Biology subjects

Huang, K. W.

Publications and source records attributed to Huang, K. W..

8 recordsLinked to original sources

bioRxiv2025

Cerebellar outputs for rapid directional refinement of forelimb movement

Much of our interaction with the world relies on the ability to move our limbs with speed and precision. The cerebellum is critical for movement coordination, yet how outputs from the cerebellum continually guide the limb and whether discrete pathways differentially contribute to adjusting motor output remain unclear. Using intersectional viral approaches in mice, we identify two spatially intermingled yet anatomically distinct cerebellar populations that drive the forelimb either toward or away from the body. Neural recordings reveal cerebellar activity that correlates with and precedes these opposing directional changes in limb movement. Both cerebellar output pathways influence motor neuron and muscle activity within milliseconds, producing reliable effects on limb trajectory despite substantial underlying variability in muscle recruitment patterns. Our findings disentangle a subtype organization to cerebellar limb control, revealing a subcortical circuit basis for online directional refinement during movement execution.

neuroscience↗

bioRxiv2021

Ascertaining cells' synaptic connections and RNA expression simultaneously with massively barcoded rabies virus libraries

Brain function depends on forming and maintaining connections between neurons of specific types, ensuring neural function while allowing the plasticity necessary for cellular and behavioral dynamics. However, systematic descriptions of how brain cell types organize into synaptic networks and which molecules instruct these relationships are not readily available. Here, we introduce SBARRO (Synaptic Barcode Analysis by Retrograde Rabies ReadOut), a method that uses single-cell RNA sequencing to reveal directional, monosynaptic relationships based on the paths of a barcoded rabies virus from its "starter" postsynaptic cell to that cells presynaptic partners1. Thousands of these partner relationships can be ascertained in a single experiment, alongside genome-wide RNA profiles - and thus cell identities and molecular states - of each host cell. We used SBARRO to describe synaptic networks formed by diverse mouse brain cell types in vitro, leveraging a system similar to those used to identify synaptogenic molecules. We found that the molecular identity (cell type/subtype) of the starter cell predicted the number and types of cells that had synapsed onto it. Rabies transmission tended to occur into cells with RNA-expression signatures related to developmental maturation and synaptic transmission. The estimated size of a cells presynaptic network, relative to that of other cells of the same type, associated with increased expression of Arpp21 and Cdh13. By tracking individual virions and their clonal progeny as they travel among host cells, single-cell, single-virion genomic technologies offer new opportunities to map the synaptic organization of neural circuits in health and disease.

neuroscience↗

bioRxiv2020

Bombesin-like peptide recruits disinhibitory cortical circuits and enhances fear memories

Disinhibitory neurons throughout the mammalian cortex are powerful enhancers of circuit excitability and plasticity. The differential expression of neuropeptide receptors in disinhibitory, inhibitory and excitatory neurons suggests that each circuit motif is controlled by distinct neuropeptidergic systems. Here, we reveal that a bombesin-like neuropeptide, gastrin-releasing peptide (GRP), recruits disinhibitory cortical microcircuits through selective targeting and activation of vasoactive intestinal peptide (VIP)-expressing cells. Using a newly-developed genetically-encoded GRP sensor and trans-synaptic tracing we reveal that GRP regulates VIP cells via extrasynaptic diffusion from several putative local and long-range sources. In vivo photometry and CRISPR/Cas9-mediated knockout of the GRP receptor (GRPR) in auditory cortex indicate that VIP cells are strongly recruited by novel sounds and aversive shocks, and that GRP-GRPR signaling enhances auditory fear memories. Our data establish peptidergic recruitment of selective disinhibitory cortical microcircuits as a mechanism to regulate fear memories.

neuroscience↗

bioRxiv2019

Social isolation uncovers a brain-wide circuit underlying context-dependent territory-covering micturition behavior

The controlled and volitional release of urine, or micturition, serves a fundamental physiological function and, in many species, is critical for social communication. In mice, the decision to release urine is modulated by external and internal factors such as environmental stimuli and social history and is transmitted to the spinal cord via the pontine micturition center (PMC). The neural pathways by which social experience and sensory stimuli interact to control PMC activity and regulate micturition are unclear. Here we establish a behavioral paradigm in which mice, depending on their strain, social experience, and immediate sensory context, display either high or low territory-covering micturition (TCM). We demonstrate that social context is represented by coordinated global activity changes in the urination network upstream of the PMC, whereas sensory context is represented by the activation of discrete nodes in the network. Furthermore, we show that the lateral hypothalamic area (LHA), which is directly upstream of PMC, is a key node that can switch micturition behavior between high and low TCM modes.

neuroscience↗

bioRxiv2019

Single-cell analysis of antiviral neuroinflammatory responses in the mouse dorsal raphe nucleus

Neuroinflammatory processes have been implicated in neurodegenerative and psychiatric diseases, and limit the utility of viruses for gene delivery. Here we analyzed 60,212 single-cell RNA profiles to assess both global and cell type-specific transcriptional responses in the mouse dorsal raphe nucleus following axonal infection of neurons by rabies viruses. We identified several leukocyte populations, which infiltrate the brain, that are distinct from resident immune cells. Additionally, we uncovered transcriptionally distinct states of microglia along an activation trajectory that may serve different functions, ranging from surveillance to antigen presentation and cytokine secretion. Our study also provides a critical evaluation of the compatibility between rabies-mediated connectivity mapping and single-cell transcriptional profiling. These findings provide additional insights into the distinct contributions of various cell types in the antiviral response, and will serve as a resource for the design of strategies to circumvent immune responses to improve the efficacy of viral gene delivery.

neuroscience↗

bioRxiv2019

Distinct neuronal subtypes of the lateral habenula differentially target ventral tegmental area dopamine neurons

The lateral habenula (LHb) is an epithalamic brain structure critical for processing and adapting to negative action outcomes. However, despite the importance of LHb to behavior and the clear anatomical and molecular diversity of LHb neurons, the neuron types of the habenula remain unknown. Here we use high-throughput single-cell transcriptional profiling, monosynaptic retrograde tracing, and multiplexed FISH to characterize the cells of the mouse habenula. We find 5 subtypes of neurons in the medial habenula (MHb) that are organized into anatomical subregions. In the LHb we describe 4 neuronal subtypes and show that they differentially target dopaminergic and GABAergic cells in the ventral tegmental area (VTA). These data provide a valuable resource for future study of habenular function and dysfunction and demonstrate neuronal subtype specificity in the LHb-VTA circuit.

neuroscience↗

bioRxiv2019

Molecular and anatomical organization of the dorsal raphe nucleus

The dorsal raphe nucleus (DRN) is an important source of neuromodulators in the brain and has been implicated in a wide variety of behavioral and neurological disorders. Although mostly studied as a source of serotonin, the DRN is comprised of multiple cell types that are subdivided into distinct anatomical subregions. However, the complex and incompletely characterized cellular organization of the DRN has impeded efforts to investigate the distinct circuit and behavioral functions of its subdomains. Here we used high-throughput single-cell RNA sequencing with in situ hybridization and viral tracing to develop a map of transcriptional and spatial profiles of cells in and around the mouse DRN. Our studies reveal the molecular and spatial organization of multiple neuron subtypes that are the cellular bases of functionally and anatomically distinct serotonergic subsystems, and provide a resource for the design of strategies for further dissection of these subsystems and their diverse functions.

neuroscience↗

bioRxiv2018

Distinct Cortical-Thalamic-Striatal Circuits Through the Parafascicular Nucleus

The thalamic parafascicular nucleus (PF), an excitatory input to the basal ganglia, is targeted with deep-brain-stimulation to alleviate a range of neuropsychiatric symptoms. Furthermore, PF lesions disrupt the execution of correct motor actions in uncertain environments. Nevertheless, the circuitry of the PF and its contribution to action selection are poorly understood. We find that, in mice, PF forms the densest subcortical projection to the striatum. This projection arises from transcriptionally- and physiologically-distinct classes of PF neurons that are also reciprocally connected with functionally-distinct cortical regions, differentially innervate striatum neurons, and are not synaptically connected in PF. Thus, mouse PF contains heterogeneous neurons that are organized into parallel and independent associative, limbic, and motor circuits. Furthermore, these subcircuits share motifs of cortical-PF-cortical and cortical-PF-striatum organization that allow each PF subregion, via its precise connectivity with cortex, to coordinate diverse inputs to striatum.

neuroscience↗