ResearchPad - cellular-neuroscience https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[Inferring a simple mechanism for alpha-blocking by fitting a neural population model to EEG spectra]]> https://www.researchpad.co/article/elastic_article_13836 One of the most striking features of the human electroencephalogram (EEG) is the presence of neural oscillations in the range of 8-13 Hz. It is well known that attenuation of these alpha oscillations, a process known as alpha blocking, arises from opening of the eyes, though the cause has remained obscure. In this study we infer the mechanism underlying alpha blocking by fitting a neural population model to EEG spectra from 82 different individuals. Although such models have long held the promise of being able to relate macroscopic recordings of brain activity to microscopic neural parameters, their utility has been limited by the difficulty of inferring these parameters from fits to data. Our approach involves fitting eyes-open and eyes-closed EEG spectra in a way that minimizes unnecessary differences in model parameters between the two states. Surprisingly, we find that changes in just one parameter, the level of external input to the inhibitory neurons in cortex, is sufficient to explain the attenuation of alpha oscillations. This indicates that opening of the eyes reduces alpha activity simply by increasing external inputs to the inhibitory neurons in the cortex.

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<![CDATA[Early correction of synaptic long-term depression improves abnormal anxiety-like behavior in adult GluN2B-C456Y-mutant mice]]> https://www.researchpad.co/article/elastic_article_13831 Mice that carry a heterozygous, autism spectrum disorder-risk C456Y mutation in the NMDA receptor (NMDAR) subunit GluN2B show decreased protein levels, hippocampal NMDAR currents, and NMDAR-dependent long-term depression and have abnormal anxiolytic-like behavior. Early, but not late, treatment of the young mice with the NMDAR agonist D-cycloserine rescues these phenotypes.

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<![CDATA[Low-rate firing limit for neurons with axon, soma and dendrites driven by spatially distributed stochastic synapses]]> https://www.researchpad.co/article/elastic_article_13830 Neurons are extended cells with multiple branching dendrites, a cell body and an axon. In an active neuronal network, neurons receive vast numbers of incoming synaptic pulses throughout their dendrites and cell body that each exhibit significant variability in amplitude and arrival time. The resulting synaptic input causes voltage fluctuations throughout their structure that evolve in space and time. The dynamics of how these signals are integrated and how they ultimately trigger outgoing spikes have been modelled extensively since the late 1960s. However, until relatively recently the majority of the mathematical formulae describing how fluctuating synaptic drive triggers action potentials have been applicable only for small neurons with the dendritic and axonal structure ignored. This has been largely due to the mathematical complexity of including the effects of spatially distributed synaptic input. Here we show that in a physiologically relevant, low-firing-rate regime, an approximate level-crossing approach can be used to provide an estimate for the neuronal firing rate even when the dendrites and axons are included. We illustrate this approach using basic neuronal morphologies that capture the fundamentals of neuronal structure. Though the models are simple, these preliminary results show that it is possible to obtain useful formulae that capture the effects of spatially distributed synaptic drive. The generality of these results suggests they will provide a mathematical framework for future studies that might require the structure of neurons to be taken into account, such as the effect of electrical fields or multiple synaptic input streams that target distinct spatial domains of cortical pyramidal cells.

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<![CDATA[Regeneration Through <i>in vivo</i> Cell Fate Reprogramming for Neural Repair]]> https://www.researchpad.co/article/elastic_article_13097 The adult mammalian central nervous system (CNS) has very limited regenerative capacity upon neural injuries or under degenerative conditions. In recent years, however, significant progress has been made on in vivo cell fate reprogramming for neural regeneration. Resident glial cells can be reprogrammed into neuronal progenitors and mature neurons in the CNS of adult mammals. In this review article, we briefly summarize the current knowledge on innate adult neurogenesis under pathological conditions and then focus on induced neurogenesis through cell fate reprogramming. We discuss how the reprogramming process can be regulated and raise critical issues requiring careful considerations to move the field forward. With emerging evidence, we envision that fate reprogramming-based regenerative medicine will have a great potential for treating neurological conditions such as brain injury, spinal cord injury (SCI), Alzheimer’s disease (AD), Parkinson’s disease (PD), and retinopathy.

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<![CDATA[Going the Extra (Synaptic) Mile: Excitotoxicity as the Road Toward Neurodegenerative Diseases]]> https://www.researchpad.co/article/elastic_article_12948 Excitotoxicity is a phenomenon that describes the toxic actions of excitatory neurotransmitters, primarily glutamate, where the exacerbated or prolonged activation of glutamate receptors starts a cascade of neurotoxicity that ultimately leads to the loss of neuronal function and cell death. In this process, the shift between normal physiological function and excitotoxicity is largely controlled by astrocytes since they can control the levels of glutamate on the synaptic cleft. This control is achieved through glutamate clearance from the synaptic cleft and its underlying recycling through the glutamate-glutamine cycle. The molecular mechanism that triggers excitotoxicity involves alterations in glutamate and calcium metabolism, dysfunction of glutamate transporters, and malfunction of glutamate receptors, particularly N-methyl-D-aspartic acid receptors (NMDAR). On the other hand, excitotoxicity can be regarded as a consequence of other cellular phenomena, such as mitochondrial dysfunction, physical neuronal damage, and oxidative stress. Regardless, it is known that the excessive activation of NMDAR results in the sustained influx of calcium into neurons and leads to several deleterious consequences, including mitochondrial dysfunction, reactive oxygen species (ROS) overproduction, impairment of calcium buffering, the release of pro-apoptotic factors, among others, that inevitably contribute to neuronal loss. A large body of evidence implicates NMDAR-mediated excitotoxicity as a central mechanism in the pathogenesis of many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD), and epilepsy. In this review article, we explore different causes and consequences of excitotoxicity, discuss the involvement of NMDAR-mediated excitotoxicity and its downstream effects on several neurodegenerative disorders, and identify possible strategies to study new aspects of these diseases that may lead to the discovery of new therapeutic approaches. With the understanding that excitotoxicity is a common denominator in neurodegenerative diseases and other disorders, a new perspective on therapy can be considered, where the targets are not specific symptoms, but the underlying cellular phenomena of the disease.

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<![CDATA[Thalamic, cortical, and amygdala involvement in the processing of a natural sound cue of danger]]> https://www.researchpad.co/article/elastic_article_7872 When others stop and silence ensues, animals respond as if threatened. This study highlights the brain areas involved in listening to the dangerous silence.

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<![CDATA[The qualitative assessment of optical coherence tomography and the central retinal sensitivity in patients with retinitis pigmentosa]]> https://www.researchpad.co/article/elastic_article_7697 To analyze the relationships between qualitative and quantitative parameters of spectral-domain optical coherence tomography (SD-OCT) and the central retinal sensitivity in patients with retinitis pigmentosa (RP).Materials and methodsNinety-three eyes of 93 patients were finally enrolled, with a median age (quartile) of 58 (24.5) years. We assessed the patients using SD-OCT and the 10–2 program of a Humphry Field Analyzer (HFA). As a qualitative parameter, two graders independently classified the patients’ SD-OCT images into five severity grades (grades 1–5) based on the severity of damage to the photoreceptor inner and outer segments (IS/OS) layer. As quantitative parameters, we measured the IS-ellipsoid zone (IS-EZ) width, IS/OS thickness, outer nuclear layer (ONL) thickness, central macular thickness (CMT, 1 and 3 mm) and macular cube (6 × 6 mm) volume and thickness. The central retinal sensitivity was defined by the best-corrected visual acuity (BCVA; logMAR), average sensitivities of the central 4 (foveal sensitivity [FS]) and 12 (macular sensitivity [MS]) points of the HFA 10–2 program and the mean deviation (MD) of the 10–2 program. Spearman’s correlation was used to assess the association between both qualitative and quantitative parameters and variables of the central retinal sensitivity. In addition, we performed a multiple regression analysis using these parameters to identify the parameters most strongly influencing the central retinal sensitivity.ResultsThe IS/OS severity grade was significantly correlated with the BCVA (ρ = 0.741, P < 0.001), FS (ρ = −0.844, P < 0.001), MS (ρ = −0.820, P < 0.001) and MD (ρ = −0.681, P < 0.001) and showed stronger correlations to them than any other quantitative parameters including the IS-EZ width, IS/OS thickness, ONL thickness, CMTs and macular cube volume/thickness. Furthermore, a step-wise multiple regression analysis indicated that the IS/OS severity grade was more strongly associated with the BCVA (β = 0.659, P < 0.001), FS (β = −0.820, P < 0.001), MS (β = −0.820, P < 0.001) and MD (β = −0.674, P < 0.001) than any other quantitative parameters. The intraclass correlation coefficient between two graders indicated substantial correlation (κ = 0.70).DiscussionThe qualitative grading of OCT based on the severity of the IS/OS layer was simple and strongly correlated with the central retinal sensitivity in patients with RP. It may be useful to assess the central visual function in patients with RP, although there is some variation in severity within the same severity grade. ]]> <![CDATA[An electrodiffusive, ion conserving Pinsky-Rinzel model with homeostatic mechanisms]]> https://www.researchpad.co/article/elastic_article_7780 Neurons generate their electrical signals by letting ions pass through their membranes. Despite this fact, most models of neurons apply the simplifying assumption that ion concentrations remain effectively constant during neural activity. This assumption is often quite good, as neurons contain a set of homeostatic mechanisms that make sure that ion concentrations vary quite little under normal circumstances. However, under some conditions, these mechanisms can fail, and ion concentrations can vary quite dramatically. Standard models are thus not able to simulate such conditions. Here, we present what to our knowledge is the first multicompartmental neuron model that accounts for ion concentration variations in a way that ensures complete and consistent ion concentration and charge conservation. In this work, we use the model to explore under which activity conditions the ion concentration variations become important for predicting the neurodynamics. We expect the model to be of great value for the field of neuroscience, as it can be used to simulate a range of pathological conditions, such as spreading depression or epilepsy, which are associated with large changes in extracellular ion concentrations.

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<![CDATA[Glucagon-Like Peptide-1 Secreting L-Cells Coupled to Sensory Nerves Translate Microbial Signals to the Host Rat Nervous System]]> https://www.researchpad.co/article/elastic_article_7601 An intact gut epithelium preserves the immunological exclusion of “non-self” entities in the external environment of the gut lumen. Nonetheless, information flows continuously across this interface, with the host immune, endocrine, and neural systems all involved in monitoring the luminal environment of the gut. Both pathogenic and commensal gastrointestinal (GI) bacteria can modulate centrally-regulated behaviors and brain neurochemistry and, although the vagus nerve has been implicated in the microbiota-gut-brain signaling axis, the cellular and molecular machinery that facilitates this communication is unclear. Studies were carried out in healthy Sprague–Dawley rats to understand cross-barrier communication in the absence of disease. A novel colonic-nerve electrophysiological technique was used to examine gut-to-brain vagal signaling by bacterial products. Calcium imaging and immunofluorescent labeling were used to explore the activation of colonic submucosal neurons by bacterial products. The findings demonstrate that the neuromodulatory molecule, glucagon-like peptide-1 (GLP-1), secreted by colonic enteroendocrine L-cells in response to the bacterial metabolite, indole, stimulated colonic vagal afferent activity. At a local level indole modified the sensitivity of submucosal neurons to GLP-1. These findings elucidate a cellular mechanism by which sensory L-cells act as cross-barrier signal transducers between microbial products in the gut lumen and the host peripheral nervous system.

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<![CDATA[Editorial: Cellular and Molecular Mechanisms of Neurotrophin Function in the Nervous System]]> https://www.researchpad.co/article/elastic_article_7545 <![CDATA[Photoreceptor Disc Enclosure Occurs in the Absence of Normal Peripherin-2/rds Oligomerization]]> https://www.researchpad.co/article/elastic_article_7507 Mutations in the peripherin-2 gene (PRPH2, also known as rds) cause a heterogeneous range of autosomal dominant retinal diseases. PRPH2 encodes a photoreceptor-specific tetraspanin protein, PRPH2, that is a main structural component of the photoreceptor outer segment. PRPH2 distributes to the rims of outer segment disc membranes as they undergo the process of disc membrane enclosure. Within these rims, PRPH2 exists in homo-oligomeric form or as a hetero-oligomer with another tetraspanin protein, ROM1. While complete loss of PRPH2 prevents photoreceptor outer segment formation, mutations affecting the state of its oligomerization, including C150S, C213Y and Y141C, produce outer segment structural defects. In this study, we addressed whether any of these mutations also affect disc enclosure. We employed recently developed methodology for ultrastructural analysis of the retina, involving tissue processing with tannic acid, to assess the status of disc enclosure in knockin mouse models bearing either one or two alleles of the C150S, C213Y and Y141C PRPH2 mutations. While varying degrees of outer segment structural abnormalities were observed in each of these mouse models, they contained both newly forming “open” discs and mature “enclosed” discs. These data demonstrate that normal PRPH2 oligomerization is not essential for photoreceptor disc enclosure.

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<![CDATA[Critical Components for Spontaneous Activity and Rhythm Generation in Spinal Cord Circuits in Culture]]> https://www.researchpad.co/article/elastic_article_7501 Neuronal excitability contributes to rhythm generation in central pattern generating networks (CPGs). In spinal cord CPGs, such intrinsic excitability partly relies on persistent sodium currents (INaP), whereas respiratory CPGs additionally depend on calcium-activated cation currents (ICAN). Here, we investigated the contributions of INaP and ICAN to spontaneous rhythm generation in neuronal networks of the spinal cord and whether they mainly involve Hb9 neurons. We used cultures of ventral and transverse slices from the E13–14 embryonic rodent lumbar spinal cord on multielectrode arrays (MEAs). All cultures showed spontaneous bursts of network activity. Blocking synaptic excitation with the AMPA receptor antagonist CNQX suppressed spontaneous network bursts and left asynchronous intrinsic activity at about 30% of the electrodes. Such intrinsic activity was completely blocked at all electrodes by both the INaP blocker riluzole as well as by the ICAN blocker flufenamic acid (FFA) and the more specific TRPM4 channel antagonist 9-phenanthrol. All three antagonists also suppressed spontaneous bursting completely and strongly reduced stimulus-evoked bursts. Also, FFA reduced repetitive spiking that was induced in single neurons by injection of depolarizing current pulses to few spikes. Other antagonists of unspecific cation currents or calcium currents had no suppressing effects on either intrinsic activity (gadolinium chloride) or spontaneous bursting (the TRPC channel antagonists clemizole and ML204 and the T channel antagonist TTA-P2). Combined patch-clamp and MEA recordings showed that Hb9 interneurons were activated by network bursts but could not initiate them. Together these findings suggest that both INaP through Na+-channels and ICAN through putative TRPM4 channels contribute to spontaneous intrinsic and repetitive spiking in spinal cord neurons and thereby to the generation of network bursts.

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<![CDATA[DUSP6 SUMOylation protects cells from oxidative damage via direct regulation of Drp1 dephosphorylation]]> https://www.researchpad.co/article/N3056015d-60a1-4521-9064-22cbc64fdc24

Our work uncovers a novel SUMOylation-dependent regulation of DUSP6 stability and its activity, which regulates Drp1 function.

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<![CDATA[Emerging Role of the Autophagy/Lysosomal Degradative Pathway in Neurodevelopmental Disorders With Epilepsy]]> https://www.researchpad.co/article/N63ca363a-e934-423f-84f9-4ef4f938563f

Autophagy is a highly conserved degradative process that conveys dysfunctional proteins, lipids, and organelles to lysosomes for degradation. The post-mitotic nature, complex and highly polarized morphology, and high degree of specialization of neurons make an efficient autophagy essential for their homeostasis and survival. Dysfunctional autophagy occurs in aging and neurodegenerative diseases, and autophagy at synaptic sites seems to play a crucial role in neurodegeneration. Moreover, a role of autophagy is emerging for neural development, synaptogenesis, and the establishment of a correct connectivity. Thus, it is not surprising that defective autophagy has been demonstrated in a spectrum of neurodevelopmental disorders, often associated with early-onset epilepsy. Here, we discuss the multiple roles of autophagy in neurons and the recent experimental evidence linking neurodevelopmental disorders with epilepsy to genes coding for autophagic/lysosomal system-related proteins and envisage possible pathophysiological mechanisms ranging from synaptic dysfunction to neuronal death.

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<![CDATA[Isolation and Characterization of Neural Progenitor Cells From Bone Marrow in Cell Replacement Therapy of Brain Injury]]> https://www.researchpad.co/article/N55e58ad3-bb28-45e4-ab36-1048547c672d

Many studies supported that bone marrow mesenchymal stem cells (BM-MSCs) can differentiate into neural cells, but few researchers detected mature and function of nerve cells, especially in vivo study. Some researchers even suggested that BM-MSCs transplantation would not be able to differentiate into functional neural cells. To figure out the dispute, this study examined bone marrow-derived sphere-like cells, harvested via neural stem cell suspension culture, then identified as bone marrow-derived neural progenitor cells (BM-NPCs) by finding the expression of neural progenitor cells genes and proteins, neural progenitor cells characteristic and nerve cell differentiation induced through both methods. Moreover, BM-NPCs transplantation showed long-term survival and improved the ethological and histological indexes of brain injury rats, demonstrating functional nervous cells differentiated from BM-NPCs. These in vitro and in vivo results confirmed BM-NPCs differentiating into mature and functional nerve cells. This study provided valuable experimental data for BM-NPCs, suggesting a potential alternative treatment of central nervous injury disease.

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<![CDATA[Delayed Nerve Stimulation Promotes Axon-Protective Neurofilament Phosphorylation, Accelerates Immune Cell Clearance and Enhances Remyelination In Vivo in Focally Demyelinated Nerves]]> https://www.researchpad.co/article/5989db03ab0ee8fa60bc757e

Rapid and efficient axon remyelination aids in restoring strong electrochemical communication with end organs and in preventing axonal degeneration often observed in demyelinating neuropathies. The signals from axons that can trigger more effective remyelination in vivo are still being elucidated. Here we report the remarkable effect of delayed brief electrical nerve stimulation (ES; 1 hour @ 20 Hz 5 days post-demyelination) on ensuing reparative events in a focally demyelinated adult rat peripheral nerve. ES impacted many parameters underlying successful remyelination. It effected increased neurofilament expression and phosphorylation, both implicated in axon protection. ES increased expression of myelin basic protein (MBP) and promoted node of Ranvier re-organization, both of which coincided with the early reappearance of remyelinated axons, effects not observed at the same time points in non-stimulated demyelinated nerves. The improved ES-associated remyelination was accompanied by enhanced clearance of ED-1 positive macrophages and attenuation of glial fibrillary acidic protein expression in accompanying Schwann cells, suggesting a more rapid clearance of myelin debris and return of Schwann cells to a nonreactive myelinating state. These benefits of ES correlated with increased levels of brain derived neurotrophic factor (BDNF) in the acute demyelination zone, a key molecule in the initiation of the myelination program. In conclusion, the tremendous impact of delayed brief nerve stimulation on enhancement of the innate capacity of a focally demyelinated nerve to successfully remyelinate identifies manipulation of this axis as a novel therapeutic target for demyelinating pathologies.

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<![CDATA[Training on an Appetitive Trace-Conditioning Task Increases Adult Hippocampal Neurogenesis and the Expression of Arc, Erk and CREB Proteins in the Dorsal Hippocampus]]> https://www.researchpad.co/article/N4a608e5b-cb0b-430f-8966-3a876849f2e0

Adult hippocampal neurogenesis (AHN) plays an essential role in hippocampal-dependent memory consolidation. Increased neurogenesis enhances learning, whereas its ablation causes memory impairment. In contrast, few reports suggest that neurogenesis reduces after learning. Although the interest in exploring the role of adult neurogenesis in learning has been growing, the evidence is still limited. The role of the trace- and delay-appetitive-conditioning on AHN and its underlying mechanism are not known. The consolidation of trace-conditioned memory requires the hippocampus, but delay-conditioning does not. Moreover, the dorsal hippocampus (DH) and ventral hippocampus (VH) may have a differential role in these two conditioning paradigms. Here, we have investigated the changes in: (A) hippocampal cell proliferation and their progression towards neuronal lineage; and (B) expression of Arc, Erk1, Erk2, and CREB proteins in the DH and VH after trace- and delay-conditioning in the rat. The number of newly generated cells significantly increased in the trace-conditioned but did not change in the delay-conditioned animals compared to the control group. Similarly, the expression of Arc protein significantly increased in the DH but not in the VH after trace-conditioning. Nonetheless, it remains unaltered in the delay-conditioned group. The expression of pErk1, pErk2, and pCREB also increased in the DH after trace-conditioning. Whereas, the expression of only pErk1 pErk2 and pCREB proteins increased in the VH after delay-conditioning. Our results suggest that appetitive trace-conditioning enhances AHN. The increased DH neuronal activation and pErk1, pErk2, and pCREB in the DH may be playing an essential role in learning-induced cell-proliferation after appetitive trace-conditioning.

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<![CDATA[Disruption of genes associated with Charcot-Marie-Tooth type 2 lead to common behavioural, cellular and molecular defects in Caenorhabditis elegans]]> https://www.researchpad.co/article/N5d50b5cf-e057-490e-9c44-60569e9f28d4

Charcot-Marie-Tooth (CMT) disease is an inherited peripheral motor and sensory neuropathy. The disease is divided into demyelinating (CMT1) and axonal (CMT2) neuropathies, and although we have gained molecular information into the details of CMT1 pathology, much less is known about CMT2. Due to its clinical and genetic heterogeneity, coupled with a lack of animal models, common underlying mechanisms remain elusive. In order to gain an understanding of the normal function of genes associated with CMT2, and to draw direct comparisons between them, we have studied the behavioural, cellular and molecular consequences of mutating nine different genes in the nematode Caenorhabditis elegans (lin-41/TRIM2, dyn-1/DNM2, unc-116/KIF5A, fzo-1/MFN2, osm-9/TRPV4, cua-1/ATP7A, hsp-25/HSPB1, hint-1/HINT1, nep-2/MME). We show that C. elegans defective for these genes display debilitated movement in crawling and swimming assays. Severe morphological defects in cholinergic motors neurons are also evident in two of the mutants (dyn-1 and unc-116). Furthermore, we establish methods for quantifying muscle morphology and use these to demonstrate that loss of muscle structure occurs in the majority of mutants studied. Finally, using electrophysiological recordings of neuromuscular junction (NMJ) activity, we uncover reductions in spontaneous postsynaptic current frequency in lin-41, dyn-1, unc-116 and fzo-1 mutants. By comparing the consequences of mutating numerous CMT2-related genes, this study reveals common deficits in muscle structure and function, as well as NMJ signalling when these genes are disrupted.

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<![CDATA[Neuroprotective effects of exogenous erythropoietin in Wistar rats by downregulating apoptotic factors to attenuate N-methyl-D-aspartate-mediated retinal ganglion cells death]]> https://www.researchpad.co/article/N85685bba-c047-422b-abfc-358a98ed1fe7

The aim of this study was to investigate whether exogenous erythropoietin (EPO) administration attenuates N-methyl-D-aspartate (NMDA)-mediated excitotoxic retinal damage in Wistar rats. The survival rate of retinal ganglion cells (RGCs) were investigated by flat mount analysis and flow cytometry. A total of 125 male Wistar rats were randomly assigned to five groups: negative control, NMDA80 (i.e., 80 nmoles NMDA intravitreally injected), NMDA80 + 10ng EPO, NMDA80 + 50ng EPO, and NMDA80 + 250ng EPO. The NMDA80 + 50ng EPO treatment group was used to evaluate various administrated points (pre-/co-/post- administration of NMDA80). Meanwhile, the transferase dUTP Nick-End Labeling (TUNEL) assay of RGCs, the inner plexiform layer (IPL) thickness and the apoptotic signal transduction pathways of μ-calpain, Bax, and caspase 9 were assessed simultaneously using an immunohistochemical method (IHC). When EPO was co-administered with NMDA80, attenuated cell death occurred through the downregulation of the apoptotic indicators: μ-calpain was activated first (peak at ~18hrs), followed by Bax and caspase 9 (peak at ~40hrs). Furthermore, the images of retinal cross sections have clearly demonstrated that thickness of the inner plexiform layer (IPL) was significantly recovered at 40 hours after receiving intravitreal injection with NMDA80 and 50ng EPO. Exogenous EPO may protect RGCs and bipolar cell axon terminals in IPL by downregulating apoptotic factors to attenuate NMDA-mediated excitotoxic retinal damage.

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<![CDATA[Clinical impact of melatonin on breast cancer patients undergoing chemotherapy; effects on cognition, sleep and depressive symptoms: A randomized, double-blind, placebo-controlled trial]]> https://www.researchpad.co/article/Nf52b3d22-02a5-4e7e-bb1d-9e73ca6c7e6b

This randomized, double-blinded, placebo-controlled trial tested the hypothesis that 20mg of melatonin before and during the first cycle of adjuvant chemotherapy for breast cancer (ACBC) reduced the side effects associated with cognitive impairment. We evaluated the effects of melatonin on cognition, depressive symptoms and sleep quality, and whether these effects were related to serum levels of Brain Derived Neurotrophic Factor (BDNF) and its receptor, tropomyosin kinase B (TrkB). Thirty-six women were randomly assigned to receive melatonin or placebo for 10 days. To evaluate cognitive performance, we used the Trail-Making-Test Parts A and B (A-B), Rey Auditory-Verbal Learning Test (RAVLT), Controlled Oral Word Association Test (COWAT) and an inhibitory task type Go / No-Go. Our results revealed that melatonin improved executive function on TMT scores, enhanced episodic memory (immediate and delayed) and recognition on RAVLT, and increased verbal fluency in the orthographic COWAT. The TMT-A-B(A-B) were negatively correlated with baseline levels of TrkB and BDNF, respectively. At the end of treatment, changes in TrkB and BDNF were inversely associated with depressive symptoms and sleep quality, but not with the TMT scores. These results suggest a neuroprotective effect of melatonin to counteract the adverse effects of ACBC on cognitive function, sleep quality and depressive symptoms.

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