Biology subjects

Yang, J. F.

Publications and source records attributed to Yang, J. F..

4 recordsLinked to original sources

bioRxiv2026

Spinal reflex modulation in the pelvic floor muscles through sensory stimulation from the lower limb

The pelvic floor muscles (PFM) are critical for maintaining continence and are a primary target of physiotherapy training to manage urinary incontinence. PFM training relies on voluntarily activating this muscle group, limiting its translation to neurological populations where recovery of bladder function is a priority. Indirect evidence suggests that sensory feedback from the lower limb can modulate PFM activity, which may provide alternative strategies for PFM training. Cutaneous reflexes have been used as a proxy to study how sensory inputs from the skin influence motoneuron excitability. To explore the feasibility of eliciting cutaneous reflexes in the PFM and their role in controlling PFM activity, this study examined: 1) the input-output relationship and 2) the nerve-specificity of PFM cutaneous reflex responses from tibial and superficial peroneal nerve stimulation. Twenty-one neurologically intact adults participated in this study. We recorded PFM and lower leg muscle electromyography while participants received cutaneous stimulation to the right distal tibial nerve, bilateral distal tibial nerve, or right superficial peroneal nerve in a standing position. We delivered stimulation at the intensity below motor threshold (MT), 1.2 x MT and 1.5 x MT and quantified tibial-PFM reflex amplitude over a 50-150 ms window after stimulation. PFM reflex responses were evoked from both nerves stimulation. Reflex amplitude increased with stimulus intensity with tibial nerve stimulation but not with superficial peroneal nerve stimulation. Bilateral tibial nerve stimulation evoked larger responses compared to unilateral stimulation. These findings support the existence of neural connections between lower limb afferents and the PFM, and open up possibilities for designing rehabilitation strategies to manage pelvic health conditions in people with neurological disorders. New & NoteworthyO_LICutaneous sensory feedback from the foot, specifically that related to limb loading, can evoke reflex responses in the pelvic floor muscles C_LIO_LINerve-specific modulation was observed. Reflex amplitudes in the pelvic floor muscles increased with tibial nerve stimulation intensity but not with superficial peroneal nerve stimulation. C_LI

neuroscience↗

bioRxiv2026

Reduced GABAB receptor activation and post activation depression of proprioceptive afferents after spinal cord injury.

Despite a long history of studying presynaptic inhibition of the Ia afferent synapse that produces the monosynaptic EPSP on motoneurons, recent evidence has upset the conventional idea that GABAA receptors mediate this inhibition and instead suggests that there are mainly GABAB receptors at this synapse. However, without targeted access to the GABAergic neurons that activate these receptors, quantifying their functional contribution to presynaptic inhibition has proven difficult. We demonstrate here that focal optogenetic activation of terminals of a subpopulation of GAD2+ GABAergic neurons that exclusively project ventrally to Ia afferent synapses produce long-lasting presynaptic inhibition that is entirely mediated by GABAB receptors and simultaneously produces a characteristic brief GABAA receptor-mediated IPSP on the motoneurons. These ventral GAD2 neurons are recurrently activated by Ia afferents, contributing to post-activation depression with repeated afferent reflex testing, with a similar long time-course to post-activation depression of the H-reflex induced in humans from either repetitive activation of the same Ia afferents or from antagonist nerve conditioning. In contrast, focal activation of dorsally projecting GAD2 neurons does not directly cause presynaptic inhibition or postsynaptic IPSPs but does produce primary afferent depolarization. Following chronic spinal cord injury (SCI), the expression of GABAB receptors on the Ia terminal is halved, and in mice and humans, is associated with a similar decrease of GABAB receptor-mediated post-activation depression of Ia-EPSPs transmission, which is reversed by the GABAB receptor agonist baclofen. In summary, GABAB receptors mediate presynaptic inhibition, but are down regulated with SCI, contributing to reflex hyperexcitability associated with spasticity. Key Points SummaryO_LIPresynaptic inhibition of Ia afferents is mediated by the recurrent activation of terminal GABAB receptors by a subpopulation of ventrally projecting GAD2+ interneurons. C_LIO_LIIn contrast, dorsally projecting GAD2+ interneurons activate GABAA receptors on Ia afferent nodes to facilitate action potential conduction through branchpoints. C_LIO_LIRepetitive activation of Ia afferents at rates of every 10 s or faster produces post-activation depression via neurotransmitter depletion and from activation of terminal GABAB receptors. C_LIO_LIThese ventrally projecting GAD2+ interneurons can also be activated by other afferents that then produce PAD-evoked spikes to produce post-activation depression from conditioning nerve stimulation. C_LIO_LIThe reduction of GABAB receptors on the Ia terminal in spinal cord injury results in reduced presynaptic inhibition and post-activation depression, contributing to reflex hyperexcitability. C_LI O_FIG O_LINKSMALLFIG WIDTH=189 HEIGHT=200 SRC="FIGDIR/small/700955v2_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@17abd51org.highwire.dtl.DTLVardef@12316baorg.highwire.dtl.DTLVardef@a92168org.highwire.dtl.DTLVardef@1d06ca0_HPS_FORMAT_FIGEXP M_FIG Abstract legend: Schematic of GABAergic circuit producing presynaptic inhibition and primary afferent depolarization (PAD) in proprioceptive Ia afferents. We propose two populations of GAD2+ GABAergic interneurons, one with dorsal projections (purple) that activate GABAA receptors on the nodes of Ia afferents to produce PAD and subsequent facilitation of Ia afferent conduction, and another ventrally projecting population (pink) that activates GABAB receptors on the Ia afferent terminal to produce presynaptic inhibition via inhibition of VCa2+ channels and reduction of neurotransmitter release and replenishment. Both are activated by first order interneurons (grey). Repetitive activation of Ia afferents (green extensor) recurrently activates twhe ventrally projecting GAD2+ neurons to activate terminal GABAB receptors and long-lasting post-activation depression of Ia EPSPs and reflexes as measured from ventral root recordings. Strong conditioning stimulation of other afferents (blue flexor) activates dorsal GAD2+ neurons that can produce PAD-evoked spikes in extensor afferents that orthodromically activate motoneurons to set up post-activation depression of subsequent extensor reflexes. Here, PAD is also evoked in other afferents (flexor) by dorsally projecting GAD2+ neurons (light pink branch) but without activation of the ventrally projecting GAD2+ neurons or presynaptic inhibition. C_FIG

neuroscience↗

bioRxiv2022

Lipid nanoparticles delivering constitutively active STING mRNA as a novel anti-cancer therapeutic approach

Treating immunosuppressive tumors represents a major challenge in cancer therapies. Activation of STING signaling has shown remarkable potential to invigorate the immunologically cold tumor microenvironment (TME). However, we and others have shown that STING is silenced in many cancers, including pancreatic ductal adenocarcinoma (PDAC) and Merkel cell carcinoma (MCC), both of which are associated with an immune-dampened TME. In this study, we applied mRNA lipid nanoparticles (LNP) to deliver a permanently active gain-of-function STINGR284S mutant into PDAC and MCC cells. Expression of STINGR284S induces cytokines and chemokines crucial for promoting intratumoral infiltration of CD8+ T cells and, importantly, also leads to robust cancer cell death while avoiding T cell entry and toxicity. Our studies demonstrated that mRNA-LNP delivery of STINGR284S could be explored as a novel therapeutic tool to reactivate antitumor response in an array of STING-deficient cancers while overcoming the toxicity and limitations of conventional STING agonists.

bioengineering↗

bioRxiv2021

Enduring motor memory of walking on a split-belt treadmill in young children and adults

Adults and children modify how they move to accommodate persistent changes in their surroundings, called motor adaptation. Walking-related motor adaption can be seen when one walks on a treadmill with two belts running at different speeds, a split-belt treadmill, where a new walking pattern is slowly adopted with practice. This has been suggested as a way to improve left-right symmetry in walking after a stroke. Central to using split-belt walking for rehabilitation is whether the adapted motor pattern is retained over days and weeks, and whether this motor memory is a function of the persons age. When first exposed to split-belt walking, the walking is asymmetric (initial error), resembling a limp. With subsequent exposure, the error is smaller than the initial error, indicating the adaptation was remembered. Here, we explored the persistence of this memory over 24 hours, one week, and two weeks, in young children (3-6 yr old), younger adults (20-30 yr old) and older adults (50-70 yr old). We found that the motor memory declines with the interval duration, but was still evident up to 2 weeks after initial exposure. Retention of the motor memory in children and younger adults was better than older adults. Further, forgetting between trials was seen on the first day of split-belt walking especially in children and older adults, but this forgetting diminished with repeated trials. The results indicate that long-term memory of motor adaptation on the split-belt treadmill is affected by age, but it may be possible to enhance the memory by more frequent and repeated exposure. This suggests that when using split-belt adaptation in rehabilitation, the sessions should ideally be less than one week apart.

neuroscience↗