ResearchPad - disorders-of-the-nervous-system https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[Vitamin D Supplementation Rescues Aberrant NF-κB Pathway Activation and Partially Ameliorates Rett Syndrome Phenotypes in <i>Mecp2</i> Mutant Mice]]> https://www.researchpad.co/article/elastic_article_13342 Rett syndrome (RTT) is a severe, progressive X-linked neurodevelopmental disorder caused by mutations in the transcriptional regulator MECP2. We previously identified aberrant NF-κB pathway upregulation in brains of Mecp2-null mice and demonstrated that genetically attenuating NF-κB rescues some characteristic neuronal RTT phenotypes. These results raised the intriguing question of whether NF-κB pathway inhibitors might provide a therapeutic avenue in RTT. Here, we investigate whether the known NF-κB pathway inhibitor vitamin D ameliorates neuronal phenotypes in Mecp2-mutant mice. Vitamin D deficiency is prevalent among RTT patients, and we find that Mecp2-null mice similarly have significantly reduced 25(OH)D serum levels compared with wild-type littermates. We identify that vitamin D rescues aberrant NF-κB pathway activation and reduced neurite outgrowth of Mecp2 knock-down cortical neurons in vitro. Further, dietary supplementation with vitamin D in early symptomatic male Mecp2 hemizygous null and female Mecp2 heterozygous mice ameliorates reduced neocortical dendritic morphology and soma size phenotypes and modestly improves reduced lifespan of Mecp2-nulls. These results elucidate fundamental neurobiology of RTT and provide foundation that NF-κB pathway inhibition might be a therapeutic target for RTT.

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<![CDATA[Reduced TUBA1A Tubulin Causes Defects in Trafficking and Impaired Adult Motor Behavior]]> https://www.researchpad.co/article/elastic_article_8074 Newly born neurons express high levels of TUBA1A α-tubulin to assemble microtubules for neurite extension and to provide tracks for intracellular transport. In the adult brain, Tuba1a expression decreases dramatically. A mouse that harbors a loss-of-function mutation in the gene encoding TUBA1A (Tuba1aND/+) allows us to ask whether TUBA1A is important for the function of mature neurons. α-Tubulin levels are about half of wild type in juvenile Tuba1aND/+ brains, but are close to normal in older animals. In postnatal day (P)0 cultured neurons, reduced TUBA1A allows for assembly of less microtubules in axons resulting in more pausing during organelle trafficking. While Tuba1aND/+ mouse behavior is indistinguishable from wild-type siblings at weaning, Tuba1aND/+ mice develop adult-onset ataxia. Neurons important for motor function in Tuba1aND/+ remain indistinguishable from wild-type with respect to morphology and number and display no evidence of axon degeneration. Tuba1aND/+ neuromuscular junction (NMJ) synapses are the same size as wild-type before the onset of ataxia, but are reduced in size in older animals. Together, these data indicate that the TUBA1A-rich microtubule tracks that are assembled during development are essential for mature neuron function and maintenance of synapses over time.

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<![CDATA[EGFR Signaling Causes Morphine Tolerance and Mechanical Sensitization in Rats]]> https://www.researchpad.co/article/elastic_article_8067 The safety and efficacy of opioids are compromised as analgesic tolerance develops. Opioids are also ineffective against neuropathic pain. Recent reports have suggested that inhibitors of the epidermal growth factor receptor (EGFR), a receptor tyrosine kinase (RTK), may have analgesic effects in cancer patients suffering from neuropathic pain. It has been shown that the platelet-derived growth factor receptor-β (PDGFR-β), an RTK that has been shown to interact with the EGFR, mediates opioid tolerance but does not induce analgesia. Therefore, we sought to determine whether EGFR signaling was involved in opioid tolerance and whether EGFR and PDGFR signaling could induce pain in rats. We found that gefitinib, an EGFR antagonist, eliminated morphine tolerance. In addition, repeated EGF administration rendered animals unresponsive to subsequent analgesic doses of morphine, a phenomenon we call “pre-tolerance.” Using a nerve injury model, we found that gefitinib alone was not analgesic. Rather, it reversed insensitivity to morphine analgesia (pre-tolerance) caused by the release of EGF by injured nerves. We also showed that repeated, but not acute EGF or PDGF-BB administration induced mechanical hypersensitivity in rats. EGFR and PDGFR-β signaling interacted to produce this sensitization. EGFR was widely expressed in primary sensory afferent cell bodies, demonstrating a neuroanatomical substrate for our findings. Taken together, our results suggest a direct mechanistic link between opioid tolerance and mechanical sensitization. EGFR antagonism could eventually play an important clinical role in the treatment of opioid tolerance and neuropathic pain that is refractory to opioid treatment.

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<![CDATA[Impaired Motor Recycling during Action Selection in Parkinson’s Disease]]> https://www.researchpad.co/article/elastic_article_8059 Behavioral studies have shown that the human motor system recycles motor parameters of previous actions, such as movement amplitude, when programming new actions. Shifting motor plans toward a new action forms a particularly severe problem for patients with Parkinson’s disease (PD), a disorder that, in its early stage, is dominated by basal ganglia dysfunction. Here, we test whether this action selection deficit in Parkinson’s patients arises from an impaired ability to recycle motor parameters shared across subsequent actions. Parkinson’s patients off dopaminergic medication (n = 16) and matched healthy controls (n = 16) performed a task that involved moving a handheld dowel over an obstacle in the context of a sequence of aiming movements. Consistent with previous research, healthy participants continued making unnecessarily large hand movements after clearing the obstacle (defined as “hand path priming effect”), even after switching movements between hands. In contrast, Parkinson’s patients showed a reduced hand path priming effect, i.e., they performed biomechanically more efficient movements than controls, but only when switching movements between hands. This effect correlated with disease severity, such that patients with more severe motor symptoms had a smaller hand path priming effect. We propose that the basal ganglia mediate recycling of movement parameters across subsequent actions.

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<![CDATA[The Epileptor Model: A Systematic Mathematical Analysis Linked to the Dynamics of Seizures, Refractory Status Epilepticus, and Depolarization Block]]> https://www.researchpad.co/article/N538242ca-4a1f-4816-abe7-9afbd7e687e4

Abstract

One characteristic of epilepsy is the variety of mechanisms leading to the epileptic state, which are still largely unknown. Refractory status epilepticus (RSE) and depolarization block (DB) are other pathological brain activities linked to epilepsy, whose patterns are different and whose mechanisms remain poorly understood. In epileptogenic network modeling, the Epileptor is a generic phenomenological model that has been recently developed to describe the dynamics of seizures. Here, we performed a detailed qualitative analysis of the Epileptor model based on dynamical systems theory and bifurcation analysis, and investigate the dynamic evolution of “normal” activity toward seizures and to the pathological RSE and DB states. The mechanisms of the transition between states are called bifurcations. Our detailed analysis demonstrates that the generic model undergoes different bifurcation types at seizure offset, when varying some selected parameters. We show that the pathological and normal activities can coexist within the same model under some conditions, and demonstrate that there are many pathways leading to and away from these activities. We here archive systematically all behaviors and dynamic regimes of the Epileptor model to serve as a resource in the development of patient-specific brain network models, and more generally in epilepsy research.

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<![CDATA[MANF Ablation Causes Prolonged Activation of the UPR without Neurodegeneration in the Mouse Midbrain Dopamine System]]> https://www.researchpad.co/article/N6eb84382-0fcb-491e-9b59-8d50a4912c9a

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<![CDATA[Collapsin Response Mediator Protein 4 (CRMP4) Facilitates Wallerian Degeneration and Axon Regeneration following Sciatic Nerve Injury]]> https://www.researchpad.co/article/Nd379ba60-5a3b-45b0-8bd6-4e69e83b3b46

Abstract

In contrast to neurons in the CNS, damaged neurons from the peripheral nervous system (PNS) regenerate, but this process can be slow and imperfect. Successful regeneration is orchestrated by cytoskeletal reorganization at the tip of the proximal axon segment and cytoskeletal disassembly of the distal segment. Collapsin response mediator protein 4 (CRMP4) is a cytosolic phospho-protein that regulates the actin and microtubule cytoskeleton. During development, CRMP4 promotes growth cone formation and dendrite development. Paradoxically, in the adult CNS, CRMP4 impedes axon regeneration. Here, we investigated the involvement of CRMP4 in peripheral nerve injury in male and female Crmp4−/− mice following sciatic nerve injury. We find that sensory axon regeneration and Wallerian degeneration are impaired in Crmp4−/− mice following sciatic nerve injury. In vitro analysis of dissociated dorsal root ganglion (DRG) neurons from Crmp4−/− mice revealed that CRMP4 functions in the proximal axon segment to promote the regrowth of severed DRG neurons and in the distal axon segment where it facilitates Wallerian degeneration through calpain-dependent formation of harmful CRMP4 fragments. These findings reveal an interesting dual role for CRMP4 in proximal and distal axon segments of injured sensory neurons that coordinately facilitate PNS axon regeneration.

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<![CDATA[Characterization of Auditory and Binaural Spatial Hearing in a Fragile X Syndrome Mouse Model]]> https://www.researchpad.co/article/N00ff5182-0467-4f00-8d65-e26c0538899a

Abstract

The auditory brainstem compares sound-evoked excitation and inhibition from both ears to compute sound source location and determine spatial acuity. Although alterations to the anatomy and physiology of the auditory brainstem have been demonstrated in fragile X syndrome (FXS), it is not known whether these changes cause spatial acuity deficits in FXS. To test the hypothesis that FXS-related alterations to brainstem circuits impair spatial hearing abilities, a reflexive prepulse inhibition (PPI) task, with variations in sound (gap, location, masking) as the prepulse stimulus, was used on Fmr1 knock-out mice and B6 controls. Specifically, Fmr1 mice show decreased PPI compared with wild-type mice during gap detection, changes in sound source location, and spatial release from masking with no alteration to their overall startle thresholds compared with wild-type mice. Last, Fmr1 mice have increased latency to respond in these tasks, suggesting additional impairments in the pathway responsible for reacting to a startling sound. This study further supports data in humans with FXS that show similar deficits in PPI.

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<![CDATA[Distinct Populations of Neurons Activated by Heroin and Cocaine in the Striatum as Assessed by catFISH]]> https://www.researchpad.co/article/N1938ebd0-ac8f-4dfe-b6a7-72c571d799a5

Despite the still prevailing notion of a shared substrate of action for all addictive drugs, there is evidence suggesting that opioid and psychostimulant drugs differ substantially in terms of their neurobiological and behavioral effects. These differences may reflect separate neural circuits engaged by the two drugs.

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<![CDATA[Long-Term Exposure to PFE-360 in the AAV-α-Synuclein Rat Model: Findings and Implications]]> https://www.researchpad.co/article/N71f0d191-80b3-43b9-af4b-a3215e8e3675

Parkinson’s disease (PD) is a progressive neurodegenerative disorder associated with impaired motor function and several non-motor symptoms, with no available disease modifying treatment. Intracellular accumulation of pathological α-synuclein inclusions is a hallmark of idiopathic PD, whereas, dominant mutations in leucine-rich repeat kinase 2 (LRRK2) are associated with familial PD that is clinically indistinguishable from idiopathic PD.

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<![CDATA[Network Properties Revealed during Multi-Scale Calcium Imaging of Seizure Activity in Zebrafish]]> https://www.researchpad.co/article/5c9e5a33d5eed0c4842443a3

Abstract

Seizures are characterized by hypersynchronization of neuronal networks. Understanding these networks could provide a critical window for therapeutic control of recurrent seizure activity, i.e., epilepsy. However, imaging seizure networks has largely been limited to microcircuits in vitro or small “windows” in vivo. Here, we combine fast confocal imaging of genetically encoded calcium indicator (GCaMP)-expressing larval zebrafish with local field potential (LFP) recordings to study epileptiform events at whole-brain and single-neuron levels in vivo. Using an acute seizure model (pentylenetetrazole, PTZ), we reliably observed recurrent electrographic ictal-like events associated with generalized activation of all major brain regions and uncovered a well-preserved anterior-to-posterior seizure propagation pattern. We also examined brain-wide network synchronization and spatiotemporal patterns of neuronal activity in the optic tectum microcircuit. Brain-wide and single-neuronal level analysis of PTZ-exposed and 4-aminopyridine (4-AP)-exposed zebrafish revealed distinct network dynamics associated with seizure and non-seizure hyperexcitable states, respectively. Neuronal ensembles, comprised of coactive neurons, were also uncovered during interictal-like periods. Taken together, these results demonstrate that macro- and micro-network calcium motifs in zebrafish may provide a greater understanding of epilepsy.

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<![CDATA[TRPV1 Agonist, Capsaicin, Induces Axon Outgrowth after Injury via Ca2+/PKA Signaling]]> https://www.researchpad.co/article/5b5a21f9463d7e02a7dbdf6b

Abstract

Preconditioning nerve injuries activate a pro-regenerative program that enhances axon regeneration for most classes of sensory neurons. However, nociceptive sensory neurons and central nervous system neurons regenerate poorly. In hopes of identifying novel mechanisms that promote regeneration, we screened for drugs that mimicked the preconditioning response and identified a nociceptive ligand that activates a preconditioning-like response to promote axon outgrowth. We show that activating the ion channel TRPV1 with capsaicin induces axon outgrowth of cultured dorsal root ganglion (DRG) sensory neurons, and that this effect is blocked in TRPV1 knockout neurons. Regeneration occurs only in NF200-negative nociceptive neurons, consistent with a cell-autonomous mechanism. Moreover, we identify a signaling pathway in which TRPV1 activation leads to calcium influx and protein kinase A (PKA) activation to induce a preconditioning-like response. Finally, capsaicin administration to the mouse sciatic nerve activates a similar preconditioning-like response and induces enhanced axonal outgrowth, indicating that this pathway can be induced in vivo. These findings highlight the use of local ligands to induce regeneration and suggest that it may be possible to target selective neuronal populations for repair, including cell types that often fail to regenerate.

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<![CDATA[Beneficial Outcome of Urethane Treatment Following Status Epilepticus in a Rat Organophosphorus Toxicity Model]]> https://www.researchpad.co/article/5b599dfe463d7e77ce8a4a38

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<![CDATA[Hypoxia-Inducible Factor 1α (HIF-1α) Counteracts the Acute Death of Cells Transplanted into the Injured Spinal Cord]]> https://www.researchpad.co/article/N1783ea66-80b1-4dd1-a19a-202b1785ca93 <![CDATA[Ultralow concentrations of bupivacaine exert anti-inflammatory effects on inflammation-reactive astrocytes]]> https://www.researchpad.co/article/5ada5620463d7e110f9582cc

Bupivacaine is a widely used, local anesthetic agent that blocks voltage-gated Na+ channels when used for neuro-axial blockades. Much lower concentrations of bupivacaine than in normal clinical use, < 10−8 m, evoked Ca2+ transients in astrocytes from rat cerebral cortex, that were inositol trisphosphate receptor-dependent. We investigated whether bupivacaine exerts an influence on the Ca2+ signaling and interleukin-1β (IL-1β) secretion in inflammation-reactive astrocytes when used at ultralow concentrations, < 10−8 m. Furthermore, we wanted to determine if bupivacaine interacts with the opioid-, 5-hydroxytryptamine- (5-HT) and glutamate-receptor systems. With respect to the μ-opioid- and 5-HT-receptor systems, bupivacaine restored the inflammation-reactive astrocytes to their normal non-inflammatory levels. With respect to the glutamate-receptor system, bupivacaine, in combination with an ultralow concentration of the μ-opioid receptor antagonist naloxone and μ-opioid receptor agonists, restored the inflammation-reactive astrocytes to their normal non-inflammatory levels. Ultralow concentrations of bupivacaine attenuated the inflammation-induced upregulation of IL-1β secretion. The results indicate that bupivacaine interacts with the opioid-, 5-HT- and glutamate-receptor systems by affecting Ca2+ signaling and IL-1β release in inflammation-reactive astrocytes. These results suggest that bupivacaine may be used at ultralow concentrations as an anti-inflammatory drug, either alone or in combination with opioid agonists and ultralow concentrations of an opioid antagonist.

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