Biology subjects

Chon, U.

Publications and source records attributed to Chon, U..

9 recordsLinked to original sources

bioRxiv2025

Inverse expression of Ten3 and Lphn2 across the developing mouse brain reveals a global strategy for circuit assembly

Precise wiring of neural circuits requires molecular strategies that ensure accurate target selection across diverse brain regions. Here, we identify inverse expression between a ligand-receptor pair, Teneurin-3 (Ten3) and Latrophilin-2 (Lphn2), across the developing mouse brain. Ten3 and Lphn2 exhibit inverse expression gradients along a retinotopic axis orthogonal to the ephrin-A and EphA gradients; along the tonotopic axis across multiple brainstem auditory nuclei; and along the dorsomedial-ventrolateral axis in striatum and pallidum. Their inverse expression also creates discrete domains of cerebellar Purkinje cells and cerebellar nuclei. Using conditional tag mice, we show that inverse Ten3 and Lphn2 expression patterns predict connectivity, following a Ten3[->]Ten3, Lphn2[->]Lphn2 rule in all above circuits, and that Lphn2 is required in executing this rule in Purkinje cells[->]cerebellar nuclei projection. Our findings suggest a global strategy of coordinating gene expression of key wiring molecules with circuit connectivity across the developing brain.

neuroscience↗

bioRxiv2023

Aging drives cerebrovascular network remodeling and functional changes in the mouse brain

Aging is the largest risk factor for neurodegenerative disorders, and commonly associated with compromised cerebrovasculature and pericytes. However, we do not know how normal aging differentially impacts the vascular structure and function in different brain areas. Here we utilize mesoscale microscopy methods (serial two-photon tomography and light sheet microscopy) and in vivo imaging (wide-field optical spectroscopy and two-photon imaging) to determine detailed changes in aged cerebrovascular networks. Whole-brain vascular tracing showed an overall [~]10% decrease in vascular length and branching density with [~]7% increase in vascular radii in aged brains. Light sheet imaging with 3D immunolabeling revealed increased arteriole tortuosity of aged brains. Notably, vasculature and pericyte densities showed selective and significant reductions in the deep cortical layers, hippocampal network, and basal forebrain areas. We also found a significant increase in blood extravasation, implying compromised blood-brain barrier function in aged brains. Moreover, in vivo imaging in awake mice identified a reduction of baseline and on-demand blood oxygenation despite relatively intact neurovascular coupling. Collectively, we uncover regional vulnerabilities of cerebrovascular network and physiological changes that can mediate cognitive decline in normal aging. Highlight- Brain-wide mapping of vasculature and pericyte changes with normal aging - Simplified vascular network with tortuous vessels in aged brains - Vascular rarefication in the deep cortical layers, hippocampus, and the basal forebrain - Intact neurovascular coupling but lower blood oxygenation in aged animals

neuroscience↗

bioRxiv2021

The cellular architecture of microvessels, pericytes and neuronal cell types in organizing regional brain energy homeostasis in mice

Cerebrovasculature and its mural cells must meet dynamic energy demands of different neuronal cell types across the brain, but their spatial relationship is largely unknown. Here, we apply brain-wide mapping methods to create a comprehensive cellular-resolution resource comprising the distribution of and quantitative relationship between cerebrovasculature, pericytes, and glutamatergic and GABAergic neurons, including neuronal nitric oxide synthase-positive (nNOS+) neurons and their subtypes, as well as simulation-ready vascular tracing data in mice. We discover strikingly high densities of vasculature and pericytes with high blood perfusion in primary motor-sensory cortices compared to association cortices that show significant positive and negative correlation with parvalbumin+ and nNOS+ neurons, respectively. Thalamo-striatal areas linked to primary motor-sensory cortices also contain high densities of vasculature and pericytes compared to association areas. Collectively, our results unveil a finely tuned spatial relationship between cerebrovascular network and neuronal cell composition in meeting regional energy needs of the brain.

neuroscience↗

bioRxiv2020

Cellular Anatomy of the Mouse Primary Motor Cortex

An essential step toward understanding brain function is to establish a cellular-resolution structural framework upon which multi-scale and multi-modal information spanning molecules, cells, circuits and systems can be integrated and interpreted. Here, through a collaborative effort from the Brain Initiative Cell Census Network (BICCN), we derive a comprehensive cell type-based description of one brain structure - the primary motor cortex upper limb area (MOp-ul) of the mouse. Applying state-of-the-art labeling, imaging, computational, and neuroinformatics tools, we delineated the MOp-ul within the Mouse Brain 3D Common Coordinate Framework (CCF). We defined over two dozen MOp-ul projection neuron (PN) types by their anterograde targets; the spatial distribution of their somata defines 11 cortical sublayers, a significant refinement of the classic notion of cortical laminar organization. We further combine multiple complementary tracing methods (classic tract tracing, cell type-based anterograde, retrograde, and transsynaptic viral tracing, high-throughput BARseq, and complete single cell reconstruction) to systematically chart cell type-based MOp input-output streams. As PNs link distant brain regions at synapses as well as host cellular gene expression, our construction of a PN type resolution MOp-ul wiring diagram will facilitate an integrated analysis of motor control circuitry across the molecular, cellular, and systems levels. This work further provides a roadmap towards a cellular resolution description of mammalian brain architecture.

neuroscience↗

bioRxiv2020

Parallel Movement-suppressing Striatal Output Pathways

The classic basal ganglia circuit model asserts a complete segregation of the two striatal output pathways. Empirical data argue that, in addition to indirect-pathway striatal projection neurons (iSPNs), direct-pathway striatal projection neurons (dSPNs) innervate the external globus pallidus (GPe). However, the functions of the latter were not known. In this study, we interrogated the organization principles of striatopallidal projections and their roles in full-body movement in mice (both males and females). In contrast to the canonical motor-promoting response of dSPNs in the dorsomedial striatum (DMSdSPNs), optogenetic stimulation of dSPNs in the dorsolateral striatum (DLSdSPNs) suppressed locomotion. Circuit analyses revealed that dSPNs selectively target Npas1+ neurons in the GPe. In a chronic 6-hydroxydopamine lesion model of Parkinsons disease, the dSPN-Npas1+ projection was dramatically strengthened. As DLSdSPN-Npas1+ projection suppresses movement, the enhancement of this projection represents a circuit mechanism for the hypokinetic symptoms of Parkinsons disease that has not been previously considered. In sum, our results suggest that dSPN input to the GPe is a critical circuit component that is involved in the regulation of movement in both healthy and parkinsonian states. Significance statementIn the classic basal ganglia model, the striatum is described as a divergent structure--it controls motor and adaptive functions through two segregated, opposing output streams. However, the experimental results that show the projection from direct-pathway neurons to the external pallidum have been largely ignored. Here, we showed that this striatopallidal sub-pathway targets a select subset of neurons in the external pallidum and is motor-suppressing. We found that this sub-pathway undergoes changes in a Parkinsons disease model. In particular, our results suggest that the increase in strength of this sub-pathway contributes to the slowness or reduced movements observed in Parkinsons disease.

neuroscience↗

bioRxiv2020

Mycobacterial HelD is a nucleic acids-clearing factor for RNA polymerase

RNA synthesis is central to life, and RNA polymerase depends on accessory factors for recovery from stalled states and adaption to environmental changes. Here we investigated the mechanism by which a helicase-like factor HelD recycles RNA polymerase. We report a cryo-EM structure of an unprecedented complex between the Mycobacterium smegmatis RNA polymerase and HelD. The crescent-shaped HelD simultaneously penetrates deep into two RNA polymerase channels that are responsible for DNA binding and substrate delivery to the active site, thereby locking RNA polymerase in an inactive state. We show that HelD prevents non-specific interactions between RNA polymerase and DNA and dissociates transcription elongation complexes, but does not inhibit RNA polymerase binding to the initiation {sigma} factor. The liberated RNA polymerase can either stay dormant, sequestered by HelD, or upon HelD release, restart transcription. Our results provide insights into the architecture and regulation of the highly medically-relevant mycobacterial transcription machinery and define HelD as a clearing factor that removes undesirable nucleic acids from RNA polymerase.

molecular biology↗

bioRxiv2019

Quantitative Cellular-Resolution Map of the Oxytocin Receptor in Postnatally Developing Mouse Brains

Oxytocin receptor (OTR) plays critical roles in social behavior development. Despite its significance, brain-wide quantitative understanding of OTR expression remains limited in postnatally developing brains. Here, we validated and utilized fluorescent reporter mice (OTRvenus/+) to examine OTR cells across postnatal periods. We developed postnatal 3D template brains to register whole brain images with cellular resolution to systematically quantify OTR cell densities. We found that cortical regions showed temporally and spatially heterogeneous patterns with transient postnatal OTR expression without cell death. Cortical OTR cells were largely not GABAergic neurons with the exception of cells in layer 6b. Subcortical regions showed similar temporal regulation except the hypothalamus. Moreover, our unbiased approach identified two hypothalamic nuclei with sexually dimorphic OTR expression. Lastly, we created a website to easily share our imaging data. In summary, we provide comprehensive quantitative data to understand postnatal OTR expression in the mouse brain.

neuroscience↗

bioRxiv2019

Npas1+-Nkx2.1+ Neurons Form A Unique Pallidal Neuron Subclass

Within the basal ganglia circuit, the external globus pallidus (GPe) is critically involved in motor control. Aside from Foxp2+ neurons and ChAT+ neurons that have been established as unique neuron types, there is little consensus on the classification of GPe neurons. Properties of the remaining neuron types are poorly-defined. In this study, we leverage new mouse lines, viral tools, and molecular markers to better define GPe neuron subtypes. We found that Sox6 represents a novel, defining marker for GPe neuron subtypes. Lhx6+ neurons that lack the expression of Sox6 were devoid of both parvalbumin and Npas1. This result confirms previous assertions of the existence of a unique Lhx6+ population. Neurons that arise from the Dbx1+ lineage were similarly abundant in the GPe and displayed a heterogeneous makeup. Importantly, tracing experiments revealed that Npas1+-Nkx2.1+ neurons represent the principal non-cholinergic, cortically-projecting neurons. In other words, they form the pallido-cortical arm of the cortico-pallido-cortical loop. Our data further described that pyramidal-tract neurons in the cortex collateralized within the GPe, forming a closed-loop system between the two brain structures. Overall, our findings reconcile some of the discrepancies that arose from differences in techniques or the reliance on pre-existing tools. While spatial distribution and electrophysiological properties of GPe neurons reaffirm the diversification of GPe subtypes, statistical analyses strongly support the notion that these neuron subtypes can be categorized under the two principal neuron classes--i.e., PV+ neurons and Npas1+ neurons.\n\nSignificance statementThe poor understanding of the neuronal composition in the GPe undermines our ability to interrogate its precise behavioral and disease involvements. In this study, twelve different genetic crosses were used, hundreds of neurons were electrophysiologically-characterized, and over 100,000 neurons were histologically- and/or anatomically-profiled. Our current study further establishes the segregation of GPe neuron classes and illustrates the complexity of GPe neurons in adult mice. Our results support the idea that Npas1+-Nkx2.1+ neurons are a distinct GPe neuron subclass. By providing a detailed analysis of the organization of the cortico-pallidal-cortical projection, our findings establish the cellular and circuit substrates that can be important for motor function and dysfunction.

neuroscience↗

bioRxiv2019

Enhanced and Unified Anatomical Labeling for a Common Mouse Brain Atlas

Anatomical atlases in standard coordinates are necessary for the interpretation and integration of research findings in a common spatial context. However, the two most-used mouse brain atlases, the Franklin and Paxinos (FP) and the common coordinate framework (CCF) from the Allen Institute for Brain Science, have accumulated inconsistencies in anatomical delineations and nomenclature, creating confusion among neuroscientists. To overcome these issues, we adopted the FP labels into the CCF to merge two labels in the single atlas framework. We used cell type specific transgenic mice and an MRI atlas to adjust and further segment our labels. Moreover, new segmentations were added to the dorsal striatum using cortico-striatal connectivity data. Lastly, we have digitized our anatomical labels based on the Allen ontology, created a web-interface for visualization, and provided tools for comprehensive comparisons between the Allen and FP labels. Our open-source labels signify a key step towards a unified mouse brain atlas.

neuroscience↗