axon terminal organization in the developing Drosophila olfactory sensory neurons

A unique and defining characteristic of the olfactory sensory circuit is its functionally organized topographic map, which requires widely dispersed olfactory sensory neurons with the same identity to converge their axons into one neuropil, a class-specific glomerulus. Understanding the process of how neuronal identity confers circuit organization is a major endeavor in the field of neurobiology due to its intricate connection to neurodegeneration and neuronal dysfunction. In the olfactory system, many aspects of circuit organization, from axon guidance to synaptic matching, are regulated by a variety of cell surface proteins (for example Robo/Slit and Toll receptors). In this paper, weve identified a novel atypical cadherin protein, Fat2 (also known as Kugelei), as a regulator of class-specific axon organization. Fat2 is expressed in olfactory receptor neurons (ORNs) and local interneurons (LNs) within the olfactory circuits, but little to no expression is found in projection neurons (PNs). Fat2 expression levels vary in a neuronal class-specific manner and peak during pupal development. In fat2 null mutants, ORN axon terminals belonging to different ORN classes present with varying phenotypic severity with the highest fat2 expressing classes being most severely affected. In the most extreme cases, fat2 mutations lead to ORN degeneration. We then show evidence that suggests Fat2 intracellular domain is necessary for Fat2 function in ORN axon organization. Within the developmental context, Fat2 is required starting at early stages of olfactory circuit development specifically for precise axon retraction to further condense class-specific glomeruli. Weve also shown that PNs and LNs expression of Fat2 likely does not contribute to ORN organization 1. Lastly, we narrow down potential Fat2 intracellular domain interactors, APC family proteins (Adenomatous polyposis coli) and dop (Drop out), that likely orchestrate the cytoskeletal remodeling required for axon retraction during protoglomerular development. Altogether, we provide a foundational understanding of how Fat2 functions in olfactory circuit organization and implicate the critical role of axon retraction during glomerular maturation.

developmental biology↗

bioRxiv2022

Molecular basis of FAAH-OUT-associated human pain insensitivity

Chronic pain affects millions of people worldwide. Studying pain insensitive individuals helps to identify novel analgesic strategies. Here we report how the recently discovered FAAH-OUT lncRNA-encoding gene, which was found from studying a pain insensitive patient with reduced anxiety and fast wound healing, regulates the adjacent key endocannabinoid system gene FAAH, which encodes the anandamide-degrading fatty acid amide hydrolase enzyme. We demonstrate that the disruption in FAAH-OUT lncRNA transcription leads to DNMT1-dependent DNA methylation within the FAAH promoter. In addition, FAAH-OUT contains a conserved regulatory element, FAAH-AMP, that acts as an enhancer for FAAH expression. Furthermore, using transcriptomic analyses we have uncovered a network of genes that are dysregulated from disruption of the FAAH-FAAH-OUT axis, thus providing a coherent mechanistic basis to understand the human phenotype observed and a platform for development of future gene and small molecule therapies.

neuroscience↗

bioRxiv2019

CRISPR interference at the FAAH-OUT genomic region reduces FAAH expression

FAAH-OUT encodes a putative long non-coding RNA which is located next to the FAAH gene on human chromosome 1. Recently an ~8 kb microdeletion, that removes upstream regulatory elements and the first 2 exons of FAAH-OUT, was reported in a pain insensitive patient (PFS) with additional clinical symptoms including a happy, non-anxious disposition, fast wound healing, fear and memory deficits, and significant post-operative nausea and vomiting induced by morphine. PFS also carries a hypomorphic SNP in FAAH that significantly reduces the activity of the encoded fatty-acid amide hydrolase enzyme. The FAAH and FAAH-OUT mutations identified in PFS result in elevated levels of anandamide (AEA), palmitoylethanolamide (PEA) and oleoylethanolamine (OEA) measured in peripheral blood. These bioactive lipids, which are normally degraded by FAAH, have diverse biological functions including known roles in pain pathways.\n\nHere we report the first mechanistic insights into how the FAAH-OUT microdeletion affects FAAH function. Gene editing in a human cell line to mimic the FAAH-OUT microdeletion observed in PFS results in reduced expression of FAAH. Furthermore, CRISPRi experiments targeting the promoter region of FAAH-OUT or a short highly evolutionarily conserved element in the first intron of FAAH-OUT also result in reduced expression of FAAH. These experiments confirm the importance of FAAH-OUT and specific genomic elements within the ~8 kb microdeleted sequence to normal FAAH expression. Our results also highlight the potential of CRISPRi and gene editing strategies that target the FAAH-OUT region for the development of novel FAAH-based analgesic and anxiolytic therapies.

genetics↗

bioRxiv2018

Atropselective Oxidation of 2,2′,3,3′,4,6′-Hexachlorobiphenyl (PCB 132) to Hydroxylated Metabolites by Human Liver Microsomes: Involvement of Arene Oxide Intermediates

PCBs and their hydroxylated metabolites have been associated with neurodevelopmental disorders. Several neurotoxic congeners display axial chirality and atropselectively affect cellular targets implicated in PCB developmental neurotoxicity; however, only limited information is available regarding the metabolism of these congeners in humans. We hypothesize that the oxidation of 2,2',3,3',4,6'-hexachlorobiphenyl (PCB 132) by human liver microsomes (HLMs) is atropselective and displays inter-individual variability. To test this hypothesis, PCB 132 (50 M) was incubated with pooled or single donor HLMs for 10, 30 or 120 min at 37 {degrees}C, and levels and enantiomeric fractions of PCB 132 and its metabolites were determined gas chromatographically. The major metabolite formed by different HLM preparations was either 2,2',3,4,4',6'-hexachlorobiphenyl-3'-ol (3'-140) or 2,2',3,3',4,6'-hexachlorobiphenyl-5'-ol (5'-132). 2,2',3,3',4,6'-Hexachlorobiphenyl-4'-ol (4'-132) and 2,2',3,3',4,6'-hexachlorobiphenyl-4',5'-diol (4',5'-132) were minor metabolites. The second eluting atropisomer of PCB 132 was slightly enriched in some HLM incubations. The formation of the first eluting atropisomer of 3'-140 was nearly enantiospecific (EF > 0.8). The second eluting atropisomer of 5'-132 was enriched in all microsomal preparations investigated. EF values differed slightly between single donor HLM preparations (EF = 0.84 to 0.96 for 3'-140; EF = 0.12 to 0.19 for 5'-132). These findings suggest that there are inter-individual differences in the atropselective biotransformation of PCB 132 to OH-PCBs in humans that may affect neurotoxic outcomes.

pharmacology and toxicology↗