Biology subjects

Ricard, J.

Publications and source records attributed to Ricard, J..

3 recordsLinked to original sources

bioRxiv2024

Mitigating sTNF/TNFR1 activation on VGluT2+ spinal cord interneurons improves immune function after mid-thoracic spinal cord injury

Spinal cord injury (SCI) is a devastating condition with 250,000 to 500,000 new cases globally each year. Respiratory infections, e.g., pneumonia and influenza are the leading cause of death after SCI. Unfortunately, there is a poor understanding of how altered neuro-immune communication impacts an individuals outcome to infection. In humans and rodents, SCI leads to maladaptive changes in the spinal-sympathetic reflex (SSR) circuit which is crucial to sympathetic function. The cause of the impaired immune function may be related to harmful neuroinflammation which is detrimental to homeostatic neuronal function, aberrant plasticity, and hyperexcitable circuits. Soluble tumor necrosis factor (sTNF) is a pro-inflammatory cytokine that is elevated in the CNS after SCI and remains elevated for several months after injury. By pharmacologically attenuating sTNF in the CNS after SCI we were able to demonstrate improved immune function. Furthermore, when we investigated the specific cellular population which may be involved in altered neuro-immune communication we reported that excessive TNFR1 activity on excitatory INs promotes immune dysfunction. Furthermore, this observation is NF-kB dependent in VGluT2+ INs. Our data is the first report of a target within the CNS, TNFR1, that contributes to SCI-induced immune dysfunction after T9-SCI and is a potential avenue for future therapeutics.

neuroscience↗

bioRxiv2023

TNFR1/p38αMAPK signaling in Nex+ supraspinal neurons regulates sex-specific chronic neuropathic pain

Upregulation of soluble tumor necrosis factor (sTNF) cytokine signaling through TNF receptor 1 (TNFR1) and subsequent neuronal hyperexcitability are observed in both animal models and human chronic neuropathic pain (CNP) (Clark et al., 2013; Empl et al., 2001; Ji et al., 2018; Lindenlaub and Sommer, 2003). To test the hypothesis that supraspinal circuitry is critical to pain chronification, we studied the intersect between supraspinal TNFR1 mediated neuronal signaling and sex specificity by selectively removing TNFR1 in Nex+ neurons in adult mice (NexCreERT2::TNFR1f/f). We determined that following chronic constriction injury (CCI), pain resolves in males; however, female acute pain transitions to chronic. Subsequently, we investigated two downstream pathways, p38MAPK and NF-{kappa}B, important in TNFR1 signaling and injury response. We detected p38MAPK and NF-{kappa}B activation in male cortical tissue; however, p38MAPK phosphorylation was reduced in NexCreERT2::TNFR1f/f males. We observed similar behavioral results following CCI in NexCreERT2::p38MAPKf/f mice. Previously, we established estrogens ability to modulate sTNF/TNFR1 signaling in CNP, which may contribute to female prevalence of CNP (Bouhassira et al., 2008; Claiborne et al., 2006; de Mos et al., 2007; Del Rivero et al., 2019; Li et al., 2009). To explore the intersection between estrogen and inflammation in CNP we used a combination therapy of an estrogen receptor {beta} (ER {beta}) inhibitor with a sTNF/TNFR1 or general p38MAPK inhibitor. We determined both combination therapies lend "male-like" therapeutic relief to females following CCI. These data suggest that TNFR1/p38MAPK signaling in Nex+ neurons in CNP is male-specific and lack of therapeutic efficacy following sTNF inhibition in females is due to ER {beta} interference. These studies highlight sex-specific differences in pathways important to pain chronification and elucidate potential therapeutic strategies that would be effective in both sexes.

neuroscience↗

bioRxiv2020

At-level allodynia after mid-thoracic contusion in the rat

The rat mid-thoracic contusion model has been used to study at-level tactile allodynia after spinal cord injury (SCI), one of the more common types of allodynia. An important advantage of this model is that not all animals develop allodynia and, therefore, it could be used to more clearly examine mechanisms that are strictly related to pain development separately from mechanisms related to the injury itself. However, how to separate those that develop allodynia from those that do not is unclear. The aims of the current study were to identify where allodynia and spasticity develop and use this information to identify metrics that separate animals that develop allodynia from those that do not in order study difference in their behavior. To accomplish these aims, a standardized grid was used to localize pain on the dorsal trunk and map it to thoracic dermatomes, providing for the development of a pain score that relied on supraspinal responses and separated subgroups of animals. Similar to human studies, the development of allodynia often occurred with the development of spasticity or hyperreflexia. Moreover, the time course and prevalence of pain phenotypes (at-, above-, or below level) produced by this model were similar to that observed in humans who have sustained an SCI. However, the amount of spared spinal matter in the injured cord did not explain the development of allodynia, as was previously reported. This approach can be used to study the mechanism underlying the development of allodynia separately from mechanisms related to the injury alone.

physiology↗