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Nod-like receptors are critical for gut-brain axis signalling in mice.
Pusceddu MM, Barboza M, Keogh CE, Schneider M, Stokes P, Sladek JA, Kim HJD, Torres-Fuentes C, Goldfild LR, Gillis SE, Brust-Mascher I, Rabasa G, Wong KA, Lebrilla C, Byndloss MX, Maisonneuve C, Bäumler AJ, Philpott DJ, Ferrero RL, Barrett KE, Reardon C, Gareau MG
(2019) J Physiol 597: 5777-5797
MeSH Terms: Animals, Anxiety, Brain, Cells, Cultured, Cognition, Female, Hypothalamo-Hypophyseal System, Intestinal Absorption, Intestinal Mucosa, Male, Mice, Mice, Inbred C57BL, Neurogenesis, Nod1 Signaling Adaptor Protein, Nod2 Signaling Adaptor Protein, Serotonin, Stress, Psychological, Synaptic Transmission
Show Abstract · Added March 30, 2020
KEY POINTS - •Nucleotide binding oligomerization domain (Nod)-like receptors regulate cognition, anxiety and hypothalamic-pituitary-adrenal axis activation. •Nod-like receptors regulate central and peripheral serotonergic biology. •Nod-like receptors are important for maintenance of gastrointestinal physiology. •Intestinal epithelial cell expression of Nod1 receptors regulate behaviour.
ABSTRACT - Gut-brain axis signalling is critical for maintaining health and homeostasis. Stressful life events can impact gut-brain signalling, leading to altered mood, cognition and intestinal dysfunction. In the present study, we identified nucleotide binding oligomerization domain (Nod)-like receptors (NLR), Nod1 and Nod2, as novel regulators for gut-brain signalling. NLR are innate immune pattern recognition receptors expressed in the gut and brain, and are important in the regulation of gastrointestinal physiology. We found that mice deficient in both Nod1 and Nod2 (NodDKO) demonstrate signs of stress-induced anxiety, cognitive impairment and depression in the context of a hyperactive hypothalamic-pituitary-adrenal axis. These deficits were coupled with impairments in the serotonergic pathway in the brain, decreased hippocampal cell proliferation and immature neurons, as well as reduced neural activation. In addition, NodDKO mice had increased gastrointestinal permeability and altered serotonin signalling in the gut following exposure to acute stress. Administration of the selective serotonin reuptake inhibitor, fluoxetine, abrogated behavioural impairments and restored serotonin signalling. We also identified that intestinal epithelial cell-specific deletion of Nod1 (VilCre Nod1 ), but not Nod2, increased susceptibility to stress-induced anxiety-like behaviour and cognitive impairment following exposure to stress. Together, these data suggest that intestinal epithelial NLR are novel modulators of gut-brain communication and may serve as potential novel therapeutic targets for the treatment of gut-brain disorders.
© 2019 The Authors. The Journal of Physiology © 2019 The Physiological Society.
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18 MeSH Terms
Bcl2-Expressing Quiescent Type B Neural Stem Cells in the Ventricular-Subventricular Zone Are Resistant to Concurrent Temozolomide/X-Irradiation.
Cameron BD, Traver G, Roland JT, Brockman AA, Dean D, Johnson L, Boyd K, Ihrie RA, Freeman ML
(2019) Stem Cells 37: 1629-1639
MeSH Terms: Animals, Antineoplastic Agents, Alkylating, Apoptosis, Chemoradiotherapy, DNA Breaks, Double-Stranded, DNA Repair, Disease Models, Animal, Drug Resistance, Female, Glioblastoma, Lateral Ventricles, Male, Mice, Mice, Inbred C57BL, Neural Stem Cells, Neurogenesis, Proto-Oncogene Proteins c-bcl-2, Temozolomide, X-Ray Therapy
Show Abstract · Added March 3, 2020
The ventricular-subventricular zone (V-SVZ) of the mammalian brain is a site of adult neurogenesis. Within the V-SVZ reside type B neural stem cells (NSCs) and type A neuroblasts. The V-SVZ is also a primary site for very aggressive glioblastoma (GBM). Standard-of-care therapy for GBM consists of safe maximum resection, concurrent temozolomide (TMZ), and X-irradiation (XRT), followed by adjuvant TMZ therapy. The question of how this therapy impacts neurogenesis is not well understood and is of fundamental importance as normal tissue tolerance is a limiting factor. Here, we studied the effects of concurrent TMZ/XRT followed by adjuvant TMZ on type B stem cells and type A neuroblasts of the V-SVZ in C57BL/6 mice. We found that chemoradiation induced an apoptotic response in type A neuroblasts, as marked by cleavage of caspase 3, but not in NSCs, and that A cells within the V-SVZ were repopulated given sufficient recovery time. 53BP1 foci formation and resolution was used to assess the repair of DNA double-strand breaks. Remarkably, the repair was the same in type B and type A cells. While Bax expression was the same for type A or B cells, antiapoptotic Bcl2 and Mcl1 expression was significantly greater in NSCs. Thus, the resistance of type B NSCs to TMZ/XRT appears to be due, in part, to high basal expression of antiapoptotic proteins compared with type A cells. This preclinical research, demonstrating that murine NSCs residing in the V-SVZ are tolerant of standard chemoradiation therapy, supports a dose escalation strategy for treatment of GBM. Stem Cells 2019;37:1629-1639.
© 2019 The Authors. Stem Cells published by Wiley Periodicals, Inc. on behalf of AlphaMed Press 2019.
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19 MeSH Terms
Quantification of DTI in the Pediatric Spinal Cord: Application to Clinical Evaluation in a Healthy Patient Population.
Reynolds BB, By S, Weinberg QR, Witt AA, Newton AT, Feiler HR, Ramkorun B, Clayton DB, Couture P, Martus JE, Adams M, Wellons JC, Smith SA, Bhatia A
(2019) AJNR Am J Neuroradiol 40: 1236-1241
MeSH Terms: Adolescent, Algorithms, Anisotropy, Child, Child, Preschool, Diffusion Tensor Imaging, Female, Humans, Image Processing, Computer-Assisted, Infant, Male, Neurogenesis, Neuroimaging, Retrospective Studies, Spinal Cord
Show Abstract · Added March 30, 2020
BACKGROUND AND PURPOSE - The purpose of the study is to characterize diffusion tensor imaging indices in the developing spinal cord, evaluating differences based on age and cord region. Describing the progression of DTI indices in the pediatric cord increases our understanding of spinal cord development.
MATERIALS AND METHODS - A retrospective analysis was performed on DTI acquired in 121 pediatric patients (mean, 8.6 years; range, 0.3-18.0 years) at Monroe Carell Jr. Children's Hospital at Vanderbilt from 2017 to 2018. Diffusion-weighted images (15 directions; = 750 s/mm; slice thickness, 5 mm; in-plane resolution, 1.0 × 1.0 mm) were acquired on a 3T scanner in the cervicothoracic and/or thoracolumbar cord. Manual whole-cord segmentation was performed. Images were masked and further segmented into cervical, upper thoracic, thoracolumbar, and conus regions. Analyses of covariance were performed for each DTI-derived index to investigate how age affects diffusion across cord regions, and 95% confidence intervals were calculated across age for each derived index and region. Post hoc testing was performed to analyze regional differences.
RESULTS - Analyses of covariance revealed significant correlations of age with axial diffusivity, mean diffusivity, and fractional anisotropy (all, < .001). There were also significant differences among cord regions for axial diffusivity, radial diffusivity, mean diffusivity, and fractional anisotropy (all, < .001).
CONCLUSIONS - This research demonstrates that diffusion evolves in the pediatric spinal cord during development, dependent on both cord region and the diffusion index of interest. Future research could investigate how diffusion may be affected by common pediatric spinal pathologies.
© 2019 by American Journal of Neuroradiology.
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15 MeSH Terms
Axonal organization defects in the hippocampus of adult conditional BACE1 knockout mice.
Ou-Yang MH, Kurz JE, Nomura T, Popovic J, Rajapaksha TW, Dong H, Contractor A, Chetkovich DM, Tourtellotte WG, Vassar R
(2018) Sci Transl Med 10:
MeSH Terms: Aging, Amyloid Precursor Protein Secretases, Animals, Animals, Newborn, Apoptosis, Aspartic Acid Endopeptidases, Axons, Cognition, Epilepsy, Gene Deletion, Hippocampus, Long-Term Potentiation, Memory Disorders, Mice, Inbred C57BL, Mice, Knockout, Myelin Sheath, Neurogenesis, Phenotype, Substrate Specificity
Show Abstract · Added April 2, 2019
β-Site APP (amyloid precursor protein) cleaving enzyme 1 (BACE1) is the β-secretase enzyme that initiates production of the toxic amyloid-β peptide that accumulates in the brains of patients with Alzheimer's disease (AD). Hence, BACE1 is a prime therapeutic target, and several BACE1 inhibitor drugs are currently being tested in clinical trials for AD. However, the safety of BACE1 inhibition is unclear. Germline BACE1 knockout mice have multiple neurological phenotypes, although these could arise from BACE1 deficiency during development. To address this question, we report that tamoxifen-inducible conditional BACE1 knockout mice in which the gene was ablated in the adult largely lacked the phenotypes observed in germline BACE1 knockout mice. However, one BACE1-null phenotype was induced after gene deletion in the adult mouse brain. This phenotype showed reduced length and disorganization of the hippocampal mossy fiber infrapyramidal bundle, the axonal pathway of dentate gyrus granule cells that is maintained by neurogenesis in the mouse brain. This defect in axonal organization correlated with reduced BACE1-mediated cleavage of the neural cell adhesion protein close homolog of L1 (CHL1), which has previously been associated with axon guidance. Although our results indicate that BACE1 inhibition in the adult mouse brain may avoid phenotypes associated with BACE1 deficiency during embryonic and postnatal development, they also suggest that BACE1 inhibitor drugs developed for treating AD may disrupt the organization of an axonal pathway in the hippocampus, an important structure for learning and memory.
Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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19 MeSH Terms
Neurotrophin Responsiveness of Sympathetic Neurons Is Regulated by Rapid Mobilization of the p75 Receptor to the Cell Surface through TrkA Activation of Arf6.
Hickman FE, Stanley EM, Carter BD
(2018) J Neurosci 38: 5606-5619
MeSH Terms: ADP-Ribosylation Factors, Animals, Neurogenesis, Neurons, Neurotrophin 3, Rats, Rats, Sprague-Dawley, Receptor, trkA, Receptors, Nerve Growth Factor, Sympathetic Nervous System
Show Abstract · Added April 4, 2019
The p75 neurotrophin receptor (p75NTR) plays an integral role in patterning the sympathetic nervous system during development. Initially, p75NTR is expressed at low levels as sympathetic axons project toward their targets, which enables neurotrophin-3 (NT3) to activate TrkA receptors and promote growth. Upon reaching nerve growth factor (NGF) producing tissues, p75NTR is upregulated, resulting in formation of TrkA-p75 complexes, which are high-affinity binding sites selective for NGF, thereby blunting NT3 signaling. The level of p75NTR expressed on the neuron surface is instrumental in regulating trophic factor response; however, the mechanisms by which p75NTR expression is regulated are poorly understood. Here, we demonstrate a rapid, translation independent increase in surface expression of p75NTR in response to NGF in rat sympathetic neurons. p75NTR was mobilized to the neuron surface from GGA3-postitive vesicles through activation of the GTPase Arf6, which was stimulated by NGF, but not NT3 binding to TrkA. Arf6 activation required PI3 kinase activity and was prevented by an inhibitor of the cytohesin family of Arf6 guanine nucleotide exchange factors. Overexpression of a constitutively active Arf6 mutant (Q67L) was sufficient to significantly increase surface expression of p75NTR even in the absence of NGF. Functionally, expression of active Arf6 markedly attenuated the ability of NT3 to promote neuronal survival and neurite outgrowth, whereas the NGF response was unaltered. These data suggest that NGF activation of Arf6 through TrkA is critical for the increase in p75NTR surface expression that enables the switch in neurotrophin responsiveness during development in the sympathetic nervous system. p75NTR is instrumental in the regulation of neuronal survival and apoptosis during development and is also implicated as a contributor to aberrant neurodegeneration in numerous conditions. Therefore, a better understanding of the mechanisms that mediate p75NTR surface availability may provide insight into how and why neurodegenerative processes manifest and reveal new therapeutic targets. Results from this study indicate a novel mechanism by which p75NTR can be rapidly shuttled to the cell surface from existing intracellular pools and explores a unique pathway by which NGF regulates the sympathetic innervation of target tissues, which has profound consequences for the function of these organs.
Copyright © 2018 the authors 0270-6474/18/385606-14$15.00/0.
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10 MeSH Terms
A Dendritic Guidance Receptor Complex Brings Together Distinct Actin Regulators to Drive Efficient F-Actin Assembly and Branching.
Zou W, Dong X, Broederdorf TR, Shen A, Kramer DA, Shi R, Liang X, Miller DM, Xiang YK, Yasuda R, Chen B, Shen K
(2018) Dev Cell 45: 362-375.e3
MeSH Terms: Actin Cytoskeleton, Animals, Caenorhabditis elegans, Caenorhabditis elegans Proteins, Cell Membrane, Dendrites, Membrane Proteins, Morphogenesis, Neurogenesis, Sensory Receptor Cells, Signal Transduction
Show Abstract · Added March 26, 2019
Proper morphogenesis of dendrites plays a fundamental role in the establishment of neural circuits. The molecular mechanism by which dendrites grow highly complex branches is not well understood. Here, using the Caenorhabditis elegans PVD neuron, we demonstrate that high-order dendritic branching requires actin polymerization driven by coordinated interactions between two membrane proteins, DMA-1 and HPO-30, with their cytoplasmic interactors, the RacGEF TIAM-1 and the actin nucleation promotion factor WAVE regulatory complex (WRC). The dendrite branching receptor DMA-1 directly binds to the PDZ domain of TIAM-1, while the claudin-like protein HPO-30 directly interacts with the WRC. On dendrites, DMA-1 and HPO-30 form a receptor-associated signaling complex to bring TIAM-1 and the WRC to close proximity, leading to elevated assembly of F-actin needed to drive high-order dendrite branching. The synergistic activation of F-actin assembly by scaffolding distinct actin regulators might represent a general mechanism in promoting complex dendrite arborization.
Copyright © 2018. Published by Elsevier Inc.
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Stimulation of entorhinal cortex-dentate gyrus circuitry is antidepressive.
Yun S, Reynolds RP, Petrof I, White A, Rivera PD, Segev A, Gibson AD, Suarez M, DeSalle MJ, Ito N, Mukherjee S, Richardson DR, Kang CE, Ahrens-Nicklas RC, Soler I, Chetkovich DM, Kourrich S, Coulter DA, Eisch AJ
(2018) Nat Med 24: 658-666
MeSH Terms: Animals, Antidepressive Agents, Behavior, Animal, Chronic Disease, Dendrites, Dentate Gyrus, Entorhinal Cortex, Glutamates, HEK293 Cells, Humans, Membrane Proteins, Mice, Inbred C57BL, Mice, Knockout, Nerve Net, Neurogenesis, Peroxins, Stress, Psychological
Show Abstract · Added April 2, 2019
Major depressive disorder (MDD) is considered a 'circuitopathy', and brain stimulation therapies hold promise for ameliorating MDD symptoms, including hippocampal dysfunction. It is unknown whether stimulation of upstream hippocampal circuitry, such as the entorhinal cortex (Ent), is antidepressive, although Ent stimulation improves learning and memory in mice and humans. Here we show that molecular targeting (Ent-specific knockdown of a psychosocial stress-induced protein) and chemogenetic stimulation of Ent neurons induce antidepressive-like effects in mice. Mechanistically, we show that Ent-stimulation-induced antidepressive-like behavior relies on the generation of new hippocampal neurons. Thus, controlled stimulation of Ent hippocampal afferents is antidepressive via increased hippocampal neurogenesis. These findings emphasize the power and potential of Ent glutamatergic afferent stimulation-previously well-known for its ability to influence learning and memory-for MDD treatment.
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17 MeSH Terms
Neuronal Fat and Dendrite Morphogenesis: The Goldilocks Effect.
Sundararajan L, Miller DM
(2018) Trends Neurosci 41: 250-252
MeSH Terms: Animals, Dendrites, Drosophila, Drosophila Proteins, Larva, Morphogenesis, Neurogenesis
Show Abstract · Added March 26, 2019
Two recent studies by Meltzer et al. and Ziegler et al. use Drosophila larvae to demonstrate that cell-autonomous regulation of lipid biosynthesis defines the complexity and function of highly branched nociceptive neurons. Their findings show that lipid biosynthesis in the neuron is fine-tuned for optimal dendrite morphology and sensitivity.
Copyright © 2018 Elsevier Ltd. All rights reserved.
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Potential Adult Neurogenesis in the Telencephalon and Cerebellar Cortex of the Nile Crocodile Revealed with Doublecortin Immunohistochemistry.
Ngwenya A, Patzke N, Herculano-Houzel S, Manger PR
(2018) Anat Rec (Hoboken) 301: 659-672
MeSH Terms: Alligators and Crocodiles, Animals, Cerebellar Cortex, Immunohistochemistry, Microtubule-Associated Proteins, Neurogenesis, Neurons, Neuropeptides, Telencephalon
Show Abstract · Added March 30, 2020
The brain of the crocodile is known to gain in mass allometrically throughout life, and the addition of neurons (as well as non-neurons) appears to play a significant role in this increasing brain mass. We used immunohistochemistry in the brains of 12 Nile crocodiles ranging between 350 g and 86 kg in body mass and 1.99 g to 7.9 g in brain mass to identify the regions of the brain in which neurons immunopositive for doublecortin (DCX), a marker for potential adult neurogenesis, are found. Similar to other reptiles, potential newly born neurons, those immunopositive for DCX, were found throughout the telencephalon, the main and accessory olfactory bulbs and the olfactory tract, and in the cerebellar cortex; however, no DCX immunopositive neurons were observed in the diencephalon or brainstem. An apparent moderate decrease in the density of DCX labeled neurons in the olfactory bulbs and tract as well as the cerebellar cortex was observed with increasing brain mass, but the observed qualitative density of labeled neurons within the telencephalon was maintained irrespective of brain mass. Three potential neurogenic zones, within the sulci of the lateral ventricle, were identified, and these are similar to those seen in other reptiles. This study indicates that at least part of the gain in brain mass with age in the Nile crocodile may be accounted for by the potential addition and integration of new neurons into the existing circuitry, especially so for the olfactory system, telencephalon and cerebellar cortex. Anat Rec, 301:659-672, 2018. © 2017 Wiley Periodicals, Inc.
© 2017 Wiley Periodicals, Inc.
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Space Invaders: Brain Tumor Exploitation of the Stem Cell Niche.
Sinnaeve J, Mobley BC, Ihrie RA
(2018) Am J Pathol 188: 29-38
MeSH Terms: Animals, Brain Neoplasms, Humans, Neural Stem Cells, Neurogenesis, Stem Cell Niche
Show Abstract · Added April 10, 2019
Increasing evidence indicates that the adult neurogenic niche of the ventricular-subventricular zone (V-SVZ), beyond serving as a potential site of origin, affects the outcome of malignant brain cancers. Glioma contact with this niche predicts worse prognosis, suggesting a supportive role for the V-SVZ environment in tumor initiation or progression. In this review, we describe unique components of the V-SVZ that may permit or promote tumor growth within the region. Cell-cell interactions, soluble factors, and extracellular matrix composition are discussed, and the role of the niche in future therapies is explored. The purpose of this review is to highlight niche intrinsic factors that may promote or support malignant cell growth and maintenance, and point out how we might leverage these features to improve patient outcome.
Copyright © 2018 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
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