Biology subjects

Wright, M. C.

Publications and source records attributed to Wright, M. C..

3 recordsLinked to original sources

bioRxiv2022

Senescent Schwann cells induced by aging and chronic denervation impair axonal regeneration after peripheral nerve injury

After peripheral nerve injuries, successful axonal growth and functional recovery requires the reprogramming of Schwann cells into a reparative phenotype, a process dependent on the activation of the transcription factor c-Jun. Nevertheless, axonal regeneration is greatly impaired in aged organisms or after chronic denervation leading to important clinical problems. This regenerative failure has been associated to a diminished c-Jun expression by Schwann cells, but whether the inability of these cells to maintain a repair state is associated to the transition into a phenotype inhibitory for axonal growth, has not been evaluated so far. We find that repair Schwann cells transitions into a senescent phenotype, characterized by diminished c-Jun expression and secretion of factor inhibitory for axonal regeneration in both aging and chronic denervation. In both conditions, elimination of senescent Schwann cells by systemic senolytic drug treatment or genetic targeting improves nerve regeneration and functional recovery in aging and chronic denervation, associated with an upregulation of c-Jun expression and a decrease in nerve inflammation. This work provides the first characterization of senescent Schwann cells and their impact over axonal regeneration in aging and chronic denervation, opening new avenues for enhancing regeneration, and functional recovery after peripheral nerve injuries.

neuroscience↗

bioRxiv2022

Conserved YKL-40 changes in mice and humans after postoperative delirium.

Delirium is a common postoperative neurologic complication among older adults. Despite its prevalence of 14-50% and likely association with inflammation, the exact mechanisms underlying postoperative delirium are unclear. This project aimed at characterizing systemic and central nervous system (CNS) inflammatory changes following surgery in both mice and humans. Matched plasma and cerebrospinal fluid (CSF) samples from the "Investigating Neuroinflammation Underlying Postoperative Brain Connectivity Changes, Postoperative Cognitive Dysfunction, Delirium in Older Adults" (INTUIT; NCT03273335) were used to parallel murine endpoints. Delirium-like behavior was evaluated in aged mice using the 5-Choice Serial Reaction Time Test (5-CSRTT). Using a well-established orthopedic surgical model in the FosTRAP reporter mouse, we detected neuronal changes in the prefrontal cortex, an area implicated in attention, but notably not in the hippocampus. In aged mice, plasma interleukin-6 (IL-6), chitinase-3-like protein 1 (YKL-40), and neurofilament light chain (NfL) levels increased after orthopedic surgery, but hippocampal YKL-40 expression was decreased. Given the growing role of YKL-40 in delirium and other neurodegenerative conditions, we assayed human plasma and CSF samples. Plasma YKL-40 levels were also similarly increased after surgery, with a trend toward greater post-operative plasma YKL-40 increase in patients with delirium. In contrast to plasma, YKL-40 levels in CSF decreased following surgery, which paralleled the findings in the mouse brain. Finally, we confirmed changes in blood-brain barrier (BBB) after surgery as early as 9 hours in mice, which warrants for more detailed and acute evaluations of BBB integrity following surgery in humans. All together, these results provide a nuanced understanding of the neuroimmune interactions underlying post-operative delirium in mice and humans, and highlight translational biomarkers to test potential cellular targets and mechanisms.

neuroscience↗

bioRxiv2020

Optogenetic evaluation of the ability of different cutaneous C-fiber afferents to evoke aversive behaviors

Most cutaneous C-fibers, including both peptidergic and non-peptidergic subtypes are presumed to be nociceptors and respond to noxious input in a graded manner. However, mechanically sensitive, non-peptidergic C-fibers also respond to mechanical input in the innocuous range, and so the degree to which they contribute to nociception remains unclear. To address this gap, we investigated the function of non-peptidergic afferents using the MrgprdCre allele. In real time place aversion studies, we found that low frequency optogenetic activation of MrgrpdCre lineage neurons was not aversive in naive mice, but became aversive after spared nerve injury (SNI). To address the underlying mechanisms of this allodynia, we recorded from lamina I spinoparabrachial (SPB) neurons using the semi-intact ex vivo preparation. Following SNI, innocuous brushing of the skin gave rise to abnormal activity in lamina I SPB neurons, consisting of an increase in the proportion of recorded neurons that responded with excitatory post synaptic potentials or action potentials. This increase was likely due, at least in part, to an increase in the proportion of lamina I (LI) SPB neurons that received input upon optogenetic activation of MrgprdCre lineage neurons. Intriguingly, in SPB neurons there was a significant increase in the EPSC latency from MrgprdCre lineage input following SNI, consistent with the possibility that the greater activation post SNI could be due to the recruitment of a new polysynaptic circuit. Together, our findings suggest MrgprdCre lineage neurons can provide mechanical input to the dorsal horn that is non-noxious before injury but becomes noxious afterwards due the engagement of a previously silent polysynaptic circuit in the dorsal horn.

neuroscience↗