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Neurology / Hippocampal plasticity and neurogenesis

Hippocampal plasticity and neurogenesis

PD Dr. rer. nat. Anja Urbach
Klinik für Neurologie,
Wissenschaftliche Mitarbeiterin
anja.urbach(at)med.uni-jena.de
phone: 03641 9 32 59 01

                                                    Researchgate: https://www.researchgate.net/profile/Anja-Urbach

Research areas

Adult Neurogenesis

It was in the 1960´s when the first evidence emerged against Cajal´s dogma that new neurons cannot be produced in the adult brain. Since then it became widely accepted that new neurons are generated continuously in two regions of the mammalian brain: the olfactory bulb and the dentate gyrus in the hippocampus. In the dentate gyrus, adult-born neurons are derived from neural progenitors and go through different stages of morphological and physiological development before reaching maturity, a process that takes several weeks and is influenced by an animal´s experience. During a critical period of their development immature neurons provide the local circuitry with unique functional properties (high excitability, enhanced synaptic plasticity). Accordingly, recent evidence suggests that adult neurogenesis plays important roles in memory and mood regulation, and perturbations of this process have been linked to neurological diseases and cognitive aging.

1. Development and aging of the adult neural stem cell pool

The source of lifelong neurogenesis lies in a small population of radial glia-like neural stem cells that is established during early postnatal development and declines with increasing age. We aim to understand from where these cells originate, the origin and the extent of their heterogeneity, and how and why they age.

2. Role of D-type cyclins in adult neurdal stem and progenitor cells

D-type cyclins are a family of proteins essential for cell cycle progression from G1- to S-phase. Among them, cyclin D2 appears to be of particular importance for adult neurogenesis. We have shown that ablation of the gene coding for cyclin D2 in mice leads to virtual absence of newborn dentate granule neurons from adolescence on. Our ongoing work is aimed to identify the role of D-type cyclins for the proliferation, fate determination and differentiation of adult stem and progenitor cells. We also investigate their role during development of the dentate gyrus and in particular for the formation of the adult stem cell pool.

2. Functional role of adult neurogenesis

Whether and how adult-born neurons contribute to brain function is a central question in the field of adult neurogenesis. Our current projects aim to characterize the contribution of newborn neurons to hippocampal function and to experience-dependent plasticity, both in the adult and in the aged brain.

Cortical spreading depolarization

Cortical spreading depolarizations (CSD) have been discovered some 70 years ago by the Brazilian physiologist Aristides P. Leao. Since then they have been identified in various species including rodents and primates. CSD are characterized by a wave of neuronal and glial depolarization that slowly propagates from a trigger point across the ipsilateral grey matter. They are associated with a transient depression of neuronal activity, as well as pronounced imbalances in ionic, metabolic and hemodynamic parameters. In recent years CSD have been demonstrated also in the human brain where they occur spontaneously in different neuropathologies (ischemic stroke, hemorrhage, traumatic brain injury and migraine). While CSD are completely reversible and benign in normoxic tissue, they lead to secondary expansion of the necrotic territory in the injured brain. In our projects we explore the potential duality (detrimental and beneficial) in how CSD contribute to the outcome of associated neuropathologies, focussing on their effects on reorganization and plasticity in healthy and remote perilesional brain areas.

Methods

  • Rodent behavior (Morris water maze, Barnes Maze, Fear conditioning, Open field, Object/Location novelty recognition, Novelty suppressed feeding, Tail suspension Test, RotaRod, Grid walk)
  • Animal models (stroke, Cortical Spreading Depolarization)
  • Immunohistochemistry, confocal laser scanning microscopy (LSM), stereology
  • Molecular biology (RNA, DNA, qRT-PCR, cloning, single cell sequencing)
  • In vitro stem cell assays
  • Transgenic mouse models
  • Electrophysiology (extracellular field potentials, EEG/ECoG in vivo)

Publications

  • Urbach A, Bruehl C, Witte OW: Microarray based long term detection of genes differentially expressed after cortical spreading depression. Eur J Neurosci, 24(3), 2006
  • Urbach A, Redecker C, Witte OW: Induction of neurogenesis in the adult dentate gyrus by cortical spreading depression. Stroke 39(11), 2008
  • Popp A, Urbach A, Witte OW, Frahm C: Adult and juvenile GAD transcripts are spatiotem-porally regulated during postnatal development in the rat brain. PlosONE 4(2), 2009
  • Ansorg A, Witte OW, Urbach A: Age-dependent kinetics of dentate gyrus neurogenesis in the absence of cyclin D2. BMC Neuroscience 13, 2012.
  • Urbach A, Robakiewicz I, Baum E, Kaczmarek L, Witte OW, Filipkowski RK: Cyclin D2 knockout mice with depleted adult neurogenesis learn Barnes maze task. Behav Neurosci 127(1), 2012
  • Schumacher L, Urbach A, Lutzenburg M, Bidmon HJ,Witte OW: Bihemispheric ischemic tolerance induced by unilateral focal cortical lesion. Brain Res 1570, 2014
  • Urbach A, Brueckner J, Witte OW: Cortical spreading depolarization stimulates gliogenesis in the rat entorhinal cortex. JCBFM, 2014; https://doi.org/10.1038/jcbfm.2014.232
  • Ansorg A, Bornkessel K, Witte OW, Urbach A: Immunohistochemistry and multiple labeling with antibodies from the same host species to study adult hippocampal neurogenesis. JoVE, https://dx.doi.org/10.3791/52551
  • Urbach A, Witte OW: Photochemical models of focal brain ischemia. In: Rodent models of stroke, Dirnagl U (ed). Humana Press, 2016
  • Urbach A, Baum E, Braun F, Witte OW: Cortical Spreading Depolarization Increases Adult Neurogenesis, and Alters Behavior and Hippocampus-Dependent Memory in Mice. JCBFM, 2016; https://doi.org/10.1177/0271678X16643736
  • Hartings JA, Shuttleworth CW, Kirov SA, Ayata C, Hinzman JM, Foreman B, Andrew D, Boutelle MG, Brennan KC, Carlson AP, Dahlem MA, Drenckhahn C, Dohmen C, Fabricius M, Farkas E, Feuerstein D, Graf R, Helbok R, Lauritzen M, Major S, Oliveira-Ferreira AI, Richter F, Rosenthal ES, Sakowitz OW, Sánchez-Porras R, Santos E, Schöll M, Strong AJ, Urbach A, Westover MB, Winkler MKL, Witte OW, Woitzik J, Dreier JP: The continuum of spreading depolarizations in acute cortical lesion development: examining Leão’s legacy. JCBFM, 2016; https://doi.org/10.1177/0271678X16654495
  • Urbach A, Witte OW: Divide or commit – Revisiting the role of cell cycle regulators in adult hippocampal neurogenesis. Frontiers in Cell and Developmental Biology, 2019;https://doi.org/10.3389/fcell.2019.00055
  • Pensold D, Reichard J, Van Loo KMJ, Ciganok N, Hahn A, Bayer C, Liebmann L, Groß J, Tittelmeier J, Lingner T, Salinas-Riester G, Symmank J, Halfmann C, González-Bermúdez L, Urbach A, Gehrmann J, Costa I, Pieler T, Hübner CA, Vatter H, Kampa B, Becker AJ, Zimmer-Bensch G: DNA Methylation-Mediated Modulation of Endocytosis as Potential Mechanism for Synaptic Function Regulation in Murine Inhibitory Cortical Interneurons. Cerebral Cortex, 2020; https://doi.org/10.1093/cercor/bhaa009

  • Trautmann C, Bock A, Urbach A, Hübner CA, Engmann O: Acute vitamin B12 supplementation evokes antidepressant response and alters Ntrk-2. Neuropharmacology, 2020. https://doi.org/10.1016/j.neuropharm.2020.108112

  • Hahn A, Bayer C, Pensold D, Tittelmeier J, Marx-Bluemel L, Gonzalez-Bermudez L, Linde J, Gross J, Salinas-Riester G, von Maltzahn J, Spehr M, Pieler T, Urbach A, Zimmer-Bensch G: DNA methyltransferase 1 (DNMT1) function is implicated in the age-related loss of cortical interneurons. Front Cell Dev Biol, 2020; https://doi.org/10.3389/fcell.2020.00639

  • Schmidt S, Gull S, Herrmann K-H, Boehme M, Irintchev A, Urbach A, Reichenbach JR, Klingner CM, Gaser C, Witte OW: Experience-dependent structural plasticity in the adult brain: How the learning brain grows. NeuroImage, 2021. doi: 10.1016/j.neuroimage.2020.117502.
  • Graf J, Zhang C, Marguet SL, Herrmann T, Flossmann T, Hinsch R, Rahmati V, Guenther M, Frahm C, Urbach A, Neves RM, Witte OW, Kiebel SJ, Isbrandt D, Hübner CA, Holthoff K, Kirmse K: A limited role of NKCC1 in telencephalic glutamatergic neurons for developing hippocampal network dynamics and behavior. Proc Natl Acad Sci U S A, 2020; doi:10.1073/pnas.2014784118
  • Grünewald G, Wickel J, Hahn N, Hörhold F, Rupp H, Chung HY, Haselmann H, Strauss AS, Schmidl L, Hempel N, Grünewald L, Urbach A, Bauer M, Toyka KV, Blaess M, Claus RA, König R, Geis C: Targeted rescue of synaptic plasticity improves cognitive decline after severe systemic inflammation. bioRxiv 2021. https://doi.org/10.1101/2021.03.04.433352

  • Gull S, Gaser C, Herrmann KH, Urbach A, Boehme M, Afzal S, Reichenbach JR, Witte OW, Schmidt S: Brain Macro-Structural Alterations in Aging Rats: A Longitudinal Lifetime Approach. Cells, 2023. https://doi.org/10.3390/cells12030432
  • Wulf S, Mizko L, Herrmann K-H, Sánchez-Carbonell M, Urbach A, Lemke C, Berndt A, Loeffler I, Wolf G: Targeted disruption of the MORG1 gene in mice causes embryonic resorption in early phase of development. Biomolecules, 2023. https://doi.org/10.3390/biom13071037
  • Jiménez Peinado P, Urbach A: From Youthful Vigor to Aging Decline: Unravelling the Intrinsic and Extrinsic Determinants of Hippocampal Neural Stem Cell Aging. Cells, 2023. https://doi.org/10.3390/cells12162086
  • Pastor-Alonso O, Zahra AS, Kaske B, García-Moreno F, Tetzlaff F, Bockelmann E, Grunwald V, Martin-Suarez S, Riecken K, Witte OW, Encinas JM, Urbach A: Generation of adult hippocampal neural stem cells occurs in the early postnatal dentate gyrus and depends on cyclin D2. EMBO Journal 2024. doi: 10.1038/s44318-023-00011-2  
  • Hagihara H, Shoji H, Hattori S, Sala G, Takamiya Y, Tanaka M, Ihara M, Shibutani M, Hatada I, Hori K, Hoshino M, Nakao A, Mori Y, Okabe S, Matsushita M, Urbach A, …, Miyakawa T: Large-scale animal model study uncovers altered brain pH and lactate levels as a transdiagnostic endophenotype of neuropsychiatric disorders involving cognitive impairment. eLife12: RP89376

Funding

  • LGSA “Funktionelle Relevanz adulter hippocampaler Neurogenese nach kortikaler Spreading Depression”, 2006-2010
  • IZKF (junior project, J15) “Relevance of adult neurogenesis for the structural and functional plasticity of the hippocampus”, 2008-2010
  • Programm zur Förderung der Drittmittelfähigkeit von NachwuchswissenschaftlerInnen "Herstellung einer Cyclin D2fl/fl Mausstammzellinie als Voraussetzung zur Erzeugung einer konditionalen Cyclin D2-knock out Maus", 2010-2011
  • GRK1715, Project “Protective and Deleterious Consequences of Ischemic Preconditioning: The Janus Face of Adaptive Stress Responses”, 2011-2014
  • Prochance travel grant, 2016
  • DAAD travel grant, 2017
  • IZKF Advanced Medical Scientist program, 2019-2022

  • Prochance travel grant, 2019
  • LIFE “Connect” research grant (collaborative project with I. Löffler, UKJ, KIM III), 2025

  • German Research Foundation (DFG) research grant (UR 197/3-1), 2026

Team

  • cand. med. Lisa Zschille
  • cand. med. Juliane Stadtkus
  • cand. med. Jonas Mücke
  • cand. med. Olivia Ainhoa Puls
  • cand. med. Sam Jarod Quaas
  • cand. med. Jule Liersch
  • cand. med. Nicolas Griesinger
  • cand. med. Niklas Herzner
  • M.Sc. Nils Krommer

Alumni

  • Dr. rer. nat. Marta Sanchéz Carbonell
  • Dr. rer. nat. Patricia Jiménez Peinado
  • Dr. rer. nat. Varunika Goyal
  • Dr. med. Judith Brückner
  • Dr. med. Urike Rüddel
  • Dr. med. Hannah Zipprich
  • Dr. med. Falko Braun
  • B.Sc. Marcel Brosch
  • B.Sc. Sissy Schaller
  • B.Sc. Felix Tetzlaff
  • B.Sc. Ronja Badelt
  • B.Sc. Bente Kaske
  • B.Sc. Enno Bockelmann
  • B.Sc. Luca Buchs
  • B.Sc. Maria Thielemann
  • B.Sc. Jule Müller
  • B.Sc. Gregor Stein
  • B.Sc. Anne Sophie Wallmann
  • B.Sc. Jan Hawlicki
  • B.Sc. Miriam Weißhaar
  • B.Sc. Miriam Lilienweiß
  • B.Sc. Maike Petersmann
  • B.Sc. Vanessa Seidel
  • M.Sc. Katja Bornkessel
  • M.Sc. Jaya Keertana Srimat Kandadai
  • M. Sc. Vanessa Knölker
  • M.Sc. Miriam Weißhaar
  • M.Sc. Nils Krommer
  • M.Sc. Anum Zahra
  • Dipl. Biol. Lena Schumacher
  • Dipl. Biol. Anne Ansorg
  • Dipl. Biol. Eileen Baum

 

Open positions

New Bachelor or Master students are always welcome. We are currently seeking for highly motivated students to support our research on the developing and aging stem cell niche.