Biology subjects

Abraira, V. E. G.

Publications and source records attributed to Abraira, V. E. G..

7 recordsLinked to original sources

bioRxiv2026

Oxytocin Modulation of Spinal Circuits Drives Therapeutic Benefits of Massage

Across social species, social touch enhances well-being and reduces pain -- two seemingly distinct benefits that enhance survival. Yet where and how the nervous system integrates these functions, and whether a single mechanism could serve both, remains unknown. Here we show that massage triggers oxytocin release, which shapes both pain and touch reward at the earliest stage of central processing -- the spinal cord -- through a single, state-dependent circuit mechanism. We report that in humans, massage enhances well-being, effects that correlate with endogenous oxytocin release. In mice, gentle touch activates hypothalamic oxytocin neurons that project directly to the spinal dorsal horn. Genetic manipulation of spinal oxytocin circuits alters behavioral responses to both gentle touch and noxious stimuli. Spinal calcium imaging and slice electrophysiology reveal that oxytocin acts on both excitatory and inhibitory spinal neurons to sculpt the relative activity of spinal ascending systems that convey both social touch and pain to the brain. Extending these findings to humans, we show that oxytocin receptors are also expressed on spinal excitatory and inhibitory neurons, and that endogenous oxytocin during massage correlates with altered spinal touch processing. Thus, spinal oxytocin signaling provides an evolutionarily conserved mechanism for the therapeutic benefits of massage.

neuroscience↗

bioRxiv2025

Neuropathic pain drives time-dependent reorganization of corticostriatal circuits

Chronic pain fundamentally alters sensorimotor integration and motivated behaviors, yet the neural mechanisms underlying this transition remain poorly understood. The striatum, composed of dopamine receptor type 1 (D1)- and type 2 (D2)-expressing spiny projection neurons (SPN), integrates cortical sensory and motor inputs to coordinate movement and motivation, making it a critical candidate for mediating pain-induced behavioral adaptations. Although spinal and cortical pain circuits are well-characterized in limited phases of pain, how corticostriatal pathways and distinct striatal cell populations contribute to the transition from acute to chronic pain states remains unclear. Here we show that neuropathic pain, after spared nerve injury in mice, produces temporally distinct, cell-type-specific changes in striatal SPN activity and corticostriatal plasticity that evolve across acute to chronic pain phases. D1 SPNs exhibit smaller amplitude and slower calcium signals during acute pain stages that persist through early chronic phases, while D2 SPNs show delayed response timing during later chronic stages, but also stimulus-specific alterations in neural activity throughout acute and chronic pain states. Critically, primary somatosensory cortex inputs to D2 SPNs develop depressing synapses specifically during intermediate chronic pain phases ([~]25 days post-injury) that disappear during more severe chronic stages (>3 months), suggesting a failed compensatory mechanism. These findings reveal that striatal circuits undergo dynamic, time-dependent reorganization after peripheral injury, with D1 and D2 pathways contributing distinct temporal signatures to pain-related behavior. The identification of critical windows of striatal plasticity provides new targets for therapeutic interventions that could prevent or reverse chronic pain states by modulating specific corticostriatal circuits during vulnerable transition periods.

neuroscience↗

bioRxiv2025

Functional synaptic connectivity of engrafted spinal cord neurons with locomotor circuitry in the injured spinal cord

Spinal cord injury (SCI) results in significant neurological deficits, with no currently available curative therapies. Neural progenitor cell (NPC) transplantation has emerged as a promising approach for neural repair, as graft-derived neurons (GDNs) can integrate into the host spinal cord and support axon regeneration. However, the mechanisms underlying functional recovery remain poorly understood. In this study, we investigate the synaptic integration of NPC-derived neurons into locomotor circuits, the projection patterns of distinct neuronal subtypes, and their potential to modulate motor circuit activity. Using transsynaptic tracing in a mouse thoracic contusion SCI model, we found that NPC-derived neurons form synaptic connections with host locomotor circuits, albeit at low frequencies. Furthermore, we mapped the axon projections of V0C and V2a interneurons, revealing distinct termination patterns within host spinal cord laminae. To assess functional integration, we employed chemogenetic activation of GDNs, which induced muscle activity in a subset of transplanted animals. However, NPC transplantation alone did not significantly improve locomotor recovery, highlighting a key challenge in the field. Our findings suggest that while GDNs can integrate into host circuits and modulate motor activity, synaptic connectivity remains a limiting factor in functional recovery. Future studies should focus on enhancing graft-host connectivity and optimizing transplantation strategies to maximize therapeutic benefits for SCI.

neuroscience↗

bioRxiv2024

Treadmill step training promotes corticospinal tract plasticity after incomplete spinal cord injury

Spinal cord injury (SCI) often impairs motor functions such as voluntary movement and fine motor control, with the corticospinal tract (CST) being a crucial pathway affected. While CST-targeted rehabilitation, such as treadmill training, supports motor recovery, gaps remain in understanding the topographical changes within the CST and how they correlate with behavioral outcomes. In this study, we utilized a custom Emx1Cre;LSL-SynGFP mouse line to quantify CST plasticity following moderate contusion SCI, both with and without exercise (treadmill) training. Fluorescent labeling of cortical synapses allowed for detailed visualization of descending CST rewiring, and we assessed its relationship to behavioral outcomes, including kinematics analysis and motivational state. Mice were stratified by motivational state using the Progressive Ratio Assay, and locomotor recovery was evaluated through the Basso Mouse Scale (BMS), joint/limb kinematics, and Motion Sequencing (MoSeq) analysis. Our findings indicate that treadmill training enhances CST rewiring, especially in highly motivated animals, leading to increased synaptic density in the ventral horn and improved BMS subscores. Motivation further influenced specific kinematic parameters, such as toe clearance, while treadmill training significantly improved speed by reducing the stance phase. Results suggest that while treadmill training induces broad beneficial outcomes, motivation may fine-tune recovery, influencing neural circuit and behavioral changes. This suggests multiple mechanisms converge to promote recovery--those we cannot control and those we can. These results underscore the combined role of task-specific training and also perhaps motivation in driving CST plasticity and functional recovery after SCI.

neuroscience↗

bioRxiv2024

Using DeepLabCut-Live to probe state dependent neural circuits of behavior with closed-loop optogenetic stimulation

BackgroundClosed-loop behavior paradigms enable us to dissect the state-dependent neural circuits underlying behavior in real-time. However, studying context-dependent locomotor perturbations has been challenging due to limitations in molecular tools and techniques for real-time manipulation of spinal cord circuits. New MethodWe developed a novel closed-loop optogenetic stimulation paradigm that utilizes DeepLabCut-Live pose estimation to manipulate primary sensory afferent activity at specific phases of the locomotor cycle in mice. A compact DeepLabCut model was trained to track hindlimb kinematics in real-time and integrated into the Bonsai visual programming framework. This allowed an LED to be triggered to photo-stimulate sensory neurons expressing channelrhodopsin at user-defined pose-based criteria, such as during the stance or swing phase. ResultsOptogenetic activation of nociceptive TRPV1+ sensory neurons during treadmill locomotion reliably evoked paw withdrawal responses. Photoactivation during stance generated a brief withdrawal, while stimulation during swing elicited a prolonged response likely engaging stumbling corrective reflexes. Comparison with Existing Methods: This new method allows for high spatiotemporal precision in manipulating spinal circuits based on the phase of the locomotor cycle. Unlike previous approaches, this closed-loop system can control for the state-dependent nature of sensorimotor responses during locomotion. ConclusionsIntegrating DeepLabCut-Live with optogenetics provides a powerful new approach to dissect the context-dependent role of sensory feedback and spinal interneurons in modulating locomotion. This technique opens new avenues for uncovering the neural substrates of state-dependent behaviors and has broad applicability for studies of real-time closed-loop manipulation based on pose estimation. ManuscriptO_ST_ABSHighlightsC_ST_ABSO_LIClosed-loop system probes state-dependent behaviors at pose-modulated instances C_LIO_LIBonsai integrates DeepLabCut models for real-time pose estimation during locomotion C_LIO_LIPhase-dependent TRPV1+ sensory afferent photostimulation elicits context-specific withdrawal responses C_LI

neuroscience↗

bioRxiv2024

The Dorsal Column Nuclei Scales Mechanical Allodynia During Neuropathic Pain

Tactile perception relies on reliable transmission and modulation of low-threshold information as it travels from the periphery to the brain. During pathological conditions, tactile stimuli can aberrantly engage nociceptive pathways leading to the perception of touch as pain, known as mechanical allodynia. Two main drivers of peripheral tactile information, low-threshold mechanoreceptors (LTMRs) and postsynaptic dorsal column neurons (PSDCs), terminate in the brainstem dorsal column nuclei (DCN). Activity within the DRG, spinal cord, and DCN have all been implicated in mediating allodynia, yet the DCN remains understudied at the cellular, circuit, and functional levels compared to the other two. Here, we show that the gracile nucleus (Gr) of the DCN mediates tactile sensitivity for low-threshold stimuli and contributes to mechanical allodynia during neuropathic pain in mice. We found that the Gr contains local inhibitory interneurons in addition to thalamus-projecting neurons, which are differentially innervated by primary afferents and spinal inputs. Functional manipulations of these distinct Gr neuronal populations resulted in bidirectional changes to tactile sensitivity, but did not affect noxious mechanical or thermal sensitivity. During neuropathic pain, silencing Gr projection neurons or activating Gr inhibitory neurons was able to reduce tactile hypersensitivity, and enhancing inhibition was able to ameliorate paw withdrawal signatures of neuropathic pain, like shaking. Collectively, these results suggest that the Gr plays a specific role in mediating hypersensitivity to low-threshold, innocuous mechanical stimuli during neuropathic pain, and that Gr activity contributes to affective, pain-associated phenotypes of mechanical allodynia. Therefore, these brainstem circuits work in tandem with traditional spinal circuits underlying allodynia, resulting in enhanced signaling of tactile stimuli in the brain during neuropathic pain.

neuroscience↗

bioRxiv2023

Using behavioral biomarkers to redefine epochs of spontaneous recovery following spinal cord injury

The brain-spinal cord axis generates movement by assembling motor primitives into coordinated sequences. Spinal cord injury (SCI) disrupts this neuroaxis, impairing not only locomotion, but the full repertoire of behavior. Traditional scales for quantifying recovery collapse this complexity into predefined locomotor-focused criteria that obscure heterogeneity in recovery. To quantify the full behavioral repertoire following SCI, we adapted motion sequencing (MoSeq) to identify sub-second behavioral "syllables" and capture their usage and sequential organization without predefined features. We identified biomechanically distinct variants within syllable classes that are shared across injury severities and found that recovery is jointly structured by injury severity and individual mouse identity. Changes in sequences, however, unfold along a conserved temporal trajectory. By compressing behavior into a single metric, we uncovered clusters of coevolving locomotor and non-locomotor behaviors. These results frame SCI recovery with repertoire-level changes, where adaptive strategies emerge from constrained access to motor primitives and their sequences.

neuroscience↗