Limbic system Neurobiology of aging and gene therapy

Team of work

Principal InvestigatorMorel

Morel, Gustavo Ramón

Gómez Martínez, Carlos D.Gómez Martínez


Diana Camila PasquiniPasquini

Research Fellow

Collaborators from other institutions

Ogundele, Olalekan Michael
Department of Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, Louisiana, USA.

Outeiro, Tiago
Department of Neurodegeneration and Restorative Research, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, University Medical Center Göttingen, Göttingen, Alemania.

Abba, Martín Carlos
Centro de Investigaciones Inmunológicas Básicas y Aplicadas (CINIBA), Facultad de Ciencias Médicas, (UNLP).

Cambiaggi, Vanina
Facultad de Ciencias Veterinarias. U.N.L.P. La Plata. Prov. de Buenos Aires. Argentina.

Hereñú, Claudia B.
IFEC- Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba.

Lacunza, Ezequiel
Centro de Investigaciones Inmunológicas Básicas y Aplicadas (CINIBA), Facultad de Ciencias Médicas, (UNLP).

Portinasky, E. L.
Facultad de Ciencias Veterinarias. U.N.L.P. La Plata. Prov. de Buenos Aires. Argentina.

Zuccolilli, Gustavo
Facultad de Ciencias Veterinarias. U.N.L.P. La Plata. Prov. de Buenos Aires. Argentina.

Line overview

In humans and in various mammalian species, the aging process generally leads to alterations in plasticity and synaptic transmission in different regions of the brain, and is correlated with behavior, learning and memory imapaiment. The knowledge that aging is the main risk factor for neurodegenerative diseases drives us to want to elucidate the mechanisms that separate the thin line between a brain with normal aging and one like the pathognomonic of Alzheimer's disease or Lewy body dementia.
Our research group has a long history of studying the aging female rat of the Sprague-Dawley strain as a model of spontaneous neural disfunction.
One of the objectives of this line is to characterize the limbic system brain structures such as the hippocampus, amygdala, hypothalamus and related brain structures in the aged (28 months old) and the middle-aged rat (12 months old). of age), which present an age-related cognitive deficit. The characterization is carried out from the cognitive, histopathological and molecular levels.
Cognitive function is assessed using the Barnes Maze which determines spatial reference memory retention and working memory. We also use other methods that determine object recognition memory in different paradigms that evaluate the object location or characteristic (SOR and NOR, respectively).
To analyze the impact of aging on brain structures, immunolabeling techniques (immunohistochemistry and immunofluorescence), are approach white bright, fluorescence and confocal microscopy coupled with morphometric methods based on stereology by software such as Image Pro Plus and Image J.
At the molecular level, gene expression is evaluated in the different brain structures by PCR or RNAseq and protein expression by Western blot.
Another objective is to imitate or reinforce the protective mechanisms that are diminished, silenced or depleted in the aging brain. As a therapeutic strategy we use gene therapy and as a biotechnological tool we construct adenoviral and lentiviral vectors that carry genes such as IGF-I, GDNF, TYROBP and the Yamanaka genes (Sox2, c-Myc, Klf4 and Oct4).

Age-related loss of recognition memory and its correlation with hippocampal and perirhinal cortex changes in female Sprague Dawley rats.
Canatelli-Mallat M, Chiavellini P, Lehmann M, Goya RG, Morel GR.
2022. Behav Brain Res. Oct 28; 435:114026.Epub 2022 Aug 5. PMID: 35940248
doi: 10.1016/j.bbr.2022.114026

Hippocampal DNA Methylation, Epigenetic Age, and Spatial Memory Performance in Young and Old Rats.
Chiavellini P, Lehmann M, Canatelli Mallat M, Zoller JA, Herenu CB, Morel GR, Horvath S, Goya RG.
2022. J Gerontol A Biol Sci Med Sci. Dec 29;77(12):2387-2394. PMID: 35917578
doi: 10.1093/gerona/glac153

Systemic oxidative stress in old rats is associated with both osteoporosis and cognitive impairment.
Torres ML, Wanionok NE, McCarthy AD, Morel GR, Fernández JM.
2021. Exp Gerontol. Dec;156:111596. Epub 2021 Oct 19. PMID: 34678425
doi: 10.1016/j.exger.2021.111596

Therapeutic potential of glial cell line-derived neurotrophic factor and cell reprogramming for hippocampal-related neurological disorders.
Chiavellini, Priscila; Canatelli-Mallat, Martina; Lehmann, Marianne; Goya, Rodolfo; Morel, Gustavo R.
2021. Neural regeneration research. Shangai: SHENYANG EDITORIAL DEPT NEURAL REGENERATION RES, vol. 17, n° 3, p. 469-476. ISSN 1673-5374

Cryopreservation of a Human Brain and Its Experimental Correlate in Rats.
Canatelli-Mallat, Martina; Lascaray, Francisco; Entraigues-Abramson, Maria; Portiansky, Enrique L.; Blamaceda, Néstor; Morel, Gustavo R.; Goya, Rodolfo G.
2020. Rejuvenation research: MARY ANN LIEBERT INC, vol. 23, n° 6, p. 516-525. ISSN 1549-1684

Mesenchymal Stem Cells Therapy Improved the Streptozotocin-Induced Behavioral and Hippocampal Impairment in Rats.
Zappa Villar, María F.; López Hanotte, Juliette; Pardo, Joaquín; Morel, Gustavo R.; Mazzolini, Guillermo; García, Mariana G; Reggiani, Paula C.
2020. Molecular neurobiology. HUMANA PRESS INC, vol. 57, p. 600-615

Mesenchymal stem cell therapy improves spatial memory and hippocampal structure in aging rats.
Zappa Villar, Maria F.; Lehmann, Marianne; García, Mariana G.; Mazzolini, Guillermo; Morel, Gustavo R.; Cónsole, Gloria M.; Podhajcer, Osvaldo; Reggiani, Paula C.; Goya, Rodolfo G.
2019: Behavioural brain research. Amsterdam: ELSEVIER SCIENCE BV, p. 1-5

Umbilical Cord Cell Therapy Improves Spatial Memory in Aging Rats.
Lehmann, Marianne; Zappa-Villar, Maria F.; García, Mariana G.; Mazzolini, Guillermo; Canatelli Mallat, Martina; Morel, Gustavo R.; Reggiani, Paula C.; Goya, Rodolfo G.
2019: Stem cell reviews and reports. SPRINGER HEIDELBERG, vol. 15, n° 4, p. 612-617

Regulatable adenovector harboring the GFP and Yamanaka genes for implementing regenerative medicine in the brain.
Lehmann, Marianne; Canatelli-Mallat, Martina; Chiavellini, Priscila; Morel, Gustavo R.; Reggiani, Paula C.; Hereñú, Claudia B.; Goya, Rodolfo G.
2019: Gene therapy. NATURE PUBLISHING GROUP, vol. 1, n° 1, p. 1-1

IGF-I Gene Therapy in Aging Rats Modulates Hippocampal Genes Relevant to Memory Function.
Pardo, J; Abba, M. C; Lacunza, E; Ogundele, O. M; Paiva, I; Morel, G. R; Outeiro, T. F; Goya, R. G.
2018. Journals of gerontology series a-biological sciences and medical sciences. GERONTOLOGICAL SOC AMER, vol. 14, n° 4, p. 459-467. ISSN 1079-5006

Intracerebroventricular streptozotocin induces impaired Barnes maze spatial memory and reduces astrocyte branching in the CA1 and CA3 hippocampal regions.
Zappa Villar, M. F; López Hanotte, J; Falomir Lockhart, E; Trípodi, L. S; Morel, G. R; Reggiani, P. C.
2018. Journal of neural transmission. General section. SPRINGER WIEN, vol. 125, n° 12, p. 1787-1803. ISSN 0300-9564

Pro-apoptotic effects of low doses of dimethoate in rat brain.
Arnal, N; Morel, G; Marra, C. A; Astiz, M.
2018. Toxicology and applied pharmacology. ACADEMIC PRESS INC ELSEVIER SCIENCE, vol. 363, p. 57-63. ISSN 0041-008X

Identification of a conserved gene signature associated with an exacerbated inflammatory environment in the hippocampus of aging rats.
Pardo, J; Abba, M. C; Lacunza, E; Francelle, L; Morel, G. R; Outeiro, T. F; Goya, R. G.
2017. Hippocampus. Apr;27(4):435-449. Doi: 10.1002/hipo.22703 Epub 2017 Jan 23. PubMed PMID: 28085212

Therapeutic potential of IGF-I on hippocampal neurogenesis and function during aging.
Morel, G. R; Lopez-León, M; Uriarte Donati, M; Reggiani, P. C; Goya, R. G.
2016. Neurogenesis, Austin (Texas): London: Taylor & Francis Group, LLC, vol. 4, n° 1, ISSN 2326-2133

Insulin-like growth factor-I gene therapy increases hippocampal neurogenesis, astrocyte branching and improves spatial memory in female aging rats.
Pardo, J; Uriarte, M; Cónsole, G. M; Reggiani, P; Outeiro, T. F; Morel, G. R; Goya, R. G.
2016. Eur J Neurosci. Aug;44(4):2120-8. Epub 2016 Jun 8. PubMed PMID: 27188415
Doi: 10.1111/ejn.13278

Cognitive impairment and morphological changes in the dorsal hippocampus of very old female rats.
Morel, G; Andersen, T; Pardo, J; Zucolilli, G. O; Cambiaggi, V. L; Hereñú, C; Goya, R. G.
2015. Neuroscience. Amsterdam: PERGAMON-ELSEVIER SCIENCE LTD, p. 189-199. ISSN 0306-4522

Neuroprotective gene therapy in the aging brain.
Pardo, J; Morel, G. R; Pereyra, A. S; López-León, M; Brown-O. A, Bellini, M. J; Goya, R. G.
2014. Estrogens and Cognition. Psycho-biological and Clinical Aspects: González-Burgos (Ed.) ISBN: 978-81-308-0550-4; pp.97-117

Gene therapy and cell reprogramming for the aging brain: achievements and promise.
Pardo, J; Morel, G. R; Astiz, M; Schwerdt, M. I; López León, M; Rodríguez, S. S;Hereñú, C. B; Goya, R. G.
2014. Curr Gene Ther; 14:24-34

Role of copper and cholesterol association in the neurodegenerative process.
Arnal, N; Morel, G. R; Tacconi de Alaniz, M. J; Dominici, L; Marra, C. A.
2013. Int J Alzheimers Dis; 2013:414817. doi: 10.1155/2013/414817. Epub 2013 Oct 29.

Restorative effect of intracerebroventricular Insulin-like Growth Factor-I gene therapy on motor performance in aging rats.
Nishida, F; Morel, G. R; Hereñú, C. B; Schwerdt, J. I; Goya, R. G; Portiansky, E. L.
2011. Neuroscience, 177: 195 - 206

Glial cell line-derived neurotrophic factor gene therapy ameliorates chronic hyperprolactinemia in senile rats.
Morel, G. R; Sosa, Y. E; Bellini, M. J; Carri, N. G; Rodriguez, S, S; Bohn, M. C; Goya, R.
2010. Neuroscience; vol. 167 p. 946 - 953

The ependymal route for insulin-like growth factor-1 gene therapy in the brain.
Hereñu C. B; Sonntag W.E; Morel G. R; Portiansky E. L; Goya R. G.
2009. Neuroscience. Elsevier, vol. 163, p. 442-447

The thymus-neuroendocrine axis: physiology, molecular biology and therapeutic potential of the thymic peptide thymulin..
Reggiani P.C; Morel G. R; Cónsole G. M; Barbeito C. G; Rodriguez S; Brown O. A; Bellini M. J; Pléau J. M; Dardenne M; Goya R. G.
2009. Annals of the New York Academy of Sciences. New York: New York Academy of Sciences. Blackwell Publishing, vol. 1153, p. 98-106

Estrogen inhibits tuberoinfundibular dopaminergic neurons but does not cause irreversible damage.
Morel, G. R; Caron, R. W; Console, G. M; Soaje, M; Sosa, Y. E; Rodríguez, S. S; Jahn, G. A; Goya, R. G.
2009. Brain Research Bulletin. Amsterdam: Elsevier, vol. 80, n° 6, p. 347-352

Insulin-like growth factor-I gene therapy reverses morphologic changes and reduces hyperprolactinemia in experimental rat prolactinomas.
Console, G. M; Hereñu, C. B; Camihort, G. A; Luna, G. C; Bracamonte, M. I; Morel, G. R; Goya, R. G.
2008. Molecular cancer. Londres: Blackwell Scientific Publications, p. 7-13

Potential of gene therapy for restoration of endocrine thymic function in thymus-deficient animal models.
Morel, G. R; Reggiani, P. C; Cónsole, G. M; Rimoldi, O. J; Vesenbeckh, S. M; García De Bravo, M; Rodríguez, S. S; Brown, O. A; Goya, R. G.
2008.Curr gene ther. Bentham Science Publishers, vol. 8 n° 1, p.49-53 ISSN 1566-5232

Neuroprotective gene therapy in the aging brain; In: Estrogens and Cognition.
Pardo J, Morel GR, Pereyra AS, López-León M, Brown-OA, Bellini MJ, Goya RG.
2014. Psychobiological and Clinical Aspects, 2014:97-117 ISBN: 978-81-308-0550-4 Editor: González-Burgos, I.

“Expresión génica diferencial de hipocampo en un modelo de envejecimiento cerebral tratado con terapia génica de largo plazo”< Presentación oral.
Trabajo: Pardo, J; Abba, M; Lacunza, E; Schwerdt, J; Cónsole, G; Outeiro, T; Morel, G; Goya, R
2015. Premio al mejor trabajo en investigación básica en el 2º Congreso Internacional de la Facultad de Cs Médicas de la UNLP.

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