Biology subjects

Sivyer, B.

Publications and source records attributed to Sivyer, B..

5 recordsLinked to original sources

bioRxiv2026

A pooled genetic approach provides multimodal access to uncharacterized retinal ganglion cell subtypes

Retinal ganglion cells (RGCs) are the sole output neurons of the retina, responsible for transmitting visual information to the brain. Recent transcriptomic studies have revealed extensive molecular diversity among RGCs that parallels their known morphological and functional heterogeneity. Although large-scale efforts have unified the transcriptomic, morphological, and physiological features for a limited number of RGC subtypes, the majority of molecularly defined types remain poorly characterized. Developing approaches that can be used to identify RGC subtypes in a reliable and reproducible manner is critical for understanding their roles in visual processing. We used a MafbmCherry-2A-Cre mouse line to genetically label four uncharacterized RGC subtypes, along with two well-established -RGC subtypes, and we systematically characterized their molecular markers, central brain targets, dendritic morphologies, and light response properties. Within the population of previously uncharacterized MAFB+ RGCs, we identified two OFF-responsive subtypes which we termed "MAFB-midi-OFF" and "MAFB-asymmetric-OFF", and two ON-OFF-responsive subtypes termed "MAFB-equal bistratified" and "MAFB-unequal bistratified". Notably, no single molecular, morphological, or functional characteristic was sufficient to distinguish all MAFB+ subtypes. Instead, accurate subtype classification emerged only through the integration of multiple complementary features, highlighting the importance of multimodal approaches for defining RGC subtype identity and resolving neuronal diversity within the retina.

neuroscience↗

bioRxiv2025

PTEN regulates starburst amacrine cell dendrite morphology during development

Neurons are subject to extensive developmental regulation to ensure precise subtype-specific morphologies that are intimately tied to their function. Starburst amacrine cells (SACs) in the mammalian retina have a highly stereotyped, radially symmetric dendritic arbor that is essential for their role in direction-selective circuits in the retina. We show that PTEN, the primary negative regulator of the PI3K-AKT-mTOR pathway that is highly implicated in neurodevelopmental disorders, regulates SAC morphology in a cell-autonomous manner. Pten-deficient SACs show a nearly twofold increase in the number of dendritic branches, while other morphological properties remain largely unchanged. These morphological changes arise late in SAC development after dendrite development is largely complete and persist into adulthood. Mechanistically, excessive dendritic branching appears to arise from dysregulated mTOR activity. Despite this dramatic increase in dendritic branches, Pten-deficient SACs maintain a normal population number, organization of synaptic outputs, and intact direction-selectivity in the retina. Collectively, these results show that PTEN is essential for the normal development of highly stereotyped neuronal morphology.

neuroscience↗

bioRxiv2024

Molecular and spatial analysis of ganglion cells on retinal flatmounts: diversity, topography, and perivascularity

Diverse retinal ganglion cells (RGCs) transmit distinct visual features from the eye to the brain. Recent studies have categorized RGCs into 45 types in mice based on transcriptomic profiles, showing strong alignment with morphological and electrophysiological properties. However, little is known about how these types are spatially arranged on the two-dimensional retinal surface--an organization that influences visual encoding--and how their local microenvironments impact development and neurodegenerative responses. To address this gap, we optimized a workflow combining imaging-based spatial transcriptomics (MERFISH) and immunohistochemical co-staining on thin flatmount retinal sections. We used computational methods to register en face somata distributions of all molecularly defined RGC types. More than 75% (34/45) of types exhibited non-uniform distributions, likely reflecting adaptations of the retinas anatomy to the animals visual environment. By analyzing the local neighborhoods of each cell, we identified perivascular RGCs located near blood vessels. Seven RGC types are enriched in the perivascular niche, including members of intrinsically photosensitive RGC (ipRGC) and direction-selective RGC (DSGC) subclasses. Orthologous human RGC counterparts of perivascular types - Melanopsin-enriched ipRGCs and ON DSGCs - were also proximal to blood vessels, suggesting their perivascularity may be evolutionarily conserved. Following optic nerve crush in mice, the perivascular M1-ipRGCs and ON DSGCs showed preferential survival, suggesting that proximity to blood vessels may render cell-extrinsic neuroprotection to RGCs through an mTOR-independent mechanism. Overall, our work offers a resource characterizing the spatial profiles of RGC types, enabling future studies of retinal development, physiology, and neurodegeneration at individual neuron type resolution across the two-dimensional space.

neuroscience↗

bioRxiv2023

Functional subtypes of rodent melanopsin ganglion cells switch roles between night and day illumination.

Intrinsically photosensitive retinal ganglion cells (ipRGCs), contain the photopigment melanopsin, and influence both image and non-image forming behaviors. Despite being categorized into multiple types (M1-M6), physiological variability within these types suggests our current understanding of ipRGCs is incomplete. We used multi-electrode array (MEA) recordings and unbiased cluster analysis under synaptic blockade to identify 8 functional clusters of ipRGCs, each with distinct photosensitivity and response timing. We used Cre mice to drive the expression of channelrhodopsin in SON-ipRGCs, enabling the localization of distinct ipRGCs in the dorsal retina. Additionally, we conducted a retrospective unbiased cluster analysis of ipRGC photoresponses to light stimuli across scotopic, mesopic, and photopic intensities, aimed at activating both rod and cone inputs to ipRGCs. Our results revealed shared and distinct synaptic inputs to the identified functional clusters, demonstrating that ipRGCs encode visual information with high fidelity at low light intensities, but poorly at photopic light intensities, when melanopsin activation is highest. Collectively, our findings support a framework with at least 8 functional subtypes of ipRGCs, each encoding luminance with distinct spike outputs, highlighting the inherent functional diversity and complexity of ipRGCs and suggesting a reevaluation of their contributions to retinal function and visual perception under varying light conditions.

neuroscience↗

bioRxiv2020

Gbx2 identifies two amacrine cell subtypes with distinct molecular, morphological, and physiological properties

Our understanding of how the nervous sytem works is limited by our ability to identify the neuronal subtypes that comprise functional circuits. Using a genetic approach, we show that the transcription factor Gbx2 labels two amacrine cell (AC) subtypes in the mouse retina that have distinct morphological, physiological, and molecular properties. One subtype of Gbx2+ ACs are likely the previously characterized On-type GABAergic CRH-1 AC. The other Gbx2+ AC population is a previously uncharacterized non-GABAergic, non-Glycinergic (nGnG) AC subtype. Gbx2+ nGnG ACs are On-Off type cells with asymmetric dendritic arbors. Gbx2+ nGnG ACs also exhibit tracer coupling to bipolar cells (BCs) through gap junctions that are modulated by dopamine signaling. This study genetically identifies a previously uncharacterized AC subtype and reveals an unusual AC-BC connectivity through gap junctions that may provide a novel model of synaptic communication and visual circuit function.

neuroscience↗