Experimental neurology
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Experimental neurology · Nov 2020
ReviewThe closed-head impact model of engineered rotational acceleration (CHIMERA) as an application for traumatic brain injury pre-clinical research: A status report.
Closed-head traumatic brain injury (TBI) is a worldwide concern with increasing prevalence and cost to society. Rotational acceleration is a primary mechanism in TBI that results from tissue strains that give rise to diffuse axonal injury. The Closed-Head Impact Model of Engineered Rotational Acceleration (CHIMERA) was recently introduced as a method for the study of impact acceleration effects in pre-clinical TBI research. ⋯ However, the majority of CHIMERA studies only utilize adult male mice. To further establish this model, more work with female animals and various age groups need to be performed, as well as studies to further establish and standardize methodologies for validation of the models for clinical relevance. Common data elements to standardize the reporting methodology for the CHIMERA literature are suggested.
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Experimental neurology · Nov 2020
Loss of diffuse noxious inhibitory control after traumatic brain injury in rats: A chronic issue.
Chronic pain is one of the most challenging and debilitating symptoms to manage after traumatic brain injury (TBI), yet the underlying mechanisms remain elusive. The disruption of normal endogenous pain control mechanisms has been linked to several forms of chronic pain and may play a role in pain after TBI. We hypothesized therefore that dysfunctional descending noradrenergic and serotonergic pain control circuits may contribute to the loss of diffuse noxious inhibitory control (DNIC), a critical endogenous pain control mechanism, weeks to months after TBI. ⋯ Intact α2 adrenoceptor signaling, however, was not required for the serotonin-mediated restoration of DNIC after TBI. These results suggest that TBI causes maladaptation of descending nociceptive signaling mechanisms and changes in the function of both adrenergic and serotonergic circuits. Such changes could predispose those with TBI to chronic pain.
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Experimental neurology · Nov 2020
Rostromedial tegmental nucleus-substantia nigra pars compacta circuit mediates aversive and despair behavior in mice.
GABAergic neurons in the rostromedial tegmental nucleus (RMTg) receive major input from the lateral habenula (LHb), which conveys negative reward and motivation related information, and project intensively to midbrain dopamine neurons, including those in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc). The RMTg-VTA circuit has been shown to be linked to the affective behavior, but the role of the RMTg-SNc circuit in aversion and depression has not been well understood. This study demonstrated that exciting or inhibiting VgatRMTg-SNc neurons was sufficient to increase or decrease immobility time in the forced swim test (FST), respectively. ⋯ Furthermore, inhibiting the VgatRMTg-SNc pathway reversed behavioral despair in chronic restraint stress (CRS) depression model mice. Manipulations of the pathway did not affect the hedonic value of the reward in the sucrose-preference test (SPT) or general motor function. In conclusion, these results indicate that the VgatRMTg-SNc pathway regulates aversive and despair behavior, which suggests that the RMTg may mediate the role of LHb in negative behaviors through regulating the activity of SNc neurons.
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Experimental neurology · Oct 2020
Improvement of lower urinary tract function by a selective serotonin 5-HT1A receptor agonist, NLX-112, after chronic spinal cord injury.
Spinal cord injury (SCI) above the lumbosacral level results in lower urinary tract dysfunction, including (1) detrusor hyperreflexia, wherein bladder compliance is low, and (2) a lack of external urethral sphincter (EUS) control, leading to detrusor-sphincter dyssynergia (DSD) with poor voiding efficiency. Experimental studies in animals have shown a dense innervation of serotonergic (5-HT) fibers and multiple 5-HT receptors in the spinal reflex circuits that control voiding function. Here, we investigated the efficacy of NLX-112 (a.k.a. befiradol or F13640), in regulating lower urinary tract function after T8 contusive SCI in rats. ⋯ These included improvements in voiding efficiency, reduction of detrusor hyperactivity, and phasic activity of EUS during the micturition period. In addition, the application of a selective 5-HT1A receptor antagonist, WAY100635, reversed the improved detrusor and EUS activity elicited by NLX-112. In summary, the current data suggest that pharmacological activation of 5-HT1A receptors by NLX-112 may constitute a novel therapeutic strategy to treat neurogenic bladder after SCI.
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Experimental neurology · Sep 2020
Regulation of JNK signaling pathway and RIPK3/AIF in necroptosis-mediated global cerebral ischemia/reperfusion injury in rats.
Receptor-interacting protein kinase 3 (RIPK3) regulates a newly discovered cell death form called necroptosis. RIPK3 nuclear translocation and inflammatory factor release are involved in necroptosis after rat global cerebral ischemia/reperfusion (I/R) injury. The purpose of this study was to investigate the effects of interactions between the RIPK3 and apoptosis-inducing factor (AIF) necroptosis pathway and the JNK-mediated inflammatory pathway. ⋯ It not only inhibits the expression of inflammatory factors p-JNK and IL-6, but also inhibits RIPK3 and AIF in the cytoplasm. Collectively, the results of our study indicate that RIPK3-mediated necroptosis interacts with the JNK-mediated inflammatory signaling pathway to participate in global cerebral I/R injury. JNK-regulated inflammatory mediators may promote the necroptosis initiation.