Biology subjects

Garraway, S. M.

Publications and source records attributed to Garraway, S. M..

3 recordsLinked to original sources

bioRxiv2024

Diet-microbiome interactions promote enteric nervous system resilience following spinal cord injury

Spinal cord injury (SCI) results in a plethora of physiological dysfunctions across all body systems, including intestinal dysmotility and atrophy of the enteric nervous system (ENS). Typically, the ENS has capacity to recover from perturbation, so it is unclear why intestinal pathophysiologies persist after traumatic spinal injury. With emerging evidence demonstrating SCI-induced alterations to the gut microbiome composition, we hypothesized that modulation of the gut microbiome could contribute to enteric nervous system recovery after injury. Here, we show that intervention with the dietary fiber, inulin prevents ENS atrophy and limits SCI-induced intestinal dysmotility in mice. However, SCI-associated microbiomes and exposure to specific SCI-sensitive gut microbes are not sufficient to modulate injury-induced intestinal dysmotility. Intervention with microbially-derived short-chain fatty acid (SCFA) metabolites prevents ENS dysfunctions and phenocopies inulin treatment in injured mice, implicating these microbiome metabolites in protection of the ENS. Notably, inulin-mediated resilience is dependent on signaling by the cytokine IL-10, highlighting a critical diet-microbiome-immune axis that promotes ENS resilience following SCI. Overall, we demonstrate that diet and microbially-derived signals distinctly impact recovery of the ENS after traumatic spinal injury. This protective diet-microbiome-immune axis may represent a foundation to uncover etiological mechanisms and future therapeutics for SCI-induced neurogenic bowel.

neuroscience↗

bioRxiv2023

Emergent epileptiform activity drives spinal sensory circuits to generate ectopic bursting in intraspinal afferent axons after cord injury

Spinal cord injury (SCI) leads to hyperexcitability and dysfunction in spinal sensory processing. As hyperexcitable circuits can become epileptiform elsewhere, we explored whether such activity emerges in spinal sensory circuits in a thoracic SCI contusion model of neuropathic pain. Recordings from spinal sensory axons in multiple below-lesion segmental dorsal roots (DRs) demonstrated that SCI facilitated the emergence of spontaneous ectopic burst spiking in afferent axons, which synchronized across multiple adjacent DRs. Burst frequency correlated with behavioral mechanosensitivity. The same bursting events were recruited by afferent stimulation, and timing interactions with ongoing spontaneous bursts revealed that recruitment was limited by a prolonged post-burst refractory period. Ectopic bursting in afferent axons was driven by GABAA receptor activation, presumably via shifting subthreshold GABAergic interneuronal presynaptic axoaxonic inhibitory actions to suprathreshold spiking. Collectively, the emergence of stereotyped bursting circuitry with hypersynchrony, sensory input activation, post-burst refractory period, and reorganization of connectivity represent defining features of epileptiform networks. Indeed, these same features were reproduced in naive animals with the convulsant 4-aminopyridine (4-AP). We conclude that SCI promotes the emergence of epileptiform activity in spinal sensory networks that promotes profound corruption of sensory signaling. This corruption includes downstream actions driven by ectopic afferent bursts that propagate via reentrant central and peripheral projections and GABAergic presynaptic circuit hypoexcitability during the refractory period.

neuroscience↗

bioRxiv2022

C-low threshold mechanoreceptor activation becomes sufficient to trigger affective pain in spinal cord-injured mice in association with increased respiratory rates

The mechanisms of neuropathic pain after spinal cord injury (SCI) are not fully understood. In addition to the plasticity that occurs within the injured spinal cord, peripheral processes, such as hyperactivity of primary nociceptors, are critical to the expression of pain after SCI. In adult rats, truncal stimulation within the tuning range of C-low threshold mechanoreceptors (C-LTMRs) contributes to pain hypersensitivity and elevates respiratory rates (RRs) after SCI. This suggests that C-LTMRs, which normally encode pleasant, affiliative touch, undergo plasticity to transmit pain sensation following injury. Because tyrosine hydroxylase (TH) expression is a specific marker of C-LTMRs, in the periphery, here we used Th-Cre adult mice to investigate more specifically the involvement of C-LTMRs in at-level pain after thoracic contusion SCI. Using a modified light-dark chamber conditioned place aversion (CPA) paradigm, we assessed chamber preferences and transitions between chambers at baseline, and in response to mechanical and optogenetic stimulation of C-LTMRs. In parallel, at baseline and select post-surgical timepoints, mice underwent non-contact RR recordings and von Frey assessment of mechanical hypersensitivity. The results showed that SCI mice avoided the chamber associated with C-LTMR stimulation, an effect that was more pronounced with optical stimulation. They also displayed elevated RRs at rest and during CPA training sessions. Importantly, these changes were restricted to chronic post-surgery timepoints, when hindpaw mechanical hypersensitivity was also evident. Together, these results suggest that C-LTMR afferent plasticity, coexisting with a potentially facilitatory state of sympathetic activation, drives at-level affective pain following SCI in adult mice. Contribution to the field statementPreclinical studies have only recently sought to understand biological mechanisms connecting peripheral afferent neuron hypersensitivity to pain. Using mechanical brush and selective optogenetic activation in transgenic mice, this study investigated the role of an implicated subpopulation of sensory afferents, the C-low threshold mechanoreceptors (C-LTMRs), that may be transformed from pleasurable touch- to pain-encoding neurons after spinal cord injury (SCI). C-LTMR activation after SCI evoked at-level conditioned pain responses associated with sympathetic activation (increased respiratory rates). These studies provide a foundation for research into the peripheral afferent mechanisms of pain that is expected to translate into new options for pain control in humans.

physiology↗