Surgical preparations, labeling strategies, and optical techniques for cell-resolved, in vivo imaging in the mouse spinal cord.
Abstract In vivo optical imaging has enabled detailed studies of cellular dynamics in the brain of rodents in both healthy and diseased states. Such studies were made possible by three advances: surgical preparations that give optical access to the brain; strategies for in vivo labeling of cells with structural and functional fluorescent indicators; and optical imaging techniques that are relatively insensitive to light scattering by tissue. In vivo imaging in the rodent spinal cord has lagged behind than that in the brain, largely due to the anatomy around the spinal cord that complicates the surgical preparation...
Source: Experimental Neurology - May 13, 2019 Category: Neurology Authors: Cheng YT, Lett KM, Schaffer CB Tags: Exp Neurol Source Type: research

GDNF pretreatment overcomes Schwann cell phenotype mismatch to promote motor axon regeneration via sensory graft.
Abstract In the clinic, severe motor nerve injury is commonly repaired by autologous sensory nerve bridging, but the ability of Schwann cells (SCs) in sensory nerves to support motor neuron axon growth is poor due to phenotype mismatch. In vitro experiments have demonstrated that sensory-derived SCs overcome phenotypic mismatch-induced growth inhibition after pretreatment with exogenous glial cell-derived neurotrophic factor (GDNF) and induce motor neuron axonal growth. Thus, we introduced a novel staging surgery: In the first stage of surgery, the denervated sensory nerve was pretreated with sustained-release GDN...
Source: Experimental Neurology - May 13, 2019 Category: Neurology Authors: Fang X, Zhang C, Yu Z, Li W, Huang Z, Zhang W Tags: Exp Neurol Source Type: research

The accumulation of T cells within acellular nerve allografts is length-dependent and critical for nerve regeneration.
Abstract Repair of traumatic nerve injuries can require graft material to bridge the defect. The use of alternatives to bridge the defect, such as acellular nerve allografts (ANAs), is being more common and desired. Although ANAs support axon regeneration across short defects (3 cm) is limited. It is unclear why alternatives, including ANAs, are functionally limited by length. After repairing Lewis rat nerve defects using short (2 cm) or long (4 cm) ANAs, we showed that long ANAs have severely reduced axon regeneration across the grafts and contain Schwann cells with a unique phenotype. But additionally, we ...
Source: Experimental Neurology - May 11, 2019 Category: Neurology Authors: Pan D, Hunter DA, Schellhardt L, Jo S, Santosa KB, Larson EL, Fuchs AG, Snyder-Warwick AK, Mackinnon SE, Wood MD Tags: Exp Neurol Source Type: research

Serotonergic mechanisms in spinal cord injury.
Abstract Spinal cord injury (SCI) is a tragic event causing irreversible losses of sensory, motor, and autonomic functions, that may also be associated with chronic neuropathic pain. Serotonin (5-HT) neurotransmission in the spinal cord is critical for modulating sensory, motor, and autonomic functions. Following SCI, 5-HT axons caudal to the lesion site degenerate, and the degree of axonal degeneration positively correlates with lesion severity. Rostral to the lesion, 5-HT axons sprout, irrespective of the severity of the injury. Unlike callosal fibers and cholinergic projections, 5-HT axons are more resistant to...
Source: Experimental Neurology - May 11, 2019 Category: Neurology Authors: Perrin FE, Noristani HN Tags: Exp Neurol Source Type: research

Time to reconsider extended erythropoietin treatment for infantile traumatic brain injury?
Abstract Pediatric traumatic brain injury (TBI) remains a leading cause of childhood morbidity and mortality worldwide. Most efforts to reduce the chronic impact of pediatric TBI involve prevention and minimization of secondary injury. Currently, no treatments are used in routine clinical care during the acute and subacute phases to actively repair injury to the developing brain. The endogenous pluripotent cytokine erythropoietin (EPO) holds promise as an emerging neuroreparative agent in perinatal brain injury (PBI). EPO signaling in the central nervous system (CNS) is essential for multiple stages of neurodevelo...
Source: Experimental Neurology - May 10, 2019 Category: Neurology Authors: Jantzie L, El Demerdash N, Newville JC, Robinson S Tags: Exp Neurol Source Type: research

Hypoactivity of the lateral habenula contributes to negative symptoms and cognitive dysfunction of schizophrenia in rats.
Abstract Dopaminergic (DAergic) hypofunction in the medial prefrontal cortex (mPFC) has been implicated in the negative and cognitive symptoms of schizophrenia and is regulated by serotonergic (5-HTergic) neurons in the dorsal raphe nucleus (DRN). The lateral habenula (LHb) is a key element in controlling DRN 5-HT neurons. We investigated how the LHb impacts the activity of mPFC neurons and whether it mediates the involvement of DRN on development of symptoms in a pharmacological animal model of schizophrenia. We used immunohisochemistry to assess cytochrome-c oxidase (COX) activity of the LHb in MK-801 model rats...
Source: Experimental Neurology - May 10, 2019 Category: Neurology Authors: Li J, Yang S, Liu X, Han Y, Li Y, Feng J, Zhao H Tags: Exp Neurol Source Type: research

Distal denervation in the SOD1 knockout mouse correlates with loss of mitochondria at the motor nerve terminal.
Abstract Impairment of mitochondrial transport has long been implicated in the pathogenesis of neuropathy and neurodegeneration. However, the role of mitochondria in stabilizing motor nerve terminals at neuromuscular junction (NMJ) remains unclear. We previously demonstrated that mice lacking the antioxidant enzyme, superoxide dismutase-1 (Sod1-/-), develop progressive NMJ denervation. This was rescued by expression of SOD1 exclusively in the mitochondrial intermembrane space (MitoSOD1/Sod1-/-), suggesting that oxidative stress within mitochondria drives denervation in these animals. However, we also observed redu...
Source: Experimental Neurology - May 10, 2019 Category: Neurology Authors: Hayes LR, Asress SA, Li Y, Galkin A, Stepanova A, Kawamata H, Manfredi G, Glass JD Tags: Exp Neurol Source Type: research

Mitochondrial methionine sulfoxide reductase B2 links oxidative stress to Alzheimer's disease-like pathology.
Abstract Methionine sulfoxide reductase B2 (MSRB2) is a mitochondrial protein that protects cell from oxidative stress. The antioxidant activity suggests that MSRB2 may play a role in the pathophysiology of Alzheimer's disease (AD). Here, we report that in APP/PS1 mice, an animal model of AD, MSRB2 protein levels were decreased in the hippocampus at both young (6 mon) and old (18 mon) age, and in the cortex only at an old age, respectively. In HEK293 cells that stably express human full-length β-amyloid precursor protein (APP, HEK/APP), MSRB2 reduced the protein and mRNA levels of APP and β-amyloid conve...
Source: Experimental Neurology - May 9, 2019 Category: Neurology Authors: Xiang XJ, Song L, Deng XJ, Tang Y, Min Z, Luo B, Wen QX, Li KY, Chen J, Ma YL, Zhu BL, Yan Z, Chen GJ Tags: Exp Neurol Source Type: research

Deferoxamine therapy reduces brain hemin accumulation after intracerebral hemorrhage in piglets.
In conclusion, hemin accumulation occurs in and around the hematoma. Increases in Hpx and CD91 may be important in scavenging that hemin. DFX treatment decreased hemin release from the hematoma and reduced the expression of Hpx and CD91. PMID: 31078524 [PubMed - as supplied by publisher] (Source: Experimental Neurology)
Source: Experimental Neurology - May 9, 2019 Category: Neurology Authors: Hu S, Hua Y, Keep RF, Feng H, Xi G Tags: Exp Neurol Source Type: research

Visual discrimination impairment after experimental stroke is associated with disturbances in the polarization of the astrocytic aquaporin-4 and increased accumulation of neurotoxic proteins.
Abstract Numerous clinical studies have documented the high incidence of cognitive impairment after stroke. However, there is only limited knowledge about the underlying mechanisms. Interestingly, there is emerging evidence suggesting that cognitive function after stroke may be affected due to reduced waste clearance and subsequent accumulation of neurotoxic proteins. To further explore this potential association, we utilised a model of experimental stroke in mice. Specifically, a photothrombotic vascular occlusion targeting motor and sensory parts of the cerebral cortex was induced in young adult mice, and change...
Source: Experimental Neurology - May 8, 2019 Category: Neurology Authors: Sanchez-Bezanilla S, TeBay C, Nilsson M, Walker FR, Ong LK Tags: Exp Neurol Source Type: research

The second generation mixed-lineage kinase-3 (MLK3) inhibitor CLFB-1134 protects against neurotoxin-induced nigral dopaminergic neuron loss.
Abstract Dopaminergic neurons express mixed lineage kinases which regulate the expression of cell death genes. In Parkinson's disease, cell death via apoptosis is prevalent, and previous work testing mixed lineage kinase inhibitors in animal models suggested the inhibitors had some neuroprotective potential. CLFB-1134 is a new brain-penetrant inhibitor specific for MLK3, tested here in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of dopaminergic depletion and nigral neuron death. After ensuring that treatment with CLFB-1134 did not alter conversion of MPTP to MPP+, we demonstrated CLFB-1134's inhibi...
Source: Experimental Neurology - May 8, 2019 Category: Neurology Authors: Kline EM, Butkovich LM, Bradner JM, Chang J, Gelbard H, Goodfellow V, Caudle WM, Tansey MG Tags: Exp Neurol Source Type: research

Bridging the gap: Mechanisms of plasticity and repair after pediatric TBI.
Abstract Traumatic brain injury is the leading cause of death and disability in the United States, and may be associated with long lasting impairments into adulthood. The multitude of ongoing neurobiological processes that occur during brain maturation confer both considerable vulnerability to TBI but may also provide adaptability and potential for recovery. This review will examine and synthesize our current understanding of developmental neurobiology in the context of pediatric TBI. Delineating this biology will facilitate more targeted initial care, mechanism-based therapeutic interventions and better long-term...
Source: Experimental Neurology - May 2, 2019 Category: Neurology Authors: Sta Maria NS, Sargolzaei S, Prins M, Dennis E, Asarnow RF, Hovda DA, Harris NG, Giza CC Tags: Exp Neurol Source Type: research

Toward development of clinically translatable diagnostic and prognostic metrics of traumatic brain injury using animal models: A review and a look forward.
Abstract Traumatic brain injury is a leading cause of cognitive and behavioral deficits in children in the US each year. There is an increasing interest in both clinical and pre-clinical studies to discover biomarkers to accurately diagnose traumatic brain injury (TBI), predict its outcomes, and monitor its progression especially in the developing brain. In humans, the heterogeneity of TBI in terms of clinical presentation, injury causation, and mechanism has contributed to the many challenges associated with finding unifying diagnosis, treatment, and management practices. In addition, findings from adult human re...
Source: Experimental Neurology - May 2, 2019 Category: Neurology Authors: Hajiaghamemar M, Seidi M, Oeur RA, Margulies SS Tags: Exp Neurol Source Type: research

Maternal high-fat diet results in cognitive impairment and hippocampal gene expression changes in rat offspring.
Abstract Consumption of a high-fat diet has long been known to increase risk for obesity, diabetes, and the metabolic syndrome. Further evidence strongly suggests that these same metabolic disorders are associated with an increased risk of cognitive impairment later in life. Now faced with an expanding global burden of obesity and increasing prevalence of dementia due to an aging population, understanding the effects of high-fat diet consumption on cognition is of increasingly critical importance. Further, the developmental origins of many adult onset neuropsychiatric disorders have become increasingly clear, indi...
Source: Experimental Neurology - April 30, 2019 Category: Neurology Authors: Cordner ZA, Khambadkone SG, Boersma GJ, Song L, Summers TN, Moran TH, Tamashiro KLK Tags: Exp Neurol Source Type: research

Dysregulation of mechanosensory circuits coordinating the actions of antagonist motor pools following peripheral nerve injury and muscle reinnervation.
Abstract Movement disorders observed following peripheral nerve injury and muscle reinnervation suggest discoordination in the activation of antagonist muscles. Although underlying mechanisms remain undecided, dysfunction in spinal reflex circuits is a reasonable candidate. Based on the well known role of reflex inhibition between agonist and antagonist muscles in normal animals, we hypothesized its reduction following muscle reinnervation, similar to that associated with other disorders exhibiting antagonist discoordination, e.g. spinal cord injury and dystonia. Experiments performed on acutely-decerebrated rats ...
Source: Experimental Neurology - April 27, 2019 Category: Neurology Authors: Horstman GM, Housley SN, Cope TC Tags: Exp Neurol Source Type: research

Gnal haploinsufficiency causes genomic instability and increased sensitivity to haloperidol.
Abstract GNAL encodes guanine nucleotide-binding protein subunit Gα(olf) which plays a key role in striatal medium spiny neuron (MSN)-dopamine signaling. GNAL loss-of-function mutations are causally-associated with isolated dystonia, a movement disorder characterized by involuntary muscle contractions leading to abnormal postures. Dopamine D2 receptor (D2R) blockers such as haloperidol are mainstays in the treatment of psychosis but may contribute to the development of secondary acute and tardive dystonia. Administration of haloperidol promotes cAMP-dependent signaling in D2R-expressing indirect pathway MSNs...
Source: Experimental Neurology - April 26, 2019 Category: Neurology Authors: Khan MM, Xiao J, Hollingsworth TJ, Patel D, Selley DE, Ring TL, LeDoux MS Tags: Exp Neurol Source Type: research

Concentration-dependent effects of CSF1R inhibitors on oligodendrocyte progenitor cells ex vivo and in vivo.
In this report, we compared the effect of two commonly used CSF1R inhibitors, PLX5622 and PLX3397, on microglia and oligodendrocyte progenitor cell (OPC) numbers. In ex vivo cerebellar slices and adult mouse brain, both PLX compounds caused robust microglia loss; the kinetics of microglial depletion was more rapid with PLX5622. While high-doses of PLX5622 and PLX3397 reduced OPC number in primary cultures in vitro and ex vivo, low-doses of PLX5622 did not affect the number of OPCs or mature oligodendroglia in culture or in vivo. In adult mice, treatment with PLX5622 had no effect on OPC numbers for 7 days; however, a mil...
Source: Experimental Neurology - April 25, 2019 Category: Neurology Authors: Liu Y, Given KS, Dickson EL, Owens GP, Macklin WB, Bennett JL Tags: Exp Neurol Source Type: research

Monoaminergic regulation of nociceptive circuitry in a Parkinson's disease rat model.
Abstract Pain is a common nonmotor symptom of Parkinson's disease (PD) that remains neglected and misunderstood. Elucidating the nondopaminergic circuitry may be key to better understanding PD and improving current treatments. We investigated the role of monoamines in nociceptive behavior and descending analgesic circuitry in a rat 6-hydroxydopamine (6-OHDA)-induced PD model and explored the resulting motor dysfunctions and inflammatory responses. Rats pretreated with noradrenaline and serotonin reuptake inhibitors were given unilateral striatal 6-OHDA injections and evaluated for mechanical hyperalgesia and motor...
Source: Experimental Neurology - April 24, 2019 Category: Neurology Authors: Campos ACP, Berzuino MB, Hernandes MS, Fonoff ET, Pagano RL Tags: Exp Neurol Source Type: research

Roscovitine, an experimental CDK5 inhibitor, causes delayed suppression of microglial, but not astroglial recruitment around intracerebral dopaminergic grafts.
kkhah G Abstract Inhibitors of cell cycle proteins are known to reduce glial activation and to be neuroprotective in a number of settings. In the context of intracerebral grafting, glial activation is documented to correlate with graft rejection. However, the effects of modification of glial reactivity following grafting in the CNS are poorly understood. Moreover, it is not completely clear if the glial cells themselves trigger the rejection process, or are they secondarily activated. The present study investigated the effect of microglial inhibition by the cyclin-dependant kinase 5 (CDK5) inhibitor roscovitine fo...
Source: Experimental Neurology - April 24, 2019 Category: Neurology Authors: Tomov N, Surchev L, Wiedenmann C, Döbrössy M, Nikkhah G Tags: Exp Neurol Source Type: research

Insulin resistance and hippocampal dysfunction: Disentangling peripheral and brain causes from consequences.
Abstract In the periphery insulin plays a critical role in the regulation of metabolic homeostasis by stimulating glucose uptake into peripheral organs. In the central nervous system (CNS), insulin plays a critical role in the formation of neural circuits and synaptic connections from the earliest stages of development and facilitates and promotes neuroplasticity in the adult brain. Beyond these physiological roles of insulin, a shared feature between the periphery and CNS is that decreases in insulin receptor activity and signaling (i.e. insulin resistance) contributes to the pathological consequences of type 2 d...
Source: Experimental Neurology - April 24, 2019 Category: Neurology Authors: Grillo CA, Woodruff J, Macht VA, Reagan LP Tags: Exp Neurol Source Type: research

Genetic and pharmacological manipulation of glial glutamate transporters does not alter infection-induced seizure activity.
Abstract The contribution of glial transporters to glutamate movement across the membrane has been identified as a potential target for anti-seizure therapies. Two such glutamate transporters, GLT-1 and system xc-, are expressed on glial cells, and modulation of their expression and function have been identified as a means by which seizures, neuronal injury, and gliosis can be reduced in models of brain injury. While GLT-1 is responsible for the majority of glutamate uptake in the brain, system xc- releases glutamate in the extracellular cleft in exchange for cystine and represents as such the major source of hipp...
Source: Experimental Neurology - April 22, 2019 Category: Neurology Authors: Loewen JL, Albertini G, Dahle EJ, Sato H, Smolders IJ, Massie A, Wilcox KS Tags: Exp Neurol Source Type: research

Probing the coding logic of thermosensation using spinal cord calcium imaging.
Abstract The spinal cord dorsal horn is the first relay station of the neural network for processing somatosensory information. High-throughput recording methods facilitate the study of sensory coding in the cortex but have not been successfully applied to study spinal cord circuitry until recently. Here, we review the development of the in vivo two-photon spinal calcium imaging preparation and biological findings from the first systematic characterization of the spinal response to cutaneous thermal stimuli, focusing on the difference between the coding of heat and cold, and the contribution of different periphera...
Source: Experimental Neurology - April 20, 2019 Category: Neurology Authors: Ran C, Chen X Tags: Exp Neurol Source Type: research

Combining molecular intervention with in vivo imaging to untangle mechanisms of axon pathology and outgrowth following spinal cord injury.
Abstract In vivo imaging of the spinal cord has allowed the observation of single axons over relatively long periods in the living mouse. After spinal cord injury, this methodology has helped to differentiate several pathological stages and tissue processes which impact axon morphology. In addition, the combination of in vivo imaging techniques with specific molecular intervention has shown that specific pathological axon changes can respond to distinct treatments. Combining in vivo imaging with molecular interventions is, hence, a powerful approach to extend our knowledge of the pathological processes leading to ...
Source: Experimental Neurology - April 13, 2019 Category: Neurology Authors: Denecke CK, Aljović A, Bareyre FM Tags: Exp Neurol Source Type: research

Understanding the axonal response to injury by in vivo imaging in the mouse spinal cord: A tale of two branches.
This article reviews evidence from in vivo spinal cord imaging that axonal branches markedly impact the degenerative and regenerative responses to injury. At a major bifurcation point, depending on whether one or both axonal branches are injured, neurons may choose either a more self-preservative response or a more dynamic response. The stabilizing effect of the spared branch may underlie a well-known divergence in neuronal responses to injury, and illustrates an example where in vivo spinal cord imaging reveals insights that are difficult to elucidate with conventional histological methods. PMID: 30986398 [PubMed - a...
Source: Experimental Neurology - April 12, 2019 Category: Neurology Authors: Zheng B, Lorenzana AO, Ma L Tags: Exp Neurol Source Type: research

OCT4B-190 protects against ischemic stroke by modulating GSK-3 β/HDAC6.
OCT4B-190 protects against ischemic stroke by modulating GSK-3β/HDAC6. Exp Neurol. 2019 Apr 11;: Authors: Chen Y, Wu Z, Zhu X, Zhang M, Zang X, Li X, Xu Y Abstract OCT4 is a key regulator in maintaining the pluripotency and self-renewal of embryonic stem cells (ESCs). Human OCT4 gene has three mRNA isoforms, termed OCT4A, OCT4B and OCT4B1. The 190-amino-acid protein isoform (OCT4B-190) is one of the major products of OCT4B mRNA, the biological function of which is still not well defined. Recent evidence suggests that OCT4B-190 may function in the cellular stress response. The glycogen synthase ki...
Source: Experimental Neurology - April 11, 2019 Category: Neurology Authors: Chen Y, Wu Z, Zhu X, Zhang M, Zang X, Li X, Xu Y Tags: Exp Neurol Source Type: research

Detection of brain specific cardiolipins in plasma after experimental pediatric head injury.
Abstract Cardiolipin (CL) is a mitochondria-specific phospholipid that is central to maintenance and regulation of mitochondrial bioenergetic and metabolic functions. CL molecular species display great tissue variation with brain exhibiting a distinct, highly diverse CL population. We recently showed that the appearance of unique brain-type CLs in plasma could serve as a brain-specific marker of mitochondrial/tissue injury in patients after cardiac arrest. Mitochondrial dysfunction has been increasingly implicated as a critical mechanism underlying the pathogenesis of traumatic brain injury (TBI). Therefore, we hy...
Source: Experimental Neurology - April 11, 2019 Category: Neurology Authors: Anthonymuthu TS, Kenny EM, Hier ZE, Clark RSB, Kochanek PM, Kagan VE, Bayır H Tags: Exp Neurol Source Type: research

Improved memory and reduced anxiety in δ-catenin transgenic mice.
Improved memory and reduced anxiety in δ-catenin transgenic mice. Exp Neurol. 2019 Apr 11;: Authors: Ryu T, Park HJ, Kim H, Cho YC, Kim BC, Jo J, Seo YW, Choi WS, Kim K Abstract δ-Catenin is abundant in the brain and affects its synaptic plasticity. Furthermore, loss of δ-catenin is related to the deficits of learning and memory, mental retardation (cri-du-chat syndrome), and autism. A few studies about δ-catenin deficiency mice were performed. However, the effect of δ-catenin overexpression in the brain has not been investigated as yet. Therefore we generated a δ-c...
Source: Experimental Neurology - April 11, 2019 Category: Neurology Authors: Ryu T, Park HJ, Kim H, Cho YC, Kim BC, Jo J, Seo YW, Choi WS, Kim K Tags: Exp Neurol Source Type: research

Depletion of microglia immediately following traumatic brain injury in the pediatric rat: Implications for cellular and behavioral pathology.
Abstract The inflammatory response is a significant component of the pathophysiology of pediatric traumatic brain injury. High levels of inflammatory mediators have been found in the cerebrospinal fluid of brain-injured children which have been linked to poor prognosis. Targeting aspects of the inflammatory response in the hopes of finding a viable post-injury therapeutic option has gained attention. Microglia are largely responsible for perpetuating the injury-induced inflammatory response but in the developing brain they play beneficial roles in both normal and disease states. Following closed head injury in the...
Source: Experimental Neurology - April 10, 2019 Category: Neurology Authors: Hanlon LA, Raghupathi R, Huh JW Tags: Exp Neurol Source Type: research

Excess glutamate secreted from astrocytes drives upregulation of P-glycoprotein in endothelial cells in amyotrophic lateral sclerosis.
In this study, we found that glutamate, which is abnormally secreted by mutant SOD1 and sporadic ALS astrocytes, drives upregulation of P-gp expression and activity levels in endothelial cells via activation of N-Methyl-D-Aspartic acid (NMDA) receptors. Surprisingly, astrocyte-secreted glutamate regulation of endothelial P-gp levels is not a mechanism shared by all forms of ALS. C9orf72-ALS astrocytes had no effect on endothelial cell P-gp expression and did not display increased glutamate secretion. Utilizing an optimized in vitro human BBB model consisting of patient-derived induced pluripotent stem cells, we showed that...
Source: Experimental Neurology - April 8, 2019 Category: Neurology Authors: Mohamed LA, Markandaiah S, Bonanno S, Pasinelli P, Trotti D Tags: Exp Neurol Source Type: research

Insulin resistance: Genetic associations with depression and cognition in population based cohorts.
Abstract Insulin resistance, broadly defined as the reduced ability of insulin to exert its biological action, has been associated with depression and cognitive dysfunction in observational studies. However, it is unclear whether these associations are causal and whether they might be underpinned by other shared factors. To address this knowledge gap, we capitalized on the stability of genetic biomarkers through the lifetime, and on their unidirectional relationship with depression and cognition. Specifically, we determined the association between quantitative measures of cognitive function and depression and gene...
Source: Experimental Neurology - April 6, 2019 Category: Neurology Authors: Frangou S, Shirali M, Adams MJ, Howard DM, Gibson J, Hall LS, Smith BH, Padmanabhan S, Murray AD, Porteous DJ, Haley CS, Deary IJ, Clarke TK, McIntosh AM Tags: Exp Neurol Source Type: research

Metabolic perturbations after pediatric TBI: It's not just about glucose.
Abstract Improved patient survival following pediatric traumatic brain injury (TBI) has uncovered a currently limited understanding of both the adaptive and maladaptive metabolic perturbations that occur during the acute and long-term phases of recovery. While much is known about the redundancy of metabolic pathways that provide adequate energy and substrates for normal brain growth and development, the field is only beginning to characterize perturbations in these metabolic pathways after pediatric TBI. To date, the majority of studies have focused on dysregulated oxidative glucose metabolism after injury; howeve...
Source: Experimental Neurology - April 2, 2019 Category: Neurology Authors: Bowman CE, Scafidi J, Scafidi S Tags: Exp Neurol Source Type: research

Understanding the link between insulin resistance and Alzheimer's disease: Insights from animal models.
ce FG Abstract Alzheimer's disease (AD) is a devastating neurodegenerative disease affecting millions of people worldwide. AD is characterized by a profound impairment of higher cognitive functions and still lacks any effective disease-modifying treatment. Defective insulin signaling has been implicated in AD pathophysiology, but the mechanisms underlying this process are not fully understood. Here, we review the molecular mechanisms underlying defective brain insulin signaling in rodent models of AD, and in a non-human primate (NHP) model of the disease that recapitulates features observed in AD brains. We furthe...
Source: Experimental Neurology - March 28, 2019 Category: Neurology Authors: De Silva NML, Gonçalves RA, Boehnke SE, Forny-Germano L, Munoz DP, De Felice FG Tags: Exp Neurol Source Type: research

MicroRNA-132 attenuates cerebral injury by protecting blood-brain-barrier in MCAO mice.
Abstract MicroRNAs (miRNAs) have been widely reported to induce posttranscriptional gene silencing and led to an explosion of new strategies for the treatment of human disease. It has been reported that the expression of MicroRNA-132 (miR-132) are altered both in the blood and brain after stroke. However, the effect of miR-132 on blood-brain barrier (BBB) disruption in ischemia stroke has not been studied. Here we will investigate the effects of miR-132 on the permeability of BBB after ischemic stroke and explore the potential mechanism underlying observed protection. Eight week-old mice were injected intracerebro...
Source: Experimental Neurology - March 28, 2019 Category: Neurology Authors: Zuo X, Lu J, Manaenko A, Qi X, Tang J, Mei Q, Xia Y, Hu Q Tags: Exp Neurol Source Type: research

Translational approach towards determining the role of cerebral autoregulation in outcome after traumatic brain injury.
Abstract Cerebral autoregulation is impaired after traumatic brain injury (TBI), contributing to poor outcome. In the context of the neurovascular unit, cerebral autoregulation contributes to neuronal cell integrity and clinically Glasgow Coma Scale is correlated to intactness of autoregulation after TBI. Cerebral Perfusion Pressure (CPP) is often normalized by use of vasoactive agents to increase mean arterial pressure (MAP) and thereby limit impairment of cerebral autoregulation and neurological deficits. However, current vasoactive agent choice used to elevate MAP to increase CPP after TBI is variable. Vasoacti...
Source: Experimental Neurology - March 27, 2019 Category: Neurology Authors: Armstead WM, Vavilala MS Tags: Exp Neurol Source Type: research

Impairment of pericyte-endothelium crosstalk leads to blood-brain barrier dysfunction following traumatic brain injury.
In conclusion, our data provide an insight that brain trauma causes an early impairment of pericyte-endothelium integrity and results in BBB dysregulation that initiates pathological consequences associated with TBI. PMID: 30926390 [PubMed - as supplied by publisher] (Source: Experimental Neurology)
Source: Experimental Neurology - March 26, 2019 Category: Neurology Authors: Bhowmick S, D'Mello V, Caruso D, Wallerstein A, Abdul-Muneer PM Tags: Exp Neurol Source Type: research

Neuroprotective effects of inter-alpha inhibitor proteins after hypoxic-ischemic brain injury in neonatal rats.
The objective of the current study was to investigate the neuroprotective effects of treatment with IAIPs given immediately or 6 h after HI in both male and female neonatal rats. HI was induced with the Rice-Vannucci method in postnatal (P) day 7 rats. After ligation of the right common carotid artery, P7 rats were exposed to 90 min of hypoxia (8% oxygen). Human plasma-derived IAIPs or placebo (phosphate buffered saline) was given at zero, 24, and 48 h after HI. Brains were perfused, weighed and fixed 72 h after HI at P10. In a second, delayed treatment group, the same procedure was followed except that IAIPs or pl...
Source: Experimental Neurology - March 23, 2019 Category: Neurology Authors: Chen X, Nakada S, Donahue JE, Chen RH, Tucker R, Qiu J, Lim YP, Stopa EG, Stonestreet BS Tags: Exp Neurol Source Type: research

Does pediatric traumatic brain injury cause adult alcohol misuse: Combining preclinical and epidemiological approaches.
Abstract Traumatic brain injury (TBI) is closely interrelated with alcohol use disorders. This is mediated, in part, by the large number of individuals who are intoxicated at the time of their injuries. However, there is also evidence, both preclinically and epidemiologically that TBI, particularly when it occurs early in life can increase the incidence of alcohol use disorders later on. This is extremely important because, drinking after TBI has been associated with much poorer long-term outcomes as compared to individuals who do not drink. However, for a number of reasons including, potential confounders and a r...
Source: Experimental Neurology - March 22, 2019 Category: Neurology Authors: Weil ZM, Karelina K, Corrigan JD Tags: Exp Neurol Source Type: research

HDAC5 promotes optic nerve regeneration by activating the mTOR pathway.
Abstract Neurons in the central nervous system (CNS) regenerate poorly compared to their counterparts in the peripheral nervous system. We previously showed that, in peripheral sensory neurons, nuclear HDAC5 inhibits the expression of regenerative associated genes. After nerve injury, HDAC5 is exported to the cytoplasm to promote axon regeneration. Here we investigated the role of HDAC5 in retinal ganglion cells (RGC), a CNS neuron which fails to survive and regenerate axons after injury. In contrast to PNS neurons, we found that HDAC5 is mostly cytoplasmic in naïve RGCs and its localization is not affected b...
Source: Experimental Neurology - March 22, 2019 Category: Neurology Authors: Pita-Thomas W, Mahar M, Joshi A, Gan D, Cavalli V Tags: Exp Neurol Source Type: research

Chronic spinal cord injury impairs primary CD8 T cell antiviral immunity but does not affect generation or function of memory CD8 T cells.
Abstract Antiviral immunity is severely compromised following trauma to the central nervous system. In mice with chronic spinal cord injury (SCI), primary infection with influenza virus leads to high mortality rates due to impaired expansion of virus-specific CD8 T cells. One strategy to increase resistance to viral infections is to generate memory immune cells that protect from recurrent infections. However, it is unknown if chronic SCI also impairs secondary immune responses to influenza challenge as it does primary responses. Here, we used a mouse model of chronic SCI and a clinically relevant influenza A infec...
Source: Experimental Neurology - March 20, 2019 Category: Neurology Authors: Norden DM, Qatanani A, Bethea JR, Jiang J Tags: Exp Neurol Source Type: research

Muscle ciliary neurotrophic factor receptor α helps maintain choline acetyltransferase levels in denervated motor neurons following peripheral nerve lesion.
Muscle ciliary neurotrophic factor receptor α helps maintain choline acetyltransferase levels in denervated motor neurons following peripheral nerve lesion. Exp Neurol. 2019 Mar 19;: Authors: Lee N, Wanek HA, MacLennan AJ Abstract Systemic ciliary neurotrophic factor (CNTF) administration protects motor neurons from denervating diseases and lesions but produces non-neuromuscular side effects. Therefore, CNTF related therapeutics will need to specifically target motor neuron protective receptor mechanisms. Expression of the essential ligand binding subunit of the CNTF receptor, CNTF receptor &alp...
Source: Experimental Neurology - March 19, 2019 Category: Neurology Authors: Lee N, Wanek HA, MacLennan AJ Tags: Exp Neurol Source Type: research

Deep brain stimulation of the ventroanterior and ventrolateral thalamus improves motor function in a rat model of Parkinson's disease.
Abstract Parkinson's disease (PD) is a neurodegenerative disease with affected individuals exhibiting motor symptoms of bradykinesia, muscle rigidity, tremor, postural instability and gait dysfunction. The current gold standard treatment is pharmacotherapy with levodopa, but long-term use is associated with motor response fluctuations and can cause abnormal movements called dyskinesias. An alternative treatment option is deep brain stimulation (DBS) with the two FDA-approved brain targets for PD situated in the basal ganglia; specifically, in the subthalamic nucleus (STN) and globus pallidus pars interna (GPi). Bo...
Source: Experimental Neurology - March 16, 2019 Category: Neurology Authors: Tucker H, Mahoney E, Chhetri A, Unger K, Mamone G, Kim G, Audil A, Moolick B, Molho ES, Pilitsis JG, Shin DS Tags: Exp Neurol Source Type: research

Outcomes and clinical implications of intranasal insulin administration to the central nervous system.
Abstract Insulin signaling in the brain plays a critical role in metabolic control and cognitive function. Targeting insulinergic pathways in the central nervous system via peripheral insulin administration is feasible, but associated with systemic effects that necessitate tight supervision or countermeasures. The intranasal route of insulin administration, which largely bypasses the circulation and thereby greatly reduces these obstacles, has now been repeatedly tested in proof-of-concept studies in humans as well as animals. It is routinely used in experimental settings to investigate the impact on eating behavi...
Source: Experimental Neurology - March 15, 2019 Category: Neurology Authors: Santiago JCP, Hallschmid M Tags: Exp Neurol Source Type: research

Nociceptor-dependent locomotor dysfunction after clinically-modeled hindlimb muscle stretching in adult rats with spinal cord injury.
Abstract In the course of investigating how common clinical treatments and adaptive technologies affect recovery after spinal cord injury (SCI), we discovered that a clinically-modeled hindlimb stretching protocol dramatically, but transiently, reduces locomotor function. Nociceptive sensory input is capable of altering motor output at the spinal level, and nociceptive neurons are sensitized after SCI. Here we tested the possibility that the stretch-induced motor deficits required the presence of nociceptors using neonatal capsaicin induced depletion of TRPV1+ nociceptive neurons. Following maturation, animals rec...
Source: Experimental Neurology - March 14, 2019 Category: Neurology Authors: Keller AV, Hainline C, Rees K, Krupp S, Prince D, Wood BD, Shum-Siu A, Burke DA, Petruska JC, Magnuson DSK Tags: Exp Neurol Source Type: research

The emerging role of neutrophils as modifiers of recovery after traumatic injury to the developing brain.
Abstract The innate immune response plays a critical role in traumatic brain injury (TBI), contributing to ongoing pathogenesis and worsening long-term outcomes. Here we focus on neutrophils, one of the "first responders" to TBI. These leukocytes are recruited to the injured brain where they release a host of toxic molecules including free radicals, proteases, and pro-inflammatory cytokines, all of which promote secondary tissue damage. There is mounting evidence that the developing brain is more vulnerable to injury that the adult brain. This vulnerability to greater damage from TBI is, in part, attribu...
Source: Experimental Neurology - March 12, 2019 Category: Neurology Authors: von Leden RE, Parker KN, Bates AA, Noble-Haeusslein LJ, Donovan MH Tags: Exp Neurol Source Type: research

Upregulation of interleukin-6 on Cav3.2 T-type calcium channels in dorsal root ganglion neurons contributes to neuropathic pain in rats with spinal nerve ligation.
Abstract The T-type calcium channels Cav3.2, one of the low voltage-activated (LVA) calcium channels, have been found to play important roles in the neuronal excitability. Recently, we and others have demonstrated that accumulation of Cav3.2 channels in the dorsal root ganglion (DRG) neurons and sensory nerves contributes to neuropathic pain after peripheral nerve injury. In the present study, we aimed to further investigate the regulation of Cav3.2 channels by interleukin-6 (IL-6) in DRG neurons in neuropathic pain rats after spinal nerve ligation (SNL). The results showed that Cav3.2 channel protein expression i...
Source: Experimental Neurology - March 11, 2019 Category: Neurology Authors: Liu Q, Chen W, Fan X, Wang J, Fu S, Cui S, Liao F, Cai J, Wang X, Huang Y, Su L, Zhong L, Yi M, Liu F, Wan Y Tags: Exp Neurol Source Type: research

Brain interrupted: Early life traumatic brain injury and addiction vulnerability.
Abstract Recent reports provide evidence for increased risk of substance use disorders (SUD) among patients with a history of early-life traumatic brain injury (TBI). Preclinical research utilizing animal models of TBI have identified injury-induced inflammation, blood-brain barrier permeability, and changes to synapses and neuronal networks within regions of the brain associated with the perception of reward. Importantly, these reward pathway networks are underdeveloped during childhood and adolescence, and early-life TBI pathology may interrupt ongoing maturation. As such, maladaptive changes induced by juvenile...
Source: Experimental Neurology - March 9, 2019 Category: Neurology Authors: Cannella LA, McGary H, Ramirez SH Tags: Exp Neurol Source Type: research

Calcium imaging approaches in investigation of pain mechanism in the spinal cord.
Abstract The continuous advancement of microscopic imaging techniques combined with the discovery and use of more powerful calcium indicators has made calcium imaging technology much more effective and has increased its use in the study of pain circuitry. Using calcium imaging to study spinal pain mechanisms causes less damage to animals compared to electrophysiological techniques and is also able to observe the firing pattern of spinal neurons and the connections between them on a large scale. These advantages allow any changes in spinal cord circuits caused by pain transmission to be observed more effectively. T...
Source: Experimental Neurology - March 7, 2019 Category: Neurology Authors: Xu Q, Dong X Tags: Exp Neurol Source Type: research

Mechanisms underlying vulnerabilities after repeat mild traumatic brain injuries.
Abstract Traumatic brain injury (TBI) has drawn national attention for its high incidence and mechanistic complexity. The majority of TBI cases are "mild" in nature including concussions and mild TBI (mTBI). Concussions are a distinct form of mTBI where diagnosis is difficult, quantification of the incidence is challenging and there is greater risk for subsequent injuries. While concussions occur in the general population, it has become a hallmark injury consistently observed among adolescent and young adult athletes and the risks for repeat TBI (rTBI) is significant. Clinical and experimental evidence s...
Source: Experimental Neurology - March 7, 2019 Category: Neurology Authors: Greco T, Ferguson L, Giza C, Prins ML Tags: Exp Neurol Source Type: research

Ethanol-induced DNA repair in neural stem cells: Is transforming growth factor β1-dependent.
This study tests the hypothesis that ethanol induces a DNA damage response (DDR) in neural stem cells (NSCs) that promotes excision repair (ER) and this repair is influenced by the growth factor environment. Non-immortalized NSCs treated with fibroblast growth factor 2 or transforming growth factor (TGF) β1 were exposed to ethanol. Ethanol increased total DNA damage, reactive oxygen species, and oxidized DNA bases. TGFβ1 potentiated these toxic effects. Transcriptional analyses of cultured NSCs revealed ethanol-induced increases in transcripts related to the DDR (e.g., Hus1 and p53), base ER (e.g., Mutyh and Nthl...
Source: Experimental Neurology - March 7, 2019 Category: Neurology Authors: Hicks SD, Miller MW Tags: Exp Neurol Source Type: research

Efgartigimod improves muscle weakness in a mouse model for muscle-specific kinase myasthenia gravis.
In conclusion, our study shows that efgartigimod has clear therapeutic potential in MuSK myasthenia gravis and forms an exciting candidate drug for many autoantibody-mediated neurological and other disorders. PMID: 30851266 [PubMed - as supplied by publisher] (Source: Experimental Neurology)
Source: Experimental Neurology - March 6, 2019 Category: Neurology Authors: Huijbers MG, Plomp JJ, van Es IE, Fillié-Grijpma YE, Majidi SK, Ulrichts P, de Haard H, Hofman E, van der Maarel SM, Verschuuren JJ Tags: Exp Neurol Source Type: research