Neuroscience
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The causal factors determining the onset and severity of multiple sclerosis (MS) are not well understood. Here, we investigated the influence of chronic stress on clinical symptoms, metabolic and epigenetic manifestations of experimental autoimmune encephalomyelitis (EAE), a common animal model of MS. Lewis rats were immunized for monophasic EAE with MBP69-88 and were exposed to chronic stress for 37days starting 7days prior to immunization. ⋯ Thus, stress may synergistically exacerbate severity of EAE by altering epigenetic regulatory pathways. The findings suggest that stress may represent a significant risk factor for symptomatic deterioration in MS. Stress-related metabolic and microRNA signatures support their value as biomarkers for predicting the risk and severity of MS.
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New therapeutics to manage post-surgical pain are needed to mitigate the liabilities of opioid and other analgesics. Our previous work shows that key modulators of excitability in peripheral nociceptors, such as extracellular signal-regulated kinases (ERK) are inhibited by activation of adenosine monophosphate activated protein kinase (AMPK). We hypothesized that AMPK activation would attenuate acute incision-evoked mechanical hypersensitivity and the development of hyperalgesic priming caused by surgery in mice. ⋯ Finally, we used dorsal root ganglion (DRG) neurons in culture to show that resveratrol and metformin given in combination shift the concentration-response curve for AMPK activation to the left and increase the magnitude of AMPK activation. Therefore, we find that topical administration is an effective treatment route of administration and combining systemic and local treatments led to anti-nociceptive efficacy in acute mechanical hypersensitivity at doses that were not effective alone. Collectively our work demonstrates a specific effect of AMPK activators on post-surgical pain and points to novel therapeutic opportunities with potential immediate impact in the clinical setting.
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The injection of safe doses of botulinum neurotoxin A (BoNT/A) have been reported to be useful for the treatment of neuropathic pain, but it is still unknown how functional recovery is induced after peripheral nerve injury. We evaluated the effects of intranerve application of BoNT/A, on regeneration and sensorimotor functional recovery in partial and complete peripheral nerve injuries in the mouse. After sciatic nerve crush (SNC) and intranerve delivery of BoNT/A (15pg), axonal regeneration was measured by nerve pinch test at different days. ⋯ We observed also a higher expression of S100 in the distal portion of BoNT/A-injected regenerated nerves. In CCI mice, BoNT/A induced an increase in reinnervation of gastrocnemius and plantar muscles. These results show that a low dose of BoNT/A, insufficient to produce muscular dysfunction, conversely speeds up sensorimotor recovery by stimulating myelinated axonal regeneration, and points out its application as a multipotent treatment for peripheral neuropathies.
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Diffuse traumatic brain injury (TBI) initiates secondary pathology, including inflammation and reduced myelination. Considering these injury-related pathologies, the many states of activated microglia as demonstrated by differing morphologies would form, migrate, and function in and through fields of growth-inhibitory myelin byproduct, specifically Nogo. Here we evaluate the relationship between inflammation and reduced myelin antigenicity in the wake of diffuse TBI and present the hypothesis that the Nogo-66 receptor antagonist peptide NEP(1-40) would reverse the injury-induced shift in distribution of microglia morphologies by limiting myelin-based inhibition. ⋯ By 7d post-injury, no differences in the distributions of microglia were noted between vehicle and NEP(1-40). This study begins to link secondary pathologies of white matter damage and inflammation after diffuse TBI. In the injured brain, secondary pathologies co-occur and likely interact, with consequences for neuronal circuit disruption leading to neurological symptoms.
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The role of Celsr3 in the development of central somatosensory projections from dorsal root ganglia.
Dorsal root ganglion (DRG) neurons receive peripheral somatosensory information and send orderly projections to second-order relay nuclei in the spinal cord and in the brainstem. Atypical cadherin Celsr3 is known to play a critical role in wiring of several central and peripheral axons. Although Celsr3 mRNA is heavily expressed in DRG neurons, its role in the development of somatosensory projections remains unexplored. ⋯ Furthermore, more Pavalbumin-positive fibers invaded the gray matter and made more contacts with spinal motor neurons in mutant than in control samples. Behavioral analysis showed that mutant animals were less sensitive to pain and more sensitive to mechanical stimulation than controls. In conclusion, Celsr3 is dispensable for the patterning of central DRG projections, but it regulates for the fine mapping of sensory fibers in the gray matter, which is important for somatosensory processing.