Biology subjects

Ding, J. B.

Publications and source records attributed to Ding, J. B..

15 recordsLinked to original sources

bioRxiv2026

Ultrasensitive voltage imaging reveals distinct electrical microdomains in neurons

For the brain to compute, electrical signals must propagate over the membranes of individual neurons, connecting synaptic inputs to synaptic outputs1. Complex neuronal morphologies coupled with the spatial organization of synaptic inputs and outputs enable diverse voltage transformations that underlie cell-type specific computations2,3. However, measuring these transformations in vivo has remained challenging, leaving a crucial gap in our mechanistic understanding of single neuron computation. Here, we develop ASAP7y, a genetically encoded voltage indicator with unprecedented subthreshold sensitivity and expanded excitation compatibility in both mice and flies. We leveraged ASAP7y combined with two-photon random-access microscopy to record sensory stimulus-evoked voltage dynamics with millisecond, subcellular, and subthreshold resolution along the neurites of individual neurons in Drosophila. We found remarkable heterogeneity in voltage propagation across cell-types, delineating a fundamental axis of electrical diversity. Leveraging a nanoscale EM reconstruction of the visual system4, we modeled the electrotonic properties of single neurons spanning 717 cell types, revealing how morphology shapes voltage transformations. Finally, we demonstrate that confined voltage propagation creates substrates for local computation, producing subcellular domains with distinct feature selectivity across multiple cell types. These results provide mechanistic insight into how critical single neuron computations arise and reveal parallel processing in single neurons.

neuroscience↗

bioRxiv2025

Motor learning drives region-specific transcriptomic remodeling in the motor cortex and dorsal striatum

Motor learning depends on coordinated activity across the motor cortex (M1) and dorsal striatum (dSTR), yet the molecular mechanisms driving learning-related synaptic and circuit remodeling remain unclear. Here, we combine activity-dependent genetic labeling (TRAP) with single-cell RNA sequencing to generate an unbiased, cell type-resolved transcriptional atlas of behaviorally engaged populations during a forelimb reaching task. We identify diverse activated neurons across M1 and dSTR, including a striking enrichment of Htr3a-expressing interneurons (Htr3a INs) in M1 that are selectively recruited during skilled reaching, as confirmed by two-photon calcium imaging. Corticostriatal projection neurons and striatal spiny projection neurons show subtype-and region-specific transcriptional remodeling involving genes linked to synaptic function, translation, and metabolism. Glial cells--including astrocytes, oligodendrocytes, and microglia-- exhibit similarly robust, stage-and region-dependent gene regulation. These findings provide a comprehensive molecular framework for motor learning and highlight coordinated, cell type-specific transcriptional programs in neurons and glia that shape the encoding and retrieval of motor memory. Highlights- Motor learning activates interneuron cell types in motor cortex and striatum - Htr3a-expressing interneurons in motor cortex are specifically activated while performing a learned reaching behavior - Transcriptome remodeling exhibited distinct patterns between motor cortex and striatum - Glial cells showed stage- and region-specific transcriptomic alteration patterns that align with those in neurons

neuroscience↗

bioRxiv2024

Thalamic integration of basal ganglia and cerebellar circuits during motor learning

The ability to control movement and learn new motor skills is one of the fundamental functions of the brain. The basal ganglia (BG) and the cerebellum (CB) are two key brain regions involved in controlling movement, and neuronal plasticity within these two regions is crucial for acquiring new motor skills. However, how these regions interact to produce a cohesive unified motor output remains elusive. Here, we discovered that a subset of neurons in the motor thalamus receive converging synaptic inputs from both BG and CB. By performing multi-site fiber photometry in mice learning motor tasks, we found that motor thalamus neurons integrate BG and CB signals and show distinct movement-related activity. Lastly, we found a critical role of these thalamic neurons and their BG and CB inputs in motor learning and control. These results identify the thalamic convergence of BG and CB and its crucial role in integrating movement signals. HighlightsO_LIIndividual neurons in motor thalamus receive converging synaptic input from SNr and DCN projections. C_LIO_LIThalamic neurons with SNr and DCN input are concentrated at the border between VM and VAL thalamic nuclei. C_LIO_LIThalamic neurons functionally integrate SNr and DCN activity and adapt with motor learning. C_LIO_LIThalamic neurons and their inputs from SNr and DCN are critical for learning and executing motor tasks. C_LI

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bioRxiv2024

Refinement of efficient encodings of movement in the dorsolateral striatum throughout learning

The striatum is required for normal action selection, movement, and sensorimotor learning. Although action-specific striatal ensembles have been well documented, it is not well understood how these ensembles are formed and how their dynamics may evolve throughout motor learning. Here we used longitudinal 2-photon Ca2+ imaging of dorsal striatal neurons in head-fixed mice as they learned to self-generate locomotion. We observed a significant activation of both direct- and indirect-pathway spiny projection neurons (dSPNs and iSPNs, respectively) during early locomotion bouts and sessions that gradually decreased over time. For dSPNs, onset- and offset-ensembles were gradually refined from active motion-nonspecific cells. iSPN ensembles emerged from neurons initially active during opponent actions before becoming onset- or offset-specific. Our results show that as striatal ensembles are progressively refined, the number of active nonspecific striatal neurons decrease and the overall efficiency of the striatum information encoding for learned actions increases.

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bioRxiv2023

Adolescent oligodendrogenesis and myelination restrict experience-dependent neuronal plasticity in adult visual cortex

BACKGROUNDDevelopmental myelination is a protracted process in the mammalian brain. One theory for why oligodendrocytes mature so slowly posits that myelination may stabilize neuronal circuits and temper neuronal plasticity as animals age. We tested this hypothesis in the visual cortex, which has a well-defined critical period for experience-dependent neuronal plasticity. OBJECTIVES/METHODSTo prevent myelin progression, we conditionally deleted Myrf, a transcription factor necessary for oligodendrocyte maturation, from oligodendrocyte precursor cells (Myrf cKO) in adolescent mice. To induce experience-dependent plasticity, adult control and Myrf cKO mice were monocularly deprived by eyelid suture. Functional and structural neuronal plasticity in the visual cortex were assessed in vivo by intrinsic signal optical imaging and longitudinal two photon imaging of dendritic spines, respectively. RESULTSDuring adolescence, visual experience modulated the rate of oligodendrocyte maturation in visual cortex. Myrf deletion from oligodendrocyte precursors during adolescence led to inhibition of oligodendrocyte maturation and myelination that persisted into adulthood. Following monocular deprivation, visual cortex activity in response to visual stimulation of the deprived eye remained stable in adult control mice, as expected for post-critical period animals. By contrast, visual cortex responses to the deprived eye decreased significantly following monocular deprivation in adult Myrf cKO mice, reminiscent of the plasticity observed in adolescent mice. Furthermore, visual cortex neurons in adult Myrf cKO mice had fewer dendritic spines and a higher level of spine turnover. Finally, monocular deprivation induced spatially coordinated spine size decreases in adult Myrf cKO, but not control, mice. CONCLUSIONSThese results demonstrate a critical role for oligodendrocytes in shaping the maturation and stabilization of cortical circuits and support the concept of myelin acting as a brake on neuronal plasticity during development.

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bioRxiv2022

Dichotomic Regulation of Striatal Plasticity by Dynorphin

Modulation of corticostriatal plasticity alters the information flow throughout basal ganglia circuits and represents a fundamental mechanism for motor learning, action selection, and reward. Synaptic plasticity in the striatal direct- and indirect-pathway spiny projection neurons (dSPNs and iSPNs) are dichotomically regulated by two distinct networks of GPCR signaling cascades. While it is well-known that dopamine D2 and adenosine A2a receptors bidirectionally regulate iSPN plasticity, it remains unclear how D1 signaling modulation of synaptic plasticity is counteracted by a dSPN-specific Gi signaling. Here, we show that striatal dynorphin selectively suppresses long-term potentiation (LTP) through Kappa Opioid Receptor (KOR) in dSPNs. Both KOR antagonism and conditional deletion of dynorphin in dSPNs enhance LTP counterbalancing with different levels of D1 receptor activation. Behaviorally, mice lacking dynorphin specifically in dSPNs show normal motor behavior and reward-based learning, but enhanced flexibility during reversal learning. These findings support a model in which D1R and KOR signaling bidirectionally modulate synaptic plasticity in striatal direct pathways and behavior.

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bioRxiv2022

Dissociating encoding of memory and salience by manipulating long-term synaptic potentiation

Neural codes are thought to be reorganized during memory formation by long-term potentiation (LTP) of synapses. Here, using a novel approach for selectively blocking LTP, we found that eliminating LTP in hippocampal or striatal circuits only produces limited effects on learning and memory. To reconcile the discrepancy between the large physiological effect of blocking LTP and the absent effect on learning, we studied how LTP impacts neuronal computations in the hippocampus using in-vivo Ca2+-imaging. Contrary to current conceptual frameworks, we found that hippocampal CA1-region LTP is not required for accurate representations of space in hippocampal neurons, but rather endows these neurons with reward- and novelty-coding properties. Thus, instead of driving formation of cognitive maps and memory engrams, CA1-region LTP incorporates salience information into cognitive representations. One-Sentence SummaryA novel approach for studying long-term potentiation reveals its surprising and selective role in salience encoding

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bioRxiv2021

Motor learning selectively strengthens cortical and striatal synapses of motor engram neurons

Learning and consolidation of new motor skills require adaptations of neuronal activity and connectivity in the motor cortex and striatum, two key motor regions of the brain. Yet, how neurons undergo synaptic changes and become recruited during motor learning to form a memory engram remains an open question. Here, we train mice on a single-pellet reaching motor learning task and use a genetic approach to identify and manipulate behavior-relevant neurons selectively in the primary motor cortex (M1). We find that the degree of reactivation of M1 engram neurons correlates strongly with motor performance. We further demonstrate that learning-induced dendritic spine reorganization specifically occurs in these M1 engram neurons. In addition, we find that motor learning leads to an increase in the number and strength of outputs from M1 engram neurons onto striatal spiny projection neurons (SPNs) and that these synapses form local clusters along SPN dendrites. These results identify a highly specific synaptic plasticity during the formation of long-lasting motor memory traces in the corticostriatal circuit. HIGHLIGHTS- Motor performance is correlated with the reactivation of motor engram neurons - Motor learning increases spine density and new spine survival selectively on M1 engram neurons - Motor learning strengthens motor engram outputs to the striatum - M1 engram outputs converge onto clusters of dendritic spines on striatal spiny projection neurons

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bioRxiv2021

A positively Tuned Voltage Indicator Reveals Electrical Correlates of Calcium Activity in the Brain

Neuronal spiking activity is routinely recorded using genetically encoded calcium indicators (GECIs), but calcium imaging is limited in temporal resolution and does not report subthreshold voltage changes. Genetically encoded voltage indicators (GEVIs) offer better temporal resolution and subthreshold sensitivity, but spike detection with fast GEVIs has required specialized imaging equipment. Here, we report the ASAP4 subfamily of genetically encoded voltage indicators (GEVIs) that brighten in response to membrane depolarization, inverting the fluorescence-voltage relationship of previous ASAP GEVIs. Two variants, ASAP4b and ASAP4e, feature 128% and 178% fluorescence increases over 100-mV of depolarization, respectively, facilitating spike detection in single trials in vivo with standard 1 and 2-photon imaging systems. Simultaneous voltage and calcium imaging confirms improved temporal resolution and spike discernment by ASAP4 GEVIs. Thus, positively tuned ASAP4 voltage indicators enable recording of neuronal spiking activity using similar equipment as calcium imaging, while providing higher temporal resolution. One Sentence SummaryUpward ASAPs increase detection capability of GEVIs in vivo.

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bioRxiv2021

Postsynaptic synucleins mediate vesicular exocytosis of endocannabinoids

Two seemingly unrelated questions have long motivated studies in neuroscience: How are endocannabinoids, among the most powerful modulators of synaptic transmission, released from neurons? What are the physiological functions of synucleins, key contributors to Parkinsons Disease? Here, we report an unexpected convergence of these two questions: Endocannabinoids are released via vesicular exocytosis from postsynaptic neurons by a synuclein-dependent mechanism. Specifically, we find that deletion of all synucleins selectively blocks all endocannabinoid-dependent synaptic plasticity; this block is reversed by postsynaptic expression of wildtype but not of mutant -synuclein. Loading postsynaptic neurons with endocannabinoids via patch-pipette dialysis suppressed presynaptic neurotransmitter release in wildtype but not in synuclein-deficient neurons, suggesting that the synuclein deletion blocks endocannabinoid release. Direct optical monitoring of endocannabinoid release confirmed the requirement of synucleins. Given the role of synucleins in vesicular exocytosis, the requirement for synucleins in endocannabinoid release indicates that endocannabinoids are secreted via exocytosis. Consistent with this hypothesis, postsynaptic expression of tetanus-toxin light chain, which cleaves synaptobrevin SNAREs, also blocked endocannabinoid-dependent plasticity and release. The unexpected finding that endocannabinoids are released via synuclein-dependent exocytosis assigns a function to synucleins and resolves a longstanding puzzle of how neurons release endocannabinoids to induce synaptic plasticity.

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bioRxiv2021

Enhancing motor learning by increasing stability of newly formed dendritic spines in motor cortex

Dendritic spine dynamics of Layer 5 Pyramidal neurons (L5PNs) are thought to be physical substrates for motor learning and memory of motor skills and altered spine dynamics are frequently correlated with poor motor performance. Here we describe an exception to this rule by studying mice lacking Paired immunoglobulin receptor B (PirB-/-). Using chronic two-photon imaging of primary motor cortex (M1) of PirB-/-;Thy1-YFP-H mice, we found a significant increase in the survival of spines on apical dendritic tufts of L5PNs, as well as increased spine formation rates and spine density. Surprisingly and contrary to expectations, adult PirB-/- mice learn a skilled reaching task more rapidly compared to wild type (WT) littermate controls. Conditional excision of PirB from forebrain pyramidal neurons in adult mice replicated these results. Furthermore, chronic imaging of L5PN dendrites throughout the learning period revealed that the stabilization of learning-induced newly formed spines is significantly elevated in PirB-/- mice. The degree of survival of newly formed spines in M1 yielded the strongest correlation with task performance, suggesting that this increased spine stability is advantageous and can translate into enhanced acquisition and maintenance of motor skills. Notably, inhibiting PirB function acutely in M1 of adult WT mice throughout training increases the survival of spines formed during early training and enhances motor learning. These results suggest that increasing the stability of newly formed spines is sufficient to improve long-lasting learning and motor performance and demonstrate that there are limits on motor learning that can be lifted by manipulating PirB, even in adulthood.

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bioRxiv2020

Ultra-sensitive measurement of brain penetration mechanics and blood vessel rupture with microscale probes

Microscale electrodes, on the order of 10-100 m, are rapidly becoming critical tools for neuroscience and brain-machine interfaces (BMIs) for their high channel counts and spatial resolution, yet the mechanical details of how probes at this scale insert into brain tissue are largely unknown. Here, we performed quantitative measurements of the force and compression mechanics together with real-time microscopy for in vivo insertion of a systematic series of microelectrode probes as a function of diameter (7.5-100 m and rectangular Neuropixels) and tip geometry (flat, angled, and electrochemically sharpened). Results elucidated the role of tip geometry, surface forces, and mechanical scaling with diameter. Surprisingly, the insertion force post-pia penetration was constant with distance and did not depend on tip shape. Real-time microscopy revealed that at small enough lengthscales (<25 m), blood vessel rupture and bleeding during implantation could be entirely avoided. This appears to occur via vessel displacement, avoiding capture on the probe surface which led to elongation and tearing for larger probes. We propose a new, three-zone model to account for the probe size dependence of bleeding, and provide mechanistic guidance for probe design. Significance StatementMicroscale neural probes are central to next-generation brain-machine interfaces, yet how they physically penetrate living brain remains poorly quantified. Using a high-sensitivity force sensor integrated with real-time microscopy, we measured in vivo force-displacement and visualized vascular responses for microwires (7.5-100 m) and Neuropixels. We find that once the brains protective pia membrane is breached, insertion force remains essentially constant with depth, while pia puncture force and pre-penetration compression scale linearly with probe diameter. Real-time imaging reveals a sub-25 m regime in which blood vessels are displaced rather than ruptured. These results motivate a three-zone model of vessel capture versus displacement and provide actionable mechanical design rules for low-trauma, high-density neural interfaces.

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bioRxiv2019

Massively Parallel Microwire Arrays Integrated with CMOS chips for Neural Recording

Multi-channel electrical recordings of neural activity in the brain is an increasingly powerful method revealing new aspects of neural communication, computation, and prosthetics. However, while planar silicon-based CMOS devices in conventional electronics scale rapidly, neural interface devices have not kept pace. Here, we present a new strategy to interface silicon-based chips with three-dimensional microwire arrays, providing the link between rapidly-developing electronics and high density neural interfaces. The system consists of a bundle of microwires mated to large-scale microelectrode arrays, such as camera chips. This system has excellent recording performance, demonstrated via single unit and local-field potential recordings in isolated retina and in the motor cortex or striatum of awake moving mice. The modular design enables a variety of microwire types and sizes to be integrated with different types of pixel arrays, connecting the rapid progress of commercial multiplexing, digitisation and data acquisition hardware together with a three-dimensional neural interface.

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bioRxiv2018

Ultra-sensitive measurement of brain penetration with microscale probes for brain machine interface considerations

Microscale electrodes are rapidly becoming critical tools for neuroscience and brain-machine interfaces (BMIs) for their high spatial and temporal resolution. However, the mechanics of how devices on this scale insert into brain tissue is unknown, making it difficult to balance between larger probes with higher stiffness, or smaller probes with lower damage. Measurements have been experimentally challenging due to the large deformations, rapid events, and small forces involved. Here we modified a nanoindentation force measurement system to provide the first ultra-high resolution force, distance, and temporal recordings of brain penetration as a function of microwire diameter (7.5 {micro}m to 100 {micro}m) and tip geometry (flat, angled, and electrosharpened). Surprisingly, both penetration force and tissue compression scaled linearly with wire diameter, rather than cross-sectional area. Linear brain compression with wire diameter strongly suggest smaller probes will cause less tissue damage upon insertion, though unexpectedly no statistical difference was observed between angled and flat tipped probes. These first of their kind measurements provide a mechanical framework for designing effective microprobe geometries while limiting mechanical damage.

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bioRxiv2018

A conserved nuclear export complex coordinates transcripts for dopaminergic synaptogenesis and neuronal surviva

Synaptic vesicle and active zone proteins are required for synaptogenesis. The molecular mechanisms for coordinated synthesis of these proteins are not understood. Using forward genetic screens, we identified the conserved THO nuclear export Complex (THOC) as master regulator of presynapse development in C.elegans dopaminergic neurons. In THOC mutants, synaptic messenger RNAs are trapped in the nucleus, resulting in dramatic decrease of synaptic protein expression, near complete loss of synapses and compromised dopamine function. cAMP-responsive element binding protein (CREB) interacts with THOC to mark activity-dependent transcripts for efficient nuclear export. Deletion of the THOC subunit Thoc5 in mouse dopaminergic neurons causes severe defects in synapse maintenance and subsequent neuronal death in the Substantia Nigra compacta (SNc). These cellular defects lead to abrogated dopamine release, ataxia and animal death. Together, our results argue that nuclear export mechanisms can select specific mRNAs and be a rate-limiting step for synapse development and neuronal survival.\n\nHighlightsO_LIDopaminergic presynapses are severely impaired in thoc mutant worms and mice\nC_LIO_LITHOC specifically controls the nuclear export of synaptic transcripts\nC_LIO_LICREB recruits THOC onto activity-dependent synaptic transcripts for efficient export\nC_LIO_LIDopamine neurons in the SNc degenerate upon conditional knock-out of thoc5\nC_LI

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