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Molecular and cellular neurosciences
Academic Press
Molecular and cellular neurosciences

Academic Press

1044-7431

Molecular and cellular neurosciences/Journal Molecular and cellular neurosciences
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    In vitro priming response in dorsal root ganglia partially mimics injury-driven pre-conditioning response and reprograms neurons for enhanced outgrowth

    Krishnan, AnandDwivedi, ShubhamChandrasekhar, AmbikaAreti, Aparna...
    11页
    查看更多>>摘要：Peripheral nerve injuries have the potential to bring about long-term disabilities in individuals. The major issue in repairing nerve injuries is the poor growth rate of axons. Although several molecules have been identified as potential candidates for improving axon growth, their potential translation into clinical practice is preliminary and largely unexplored. This necessitates identifying additional molecular candidates with superior potential to improve axon growth. Lack of a simple non-surgical screening model also poses a hurdle in rapidly screening potential candidate molecules. In this work, we developed a novel, rapid screening model for nerve regeneration therapeutics that retains a focus on adult neurons. The model involves simple incubation of sensory ganglia over a period of 24 h prior to dissociation. Surprisingly, this model features unique events that reprogram both sensory neurons and supporting glia favoring axon growth. Moreover, several associated cellular and molecular changes involved in this model partially mimic classic axotomy-induced changes in sensory ganglia. Overall, this model presents with a platform that not only allows rapid screening of drug candidates but offers opportunities in studying novel intrinsic molecular changes in both neurons and glial cells directed towards improving the pace of axon growth.
      原文链接:
    • NSTL
    • Elsevier

    Blockade of metabotropic glutamate receptor 5 attenuates axonal degeneration in 6-hydroxydopamine-induced model of Parkinson's disease

    Zhang, Jian-NanHuang, Yan-LinYang, Hui-MinWang, Yuan...
    11页
    查看更多>>摘要：Although there are numerous strategies to counteract the death of dopaminergic neurons in Parkinson's disease (PD), there are currently no treatments that delay or prevent the disease course, indicating that early protective treatments are needed. Targeting axonal degeneration, a key initiating event in PD, is required to develop novel therapies; however, its underlying molecular mechanisms are not fully understood. Here, we studied axonal degeneration induced by 6-hydroxydopamine (6-OHDA) in vitro and in vivo. We found that metabotropic glutamate receptor 5 (mGluR5) expression increased during 6-OHDA-induced axonal degeneration in primary neurons and that blockade of mGluR5 by its antagonists 2-methyl-6-(phenylethynyl)-pyridine (MPEP) and 3-[(2 methyl-1, 3-thiazol-4-yl) ethynyl]-pyridine (MTEP) almost completely attenuated the degenerative process in vitro. Furthermore, a rapid increase in intra-axonal calcium levels following 6-OHDA treatment was visualized using a calcium-sensitive fluorescence probe and a calcium chelator prevented the axonal degenerative process induced by 6-OHDA in vitro, whereas application of the mGluR5 antagonist MPEP partially attenuated the increase in intra-axonal calcium. The screening of calcium targets revealed that calpain activation and an increase in phosphorylated extracellular signal-regulated kinase (p-ERK) were calcium dependent during 6-OHDAinduced axonal degeneration in vitro. Consistent with these in vitro findings, blockade of mGluR5 with MPEP attenuated the degeneration of dopaminergic axons induced by 6-OHDA injection into the striatum prior to soma death in the early stage of PD in an in vivo animal model. In addition, MPEP inhibited the increase in mGluR5 expression levels, calpain activation and the elevation of p-ERK in the striatum triggered by 6-OHDA injection in vivo. Taken together, these data identify an mGluR5-calcium-dependent cascade that causes axonal degeneration, and suggest that mGluR5 antagonists could provide effective therapy to prevent the disease process of PD.
      原文链接:
    • NSTL
    • Elsevier

    Resilience to fear: The role of individual factors in amygdala response to stressors

    Fonseca, RosalinaMadeira, NataliaSimoes, Carla
    14页
    查看更多>>摘要：Resilience to stress is an adaptive process that varies individually. Resilience refers to the adaptation, or the ability to maintain or regain mental health, despite being subject to adverse situation. Resilience is a dynamic concept that reflects a combination of internal individual factors, including age and gender interacting with external factors such as social, cultural and environmental factors. In the last decade, we have witnessed an increase in the prevalence of anxiety disorders, including post-traumatic stress disorder. Given that stress in unavoidable, it is of great interest to understand the neurophysiological mechanisms of resilience, the individual factors that may contribute to susceptibility and promote efficacious approaches to improve resilience. Here, we address this complex question, attempting at defining clear and operational definitions that may allow us to improve our analysis of behavior incorporating individuality. We examine how individual perception of the stressor can alter the outcome of an adverse situation using as an example, the fear-conditioning paradigm and discuss how individual differences in the reward system can contribute to resilience. Given the central role of the endocannabinoid system in regulating fear responses and anxiety, we discuss the evidence that polymorphisms in several molecules of this signaling system contribute to different anxiety phenotypes. The endocannabinoid system is highly interconnected with the serotoninergic and dopaminergic modulatory systems, contributing to individual differences in stress perception and coping mechanisms. We review how the individual variability in these modulatory systems can be used towards a multivariable assessment of stress risk. Incorporating individuality in our research will allow us to define biomarkers of anxiety disorders as well as assess prognosis, towards a personalized clinical approach to mental health.
      原文链接:
    • NSTL
    • Elsevier

    Inhibitory signaling in mammalian olfactory transduction potentially mediated by G alpha(o)

    Corey, Elizabeth A.Ukhanov, KirillBobkov, Yuriy V.McIntyre, Jeremy C....
    11页
    查看更多>>摘要：Olfactory GPCRs (ORs) in mammalian olfactory receptor neurons (ORNs) mediate excitation through the G alpha(s) family member G alpha(olf). Here we tentatively associate a second G protein, G alpha(o), with inhibitory signaling in mammalian olfactory transduction by first showing that odor evoked phosphoinositide 3-kinase (PI3K)-dependent inhibition of signal transduction is absent in the native ORNs of mice carrying a conditional OMP-Cre based knockout of G alpha(o). We then identify an OR from native rat ORNs that are activated by octanol through cyclic nucleotide signaling and inhibited by citral in a PI3K-dependent manner. We show that the OR activates cyclic nucleotide signaling and PI3K signaling in a manner that reflects its functionality in native ORNs. Our findings lay the groundwork to explore the interesting possibility that ORs can interact with two different G proteins in a functionally identified, ligand-dependent manner to mediate opponent signaling in mature mammalian ORNs.
      原文链接:
    • NSTL
    • Elsevier

    Polyglutamine expanded Ataxin-7 induces DNA damage and alters FUS localization and function

    Niss, FridaZaidi, WajihaHallberg, EinarStrom, Anna-Lena...
    11页
    查看更多>>摘要：Polyglutamine (polyQ) diseases, such as Spinocerebellar ataxia type 7 (SCA7), are caused by expansions of polyQ repeats in disease specific proteins. The sequestration of vital proteins into aggregates formed by polyQ proteins is believed to be a common pathological mechanism in these disorders. The RNA-binding protein FUS has been observed in polyQ aggregates, though if disruption of this protein plays a role in the neuronal dysfunction in SCA7 or other polyQ diseases remains unclear. We therefore analysed FUS localisation and function in a stable inducible PC12 cell model expressing the SCA7 polyQ protein ATXN7. We found that there was a high degree of FUS sequestration, which was associated with a more cytoplasmic FUS localisation, as well as a decreased expression of FUS regulated mRNAs. In contrast, the role of FUS in the formation of gamma H2AX positive DNA damage foci was unaffected. In fact, a statistical increase in the number of gamma H2AX foci, as well as an increased trend of single and double strand DNA breaks, detected by comet assay, could be observed in mutant ATXN7 cells. These results were further corroborated by a clear trend towards increased DNA damage in SCA7 patient fibroblasts. Our findings suggest that both alterations in the RNA regulatory functions of FUS, and increased DNA damage, may contribute to the pathology of SCA7.
      原文链接:
    • NSTL
    • Elsevier

    Dissecting Alzheimer's disease pathogenesis in human 2D and 3D models

    Flitsch, Lea J.Breitkreuz, YannikTanzi, Rudolph E.Kim, Doo Yeon...
    19页
    查看更多>>摘要：The incidence of Alzheimer's disease is increasing with the aging population, and it has become one of the main health concerns of modern society. The dissection of the underlying pathogenic mechanisms and the development of effective therapies remain extremely challenging, also because available animal and cell culture models do not fully recapitulate the whole spectrum of pathological changes. The advent of human pluripotent stem cells and cell reprogramming has provided new prospects for tackling these challenges in a human and even patient specific setting. Yet, experimental modeling of non-cell autonomous and extracellular disease-related alterations has remained largely inaccessible. These limitations are about to be overcome by advances in the development of 3D cell culture systems including organoids, neurospheroids and matrix-embedded 3D cultures, which have been shown to recapitulate extracellular pathologies such as plaque formation in vitro. Recent xenograft studies have even taken human stem cell-based disease modeling to an in vivo scenario where grafted neurons are probed in a disease background in the context of a rodent brain. Here, we review the latest developments in this emerging field along with their advantages, challenges, and future prospects.
      原文链接:
    • NSTL
    • Elsevier

    Reprogramming the brain in and out of diseased states

    Karagiannis, PeterMuotri, AlyssonInoue, Haruhisa
    2页
      原文链接:
    • NSTL
    • Elsevier

    Neuroprotection with the cannabigerol quinone derivative VCE-003.2 and its analogs CBGA-Q and CBGA-Q-Salt in Parkinson's disease using 6-hydroxydopamine-lesioned mice

    Gonzalo-Consuegra, ClaudiaMunoz, EduardoMunoz, EvaFernandez-Ruiz, Javier...
    12页
    查看更多>>摘要：The quinone derivative of the non-psychotropic cannabinoid cannabigerol (CBG), so-called VCE-003.2, has been recently investigated for its neuroprotective properties in inflammatory models of Parkinson's disease (PD) in mice. Such potential derives from its activity at the peroxisome proliferator-activated receptor-gamma (PPAR-gamma). In the present study, we investigated the neuroprotective properties of VCE-003.2 against the parkinsonian neurotoxin 6-hydroxydopamine (6-OHDA), in comparison with two new CBG-related derivatives, the cannabigerolic acid quinone (CBGA-Q) and its sodium salt CBGA-Q-Salt, which, similarly to VCE-003.2, were found to be active at the PPAR-gamma receptor, but not at the cannabinoid CB1 and CB2 receptors. First, we investigated their cytoprotective properties in vitro by analyzing cell survival in cultured SH-SY5Y cells exposed to 6-OHDA. We found an important cytoprotective effect of VCE-003.2 at a concentration of 20 mu M, which was not reversed by the blockade of PPAR-gamma receptors with GW9662, supporting its activity at an alternative site (non-sensitive to classic antagonists) in this receptor. We also found CBGA-Q and CBGA-Q-Salt being cytoprotective in this cell assay, but their effects were completely eliminated by GW9662, thus indicating that they are active at the canonical site in the PPAR-gamma receptor. Then, we moved to in vivo testing using mice unilaterally lesioned with 6-OHDA. Our data confirmed that VCE-003.2 administered orally (20 mg/kg) preserved tyrosine hydroxylase (TH)-positive nigral neurons against 6-OHDA-induced damage, whereas it completely attenuated the astroglial (GFAP) and microglial (CD68) reactivity found in the substantia nigra of lesioned mice. Such neuroprotective effects caused an important recovery in the motor deficiencies displayed by 6-OHDA-lesioned mice in the pole test and the cylinder rearing test. We also investigated CBGA-Q, given orally (20 mg/kg) or intraperitoneally (10 mg/kg, i.p.), having similar benefits compared to VCE-003.2 against the loss of TH-positive nigral neurons, glial reactivity and motor defects caused by 6-OHDA. Lastly, the sodium salt of CBGA-Q, given orally (40 mg/kg) to 6-OHDA-lesioned mice, also showed benefits at behavioral and histopathological levels, but to a lower extent compared to the other two compounds. In contrast, when given i.p., CBGA-Q-Salt (10 mg/kg) was poorly active. We also analyzed the concentrations of dopamine and its metabolite DOPAC in the striatum of 6-OHDA-lesioned mice after the treatment with the different compounds, but recovery in the contents of both dopamine and DOPAC was only found after the treatment with VCE-003.2. In summary, our data confirmed the neuroprotective potential of VCE003.2 in 6-OHDA-lesioned mice, which adds to its previous activity found in an inflammatory model of PD (LPSlesioned mice). Additional phytocannabinoid derivatives, CBGA-Q and CBGA-Q-Salt, also afforded neuroprotection in 6-OHDA-lesioned mice, but their effects were lower compared to VCE-003.2, in particular in the case of CBGA-Q-Salt. In vitro studies confirmed the relevance of PPAR-gamma receptors for these effects.
      原文链接:
    • NSTL
    • Elsevier