Exercise changes astrocytes and eases symptoms of neurodegenerative disorders

Astrocytes (GFAP) in the dentate gyrus of a mouse hippocampus. Image courtesy of Dr. Ahmad Salehi, Stanford University. 

It is well known that physical exercise eases the symptoms of neurodegenerative disorders like Alzheimer’s disease and helps to prevent their onset. Researchers at Stanford University are working on figuring out how it happens.

In their study, published in the journal Brain Structure and Function, scientists in Dr. Ahmad Salehi’s lab examined the effects of physical exercise on astrocytes in a region of the mouse brain that is critical for cognition – the dentate gyrus of the hippocampus. Previous studies have shown that an increase in the expression of brain-derived neurotrophic factor (Bdnf) occurs in this region after exercise (Philips, Salehi et al 2014). Bdnf is a protein that supports the survival of existing neurons and encourages new growth, playing an important role in cognitive function.

While the current study reconfirms that exercise generates increased levels of Bdnf (more than a fourfold increase in exercised mice versus non-exercised mice), it also describes several new findings including increased synaptic load in the dentate gyrus, alterations in the morphology of astrocytes, and changes in the orientation of astrocytic projections toward dentate granule cells.

The authors speculate that the changes they observed may be attributed to increased expression of a receptor called TrkB, which astrocytes express in response to increases in Bdnf levels. According to the paper, TrkB binds to Bdnf, activating the mechanisms behind neuronal development.

“Our study suggests that astrocytes actively respond and could indeed mediate the positive effects of physical exercise on the central nervous system and potentially counter degenerative processes during aging and neurodegenerative disorders,” (Fahimi, et al 2016).

The researchers used Neurolucida to determine the location, the extent, and orientation of astrocytic projections, finding a significant increase in the length of astrocytic projections in exercised mice.

“Neurolucida is one of the very few systems that combines complex morphometrical quantification with beautiful display of the results,” said Dr. Salehi, Clinical Professor, Department of Psychiatry and Behavioral Sciences at Stanford Medical School.

Since astrocytes help prevent excitotoxicity in the brain by removing excess glutamate from extracellular space, the researchers speculate that the increased length of astrocytic projections they observed in exercised mice could make this process more efficient.

Differences in the orientation of astrocytic projections were also reported, with the majority of projections of exercised mice directed toward the dentate granule cell layer – a region featuring increased levels of Bdnf release and synthesis after exercise.

The number of astrocytes in the molecular layer of the dentate gyrus in exercised and non-exercised mice was quantified with Stereo Investigator, however, there was no significant difference in astrocyte populations between the two groups.

“In summary, our study suggests that astrocytes constitute an important element in mediating the positive effects of physical exercise in the dentate gyrus of the hippocampus. Furthermore, it appears that physical exercise-induced release of Bdnf by the DG leads to a significant alteration in structure and function of astrocytes in protection against glutamate toxicity during aging and a number of neurodegenerative disorders,” (Fahimi et al 2016)

Fahimi, A., Baktir, M.A., Moghadam, S., Mojabi, F.S., Sumanth, K., McNerney, M.W., Ponnusamy, R., Salehi, A. Brain Struct Funct (2016). doi:10.1007/s00429-016-1308-8

Phillips, C., Baktir, M.A., Srivatsam, M., Salehi, A. Front. Cell. Neurosci., (2014) https://doi.org/10.3389/fncel.2014.00170

Researchers cited MBF systems in 14 papers between 1/20/2017 and 1/27/2017

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Doerr, J., Schwarz, M. K., Wiedermann, D., Leinhaas, A., Jakobs, A., Schloen, F., . . . Brüstle, O. (2017). Whole-brain 3D mapping of human neural transplant innervation. Nature Communications, 8, 14162. doi: 10.1038/ncomms14162

Fields, J. A., Metcalf, J., Overk, C., Adame, A., Spencer, B., Wrasidlo, W., . . . Masliah, E. (2017). The anticancer drug sunitinib promotes autophagyand protects from neurotoxicity in an HIV-1 Tat model of neurodegeneration. Journal of Neurovirology, 1-14. doi: 10.1007/s13365-016-0502-z.

Haidar, M., Guèvremont, G., Zhang, C., Bathgate, R. A. D., Timofeeva, E., Smith, C. M., & Gundlach, A. L. (2017). Relaxin-3 Inputs Target Hippocampal Interneurons and Deletion of Hilar Relaxin-3 Receptors in ‘Floxed-RXFP3′ Mice Impairs Spatial Memory. Hippocampus, n/a-n/a. doi: 10.1002/hipo.22709.

Kelly, S. C., He, B., Perez, S. E., Ginsberg, S. D., Mufson, E. J., & Counts, S. E. (2017). Locus coeruleus cellular and molecular pathology during the progression of Alzheimer’s disease. Acta Neuropathologica Communications, 5(1), 8. doi: 10.1186/s40478-017-0411-2.

Shen, X.-L., Song, N., Du, X.-X., Li, Y., Xie, J.-X., & Jiang, H. (2017). Nesfatin-1 protects dopaminergic neurons against MPP+/MPTP-induced neurotoxicity through the C-Raf–ERK1/2-dependent anti-apoptotic pathway. Scientific Reports, 7, 40961. doi: 10.1038/srep40961

Turner, R. C., Naser, Z. J., Lucke-Wold, B. P., Logsdon, A. F., Vangilder, R. L., Matsumoto, R. R., . . . Rosen, C. L. (2017). Single low-dose lipopolysaccharide preconditioning: neuroprotective against axonal injury and modulates glial cells. [Lipopolysaccharide preconditioning, oncostatin M receptor, diffuse axonal injury, gliosis, neuroprotection]. Neuroimmunology and Neuroinflammation, 4(1), 6-15.

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Researchers cited MBF systems in 25 papers between 1/13/2017 and 1/20/2017

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Allegra, M., Spalletti, C., Vignoli, B., Azzimondi, S., Busti, I., Billuart, P., . . . Caleo, M. (2017). Pharmacological rescue of adult hippocampal neurogenesis in a mouse model of X-linked intellectual disability. Neurobiology of Disease, 100, 75-86.

Anan, J., Hijioka, M., Kurauchi, Y., Hisatsune, A., Seki, T., & Katsuki, H. (2017). Cortical hemorrhage-associated neurological deficits and tissue damage in mice are ameliorated by therapeutic treatment with nicotine. Journal of Neuroscience Research, n/a-n/a. doi: 10.1002/jnr.24016.

Ardestani, P. M., Evans, A. K., Yi, B., Nguyen, T., Coutellier, L., & Shamloo, M. (2017). Modulation of neuroinflammation and pathology in the 5XFAD mouse model of Alzheimer’s disease using a biased and selective beta-1 adrenergic receptor partial agonist. Neuropharmacology.

Estrada, L. I., Robinson, A. A., Amaral, A. C., Giannaris, E. L., Heyworth, N. C., Mortazavi, F., . . . Rosene, D. L. (2017). Evaluation of Long-Term Cryostorage of Brain Tissue Sections for Quantitative Histochemistry. Journal of Histochemistry and Cytochemistry, 0022155416686934. doi: 10.1369/0022155416686934.

Klocke, C., Allen, J. L., Sobolewski, M., Mayer-Pröschel, M., Blum, J. L., Lauterstein, D., . . . Cory-Slechta, D. A. (2017). Neuropathological Consequences of Gestational Exposure to Concentrated Ambient Fine and Ultrafine Particles in the Mouse. Toxicological Sciences. doi: 10.1093/toxsci/kfx010.

Loris, Z. B., Pieper, A. A., & Dalton Dietrich, W. (2017). The neuroprotective compound P7C3-A20 promotes neurogenesis and improves cognitive function after ischemic stroke. Experimental Neurology, 290, 63-73. doi: http://dx.doi.org/10.1016/j.expneurol.2017.01.006.

Luo, L., Chen, J., Su, D., Chen, M., Luo, B., Pi, R., . . . Wang, R. (2017). L-F001, a Multifunction ROCK Inhibitor Prevents 6-OHDA Induced Cell Death Through Activating Akt/GSK-3beta and Nrf2/HO-1 Signaling Pathway in PC12 Cells and Attenuates MPTP-Induced Dopamine Neuron Toxicity in Mice. Neurochemical Research, 1-10. doi: 10.1007/s11064-016-2117-4.

Moore, B. A., Tyrrell, L. P., Pita, D., Bininda-Emonds, O. R. P., & Fernández-Juricic, E. (2017). Does retinal configuration make the head and eyes of foveate birds move? . Scientific Reports, 7, 38406. doi: 10.1038/srep38406

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Uncovering the role of microglia in fetal alcohol spectrum disorders


Representative images of Iba-1+ microglia in the postnatal day 10 rat hippocampus. Image courtesy of Anna Klintsova, PhD.

Children born with fetal alcohol spectrum disorders face a range of physical and cognitive impairments including long-term deficits in learning, behavior, and immune function. In a paper published in Neuroscience, Dr. Anna Klintsova and her lab at the University of Delaware report that activation of the brain’s immune response may contribute to some of the damage caused by fetal alcohol spectrum disorders.

In their study, the researchers used Stereo Investigator and Neurolucida to examine the hypothesis that exposure to alcohol while the brain is growing rapidly is associated with abnormal microglial activation and high levels of pro-inflammatory proteins which impair learning-related plasticity; leading to neuro-developmental and psychopathological disorders.

“My lab has been using both Stereo Investigator and Neurolucida for more than a decade in all quantitative neuroanatomical studies, including the featured one,” said Dr. Anna Klintsova. “We find this software to be user-friendly, reliable and essential for obtaining unbiased results.”

They used Stereo Investigator to quantify the number of microglia in the hippocampus of neonatal rats who were exposed to alcohol during the equivalent of the third trimester of a human pregnancy. The researchers expected to see an increased number of microglia in alcohol-exposed neonatal rats, however they found a decreased number of microglia. Despite the decrease in microglia number, there was a significant increase in pro-inflammatory proteins expressed by microglia and an increase in microglial activation.

To measure microglial activation, the researchers quantified the area of cell territory using Neurolucida. Activated microglia have a smaller cell territory than resting microglia, so the smaller cell territory found in alcohol exposed rats indicates a more active state.

This research supports the hypothesis that abnormal microglia activation plays a role in fetal alcohol spectrum disorders, however more research is needed to further understand the relationship.

Boschen, K., Ruggiero, M.J., Klintsova, A.Y., (2016) Neonatal binge alcohol exposure increases microglial activation in the developing rat hippocampus. Neuroscience 324: 355–366. DOI: 10.1016/j.neuroscience.2016.03.033


Researchers cited MBF systems in 21 papers between 12/16/2016 and 1/6/2017

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Campolo, M., Casili, G., Biundo, F., Crupi, R., Cordaro, M., Cuzzocrea, S., & esposito, e. (2016). The neuroprotective effect of dimethyl fumarate in a MPTP-mouse model of Parkinson’s disease: involvement of reactive oxygen species/nuclear factor-κB/nuclear transcription factor related to NF-E2. Antioxidants & redox signaling. doi: 10.1089/ars.2016.6800.

Charvet, C. J., Stimpson, C. D., Kim, Y. D., Raghanti, M. A., Lewandowski, A. H., Hof, P. R., . . . Sherwood, C. C. (2016). Gradients in cytoarchitectural landscapes of the isocortex: diprotodont marsupials in comparison to eutherian mammals. Journal of Comparative Neurology, n/a-n/a. doi: 10.1002/cne.24160.

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Güleç, A., Bakkalbaşı, B. Ç., Cumbul, A., Uslu, Ü., Alev, B., & Yarat, A. (2017). Effects of local platelet-rich plasma injection on the rate of orthodontic tooth movement in a rat model: A histomorphometric study. American Journal of Orthodontics and Dentofacial Orthopedics, 151(1), 92-104. doi: http://dx.doi.org/10.1016/j.ajodo.2016.05.016.

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Researchers cited MBF systems in 18 papers during the week of 12/12/2016

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Alberico, S. L., Kim, Y.-C., Lence, T., & Narayanan, N. S. (2016). Axial levodopa-induced dyskinesias and neuronal activity in the dorsal striatum. Neuroscience. doi: http://dx.doi.org/10.1016/j.neuroscience.2016.11.046.

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Ghosh, A., Tyson, T., George, S., Hildebrandt, E. N., Steiner, J. A., Madaj, Z., . . . Brundin, P. (2016). Mitochondrial pyruvate carrier regulates autophagy, inflammation, and neurodegeneration in experimental models of Parkinson’s disease. [10.1126/scitranslmed.aag2210]. Science translational medicine, 8(368), 368ra174.

Jacinto, L. R., Mata, R., Novais, A., Marques, F., & Sousa, N. (2016). The habenula as a critical node in chronic stress-related anxiety. Experimental Neurology. doi: http://dx.doi.org/10.1016/j.expneurol.2016.12.003.

Jobe, E. M., Gao, Y., Eisinger, B. E., Mladucky, J. K., Giuliani, C. C., Kelnhofer, L. E., & Zhao, X. (2016). Methyl-CpG binding protein MBD1 regulates neuronal lineage commitment through maintaining adult neural stem cell identity. [10.1523/JNEUROSCI.1075-16.2016]. The Journal of Neuroscience.

Mandolesi, G., De Vito, F., Musella, A., Gentile, A., Bullitta, S., Fresegna, D., . . . Mori, F. (2016). miR-142-3p is a key regulator of IL-1β-dependent synaptopathy in neuroinflammation. Journal of Neuroscience, 0851-0816.

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Researchers cited MBF systems in 18 papers during the week of 12/05/2016

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Alia, C., Spalletti, C., Lai, S., Panarese, A., Micera, S., & Caleo, M. (2016). Reducing GABAA-mediated inhibition improves forelimb motor function after focal cortical stroke in mice. Scientific Reports, 6, 37823. doi: 10.1038/srep37823

Chareyron, L. J., Amaral, D. G., & Lavenex, P. (2016). Selective lesion of the hippocampus increases the differentiation of immature neurons in the monkey amygdala. Proceedings of the National Academy of Sciences. doi: 10.1073/pnas.1604288113.

Dijkstra, A. A., Lin, L.-C., Nana, A. L., Gaus, S. E., & Seeley, W. W. (2016). Von Economo Neurons and Fork Cells: A Neurochemical Signature Linked to Monoaminergic Function. Cerebral Cortex. doi: 10.1093/cercor/bhw358.

Koprich, J. B., Johnston, T. H., Reyes, G., Omana, V., & Brotchie, J. M. (2016). Towards a Non-Human Primate Model of Alpha-Synucleinopathy for Development of Therapeutics for Parkinson’s Disease: Optimization of AAV1/2 Delivery Parameters to Drive Sustained Expression of Alpha Synuclein and Dopaminergic Degeneration in Macaque. Plos one, 11(11), e0167235. doi: 10.1371/journal.pone.0167235.

Mudannayake, J. M., Mouravlev, A., Fong, D. M., & Young, D. (2016). Transcriptional activity of novel ALDH1L1 promoters in the rat brain following AAV vector-mediated gene transfer.  Molecular Therapy — Methods & Clinical Development, 3, 16075. doi: 10.1038/mtm.2016.75

Murata, Y., Narisawa, Y., Shimono, R., Ohmori, H., Mori, M., Ohe, K., . . . Enjoji, M. (2017). A high fat diet-induced decrease in hippocampal newly-born neurons of male mice is exacerbated by mild psychological stress using a Communication Box. Journal of Affective Disorders, 209, 209-216. doi: http://dx.doi.org/10.1016/j.jad.2016.11.046.

Richter, F., Gabby, L., McDowell, K. A., Mulligan, C. K., De La Rosa, K., Sioshansi, P. C., . . . Chesselet, M.-F. (2016). Effects of decreased dopamine transporter levels on nigrostriatal neurons and paraquat/maneb toxicity in mice. Neurobiology of Aging. doi: http://dx.doi.org/10.1016/j.neurobiolaging.2016.11.015.

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Researchers cited MBF systems in 16 papers between 11/1/2016 and 11/11/2016

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Bode, C., Richter, F., Spröte, C., Brigadski, T., Bauer, A., Fietz, S., . . . Richter, A. (2017). Altered postnatal maturation of striatal GABAergic interneurons in a phenotypic animal model of dystonia. Experimental Neurology, 287, Part 1, 44-53. doi: http://dx.doi.org/10.1016/j.expneurol.2016.10.013.

Calvez, J., de Ávila, C., Guèvremont, G., & Timofeeva, E. (2016). Sex-specific effects of chronic administration of relaxin-3 on food intake, body weight and hypothalamo-pituitary-gonadal axis in rats. Journal of Neuroendocrinology, n/a-n/a. doi: 10.1111/jne.12439.

Haight, J. L., Fuller, Z. L., Fraser, K. M., & Flagel, S. B. (2016). A food-predictive cue attributed with incentive salience engages subcortical afferents and efferents of the paraventricular nucleus of the thalamus. Neuroscience. doi: http://dx.doi.org/10.1016/j.neuroscience.2016.10.043.

He, H., Guo, W.-W., Xu, R.-R., Chen, X.-Q., Zhang, N., Wu, X., & Wang, X.-M. (2016). Alkaloids from piper longum protect dopaminergic neurons against inflammation-mediated damage induced by intranigral injection of lipopolysaccharide. BMC Complementary and Alternative Medicine, 16(1), 412. doi: 10.1186/s12906-016-1392-6.

Jin, T., Nicholls, F. J., Crum, W. R., Ghuman, H., Badylak, S. F., & Modo, M. (2017). Diamagnetic chemical exchange saturation transfer (diaCEST) affords magnetic resonance imaging of extracellular matrix hydrogel implantation in a rat model of stroke. Biomaterials, 113, 176-190. doi: http://dx.doi.org/10.1016/j.biomaterials.2016.10.043.

Kyyriäinen, J., Ekolle Ndode-Ekane, X., & Pitkänen, A. (2016). Dynamics of PDGFRβ expression in different cell types after brain injury. Glia, n/a-n/a. doi: 10.1002/glia.23094.

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Researchers cited MBF systems in 15 papers during the week of 10/24/2016

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Casaca-Carreira, J., Temel, Y., Larrakoetxea, I., & Jahanshahi, A. (2016). Distribution and Penetration of Intracerebroventricularly Administered 2′OMePS Oligonucleotide in the Mouse Brain. Nucleic Acid Therapeutics. doi: 10.1089/nat.2016.0642.

Guatteo, E., Rizzo, F. R., Federici, M., Cordella, A., Ledonne, A., Latini, L., . . . Mercuri, N. B. (2017). Functional alterations of the dopaminergic and glutamatergic systems in spontaneous α-synuclein overexpressing rats. Experimental Neurology, 287, Part 1, 21-33.

Gupta, R., Saini, S., Sharma, S., Jacob, T. G., & Roy, T. S. (2017). Morphology of the Human Pancreas During Development and Aging. In P. C. Rath, R. Sharma & S. Prasad (Eds.), Topics in Biomedical Gerontology (pp. 67-89). Singapore: Springer Singapore.

Hook, M., Woller, S., Bancroft, E., Aceves, M., Funk, M. K., Hartman, J., & Garraway, S. M. (2016). Neurobiological effects of Morphine following Spinal Cord Injury. Journal of Neurotrauma. doi: 10.1089/neu.2016.4507. http://dx.doi.org/10.1089/neu.2016.4507

Schaeffer, E. L., Catanozi, S., West, M. J., & Gattaz, W. F. (2016). Stereological investigation of the CA1 pyramidal cell layer in untreated and lithium-treated 3xTg-AD and wild-type mice. Annals of Anatomy – Anatomischer Anzeiger. doi: http://dx.doi.org/10.1016/j.aanat.2016.10.002.

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Researchers cited MBF systems in 14 papers during the week of 10/17/2016

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Bacigaluppi, M., Russo, G. L., Peruzzotti-Jametti, L., Rossi, S., Sandrone, S., Butti, E., . . . Martino, G. (2016). Neural Stem Cell Transplantation Induces Stroke Recovery by Upregulating Glutamate Transporter GLT-1 in Astrocytes.  The Journal of Neuroscience, 36(41), 10529.

Beck, M. H., Haumesser, J. K., Kühn, J., Altschüler, J., Kühn, A. A., & van Riesen, C. (2016). Short- and long-term dopamine depletion causes enhanced beta oscillations in the cortico-basal ganglia loop of parkinsonian rats. Experimental Neurology, 286, 124-136. doi: http://dx.doi.org/10.1016/j.expneurol.2016.10.005.

Huang, C.-W., Chen, Y.-W., Lin, Y.-R., Chen, P.-H., Chou, M.-H., Lee, L.-J., . . . Chen, S.-L. (2016). Conditional Knockout of Breast Carcinoma Amplified Sequence 2 (BCAS2) in Mouse Forebrain Causes Dendritic Malformation via β-catenin.  Scientific Reports, 6, 34927. doi: 10.1038/srep34927

Sack, M., Lenz, J. N., Jakovcevski, M., Biedermann, S. V., Falfán-Melgoza, C., Deussing, J., . . . Auer, M. K. (2016). Early effects of a high-caloric diet and physical exercise on brain volumetry and behavior: a combined MRI and histology study in mice. Brain Imaging and Behavior, 1-12. doi: 10.1007/s11682-016-9638-y.

Schelle, J., Häsler, L., Göpfert, J. C., Joos, T. O., Vanderstichele, H., Stoops, E., . . . Kaeser, S. A. (2016). Prevention of tau increase in cerebrospinal fluid of APP transgenic mice suggests downstream effect of BACE1 inhibition. Alzheimer’s & Dementia. doi: http://dx.doi.org/10.1016/j.jalz.2016.09.005.

Teo, J. D., Morris, M. J., & Jones, N. M. (2016). Maternal obesity increases inflammation and exacerbates damage following neonatal hypoxic-ischaemic brain injury in rats. Brain, Behavior, and Immunity. doi:http://dx.doi.org/10.1016/j.bbi.2016.10.010.

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