Experimental neurology
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Experimental neurology · Jan 2019
Distinct roles of angiotensin receptors in autonomic dysreflexia following high-level spinal cord injury in mice.
Autonomic dysreflexia (AD), a syndrome caused by loss of supraspinal control over sympathetic activity and amplified vascular reflex upon sensory stimuli below injury level, is a major health problem in high-level spinal cord injury (SCI). After supraspinal sympathetic control of the vasculature below the lesion is lost, the renin-angiotensin system (RAS) is thought to be involved in AD by regulating blood pressure and vascular reactivity. In this study, we aimed to assess the role of different RAS receptors during AD following SCI. ⋯ CRD did not influence the reactivity of femoral arteries which are innervated from ganglia more distal to thoracic level T4, in response to Ang II in AD. In conclusion, we identified a specific role of the Ang-(1-7) receptor Mas in regulating the systemic blood pressure increase in AD in T4-SCI mice. Furthermore, AT1a signaling is not involved in this hemodynamic response, but underlies increased vascular reactivity in mesenteric arteries in response to Ang II, where it may contribute to adaptive changes in regional blood flow.
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Experimental neurology · Dec 2018
ReviewCriteria to define mild, moderate, and severe traumatic brain injury in the mouse controlled cortical impact model.
Traumatic brain injury (TBI) is a major health concern in the United States resulting in a substantial number of hospitalizations and in a broad spectrum of symptoms and disabilities. In the clinical setting, neurological responsiveness and structural imaging are used to classify mild, moderate and severe TBI. To evaluate the complex secondary and severity-specific injury response, investigators have relied on pre-clinical rodent models. ⋯ Inconsistent with clinical evaluation, injury severity in the CCI model has predominately relied on the extent of tissue damage. In the present review, we discuss variations in surgical parameters for injury induction as well as the criteria used to determine injury severity. Additionally, we propose guiding principles for the induction and defining of mild, moderate and severe TBI in the craniectomy-dependent experimental mouse CCI model.
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Experimental neurology · Nov 2018
Bromodomain and extraterminal domain-containing protein inhibition attenuates acute inflammation after spinal cord injury.
Inflammation is a major contributor to the secondary damage that occurs after spinal cord injury (SCI). The inflammatory response is coordinated by many different signaling modalities including the epigenetic modification of promoters and enhancers. Bromodomain and extraterminal domain-containing proteins (BETs; Brd2, Brd3, Brd4, BrdT) are epigenetic readers that bind acetylated histones to promote transcription of pro-inflammatory genes. ⋯ By 3 days post-injury, BET inhibition significantly decreased pro-inflammatory cytokine expression and leukocyte recruitment to the injury site. However, this decrease did not lead to locomotor improvements or smaller lesion size. Taken together, our data implicate BETs as regulators of multiple key pro-inflammatory cytokines, and suggest that BETs can be pharmacologically inhibited to reduce inflammation acutely after SCI.
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Experimental neurology · Sep 2018
Spatial distribution affects the role of CSPGs in nerve regeneration via the actin filament-mediated pathway.
CSPGs are components of the extracellular matrix in the nervous system, where they serve as cues for axon guidance during development. After a peripheral nerve injury, CSPGs switch roles and become axon inhibitors and become diffusely distributed at the injury site. To investigate whether the spatial distribution of CSPGs affects their role, we combined in vitro DRG cultures with CSPG stripe or coverage assays to simulate the effect of a patterned substrate or dispersive distribution of CSPGs on growing neurites. ⋯ The application of an actin polymerization inducer, jasplakinolide, allowed neurites to break through the CSPG boundary and grow on CSPG-coated surfaces. The results of our study collectively reveal a novel mechanism that explains how the spatial distribution of CSPGs determines whether they act as a cue for axon guidance or as an axon-inhibiting factor. Increasing our understanding of this issue may promote the development of novel therapeutic strategies that regulate the spatial distributions of CSPGs to use them as an axon guidance cue.
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Experimental neurology · Aug 2018
Ionic plasticity and pain: The loss of descending serotonergic fibers after spinal cord injury transforms how GABA affects pain.
Activation of pain (nociceptive) fibers can sensitize neural circuits within the spinal cord, inducing an increase in excitability (central sensitization) that can foster chronic pain. The development of spinally-mediated central sensitization is regulated by descending fibers and GABAergic interneurons. In adult animals, the co-transporter KCC2 maintains a low intracellular concentration of the anion Cl-. ⋯ Supporting this, blocking the 5HT-1A receptor, or lesioning the DLF, emulated the effect of SCI. Conversely, spinal application of a 5HT-1A agonist up-regulated KCC2 and reversed the effect of bicuculline treatment. Finally, lesioning the DLF reversed how a GABA-A antagonist affects a capsaicin-induced aversion in a place conditioning task; in sham operated animals, bicuculline enhanced aversion whereas in DLF-lesioned rats biciculline had an antinociceptive effect.