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Project 02
Adult neurogenesis
in animal models of disease
Spanish Ministry of Science and Innovation, PID2020-113007RB-I00.
The Alzheimer´s Association, AARG-17-528125-RAPID and AARG-17-528125.
Further reading
The award of several grants by the Spanish Ministry of Science and Innovation (PID2020-113007RB-I00) and The Alzheimer´s Association (AARG-17-528125-RAPID and AARG-17-528125) will allow us to deepen our knowledge on the regulation of adult hippocampal neurogenesis in distinct model organisms.
Principal Investigator
María Llorens-Martín
Summary
We are developing innovative viral tools to explore the synaptic integration of newborn dentate granule cells from a holistic point of view. Not only we study the establishment and maturation of synaptic contacts made onto these cells, but also the modulation of this process exerted by other elements, such as microglia, astrocytes, interneurons, and vascular elements, which orchestrate the hippocampal trisynaptic circuitry. The use of the novel viral tools developed in our lab, combined with the application of advanced microscopy techniques are currently bringing to light the complex remodeling of the hippocampal dentate gyrus neurogenic niche that occurs throughout physiological and pathological aging in mice. We are also assessing the therapeutic potential of novel strategies, either pharmacological or non-pharmacological, to reverse both the cellular and behavioral alterations observed in mouse models throughout aging and under neurodegenerative conditions. Whether or not certain mammalian species are capable of sustaining neurogenesis throughout adult life is still a matter of debate in the field. We are applying the knowledge obtained from human studies to shed some light on these crucial phylogenetic aspects.
Members of the team involved
María Llorens-Martín (Principal Investigator)
Berenice Márquez-Valadez
Carla Rodríguez-Moreno
Elena Moreno-Jiménez
Fabio Cafini (Collaborator)
Julia Terreros-Roncal
Marta Gallardo
Miguel Flor-García
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Participating Institutions
Spanish Research Council (CSIC) (Spain) (Host Institution)
CIBERNED (Spain)
Results Obtained
Publications
a
GSK-3β S9A overexpression leads murine hippocampal neural precursors to acquire an astroglial phenotype in vivo.
Flor-García M, Ávila J, Llorens-Martín M. (2021)
Developmental Neurobiology
81(5):710-723.
doi: 10.1002/dneu.22823.
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Expand Abstract: The addition of new neurons to the existing hippocampal circuitry persists in the adult dentate gyrus (DG). During this process, named adult hippocampal neurogenesis (AHN), adult hippocampal progenitor cells (AHPs) give rise to newborn dentate granule cells (DGCs). The acquisition of a neuronal lineage by AHPs is tightly regulated by numerous signaling molecules and transcription factors. In this regard, glycogen synthase kinase 3β (GSK-3β) is a master regulator of the maturation of AHPs in vitro. Here we analyzed the cell-autonomous effects of overexpressing a constitutively active form of GSK-3β (GSK-3β S9A) in AHPs in vivo. To this end, we stereotaxically injected a GSK-3β S9A-encoding retrovirus (GSK-3β-V5) into the DG of young adult C57BL6/J Ola Hsd female mice and studied the cell lineage acquisition, migratory and marker expression patterns, and the morphological maturation of the infected cells over time.
Strikingly, GSK-3β S9A-transduced cells expressed glial fibrillary acidic protein (GFAP) and NG2, thereby acquiring an immature astroglial phenotype, which differed markedly from the neuronal phenotype observed in cells transduced with a control retrovirus that encoded GFP. Accordingly, the morphology and migration patterns of cells transduced by the two retroviruses are remarkably divergent. These observations support the role of GSK-3β as a cornerstone that regulates the balance between new astocytes/neurons generated in the adult murine DG.
b
Activity-Dependent Reconnection of Adult-Born Dentate Granule Cells in a Mouse Model of Frontotemporal Dementia.
Terreros-Roncal J, Flor-García M, Moreno-Jiménez EP, Pallas-Bazarra N, Rábano A, Sah N, van Praag H, Giacomini D, Schinder AF, Ávila J, Llorens-Martín M. (2019)
Journal of Neuroscience
39(29):5794-5815.
doi: 10.1523/JNEUROSCI.2724-18.2019.
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Expand Abstract: Frontotemporal dementia (FTD) is characterized by neuronal loss in the frontal and temporal lobes of the brain. Here, we provide the first evidence of striking morphological alterations in dentate granule cells (DGCs) of FTD patients and in a mouse model of the disease, TauVLW mice. Taking advantage of the fact that the hippocampal dentate gyrus (DG) gives rise to newborn DGCs throughout the lifetime in rodents, we used RGB retroviruses to study the temporary course of these alterations in newborn DGCs of female TauVLW mice. In addition, retroviruses that encode either PSD95:GFP or Syn:GFP revealed striking alterations in the afferent and efferent connectivity of newborn TauVLW DGCs, and monosynaptic retrograde rabies virus tracing showed that these cells are disconnected from distal brain regions and local sources of excitatory innervation.
However, the same cells exhibited a predominance of local inhibitory innervation. Accordingly, the expression of presynaptic and postsynaptic markers of inhibitory synapses was markedly increased in the DG of TauVLW mice and FTD patients. Moreover, an increased number of neuropeptide Y-positive interneurons in the DG correlated with a reduced number of activated egr-1+ DGCs in TauVLW mice. Finally, we tested the therapeutic potential of environmental enrichment and chemoactivation to reverse these alterations in mice. Both strategies reversed the morphological alterations of newborn DGCs and partially restored their connectivity in a mouse model of the disease. Moreover, our data point to remarkable morphological similarities between the DGCs of TauVLW mice and FTD patients.
c
The Social Component of Environmental Enrichment Is a Pro-neurogenic Stimulus in Adult c57BL6 Female Mice. Moreno-Jiménez EP, Jurado-Arjona J, Ávila J, Llorens-Martín M. (2019) Frontiers in Cell and Developmental Biology 7:62. doi: 10.3389/fcell.2019.00062.
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Expand Abstract: In rodents, the hippocampal dentate gyrus gives rise to newly generated dentate granule cells (DGCs) throughout life. This process, named adult hippocampal neurogenesis (AHN), converges in the functional integration of mature DGCs into the trisynaptic hippocampal circuit. Environmental enrichment (EE) is one of the most potent positive regulators of AHN. This paradigm includes the combination of three major stimulatory components, namely increased physical activity, constant cognitive stimulation, and higher social interaction. In this regard, the pro-neurogenic effects of physical activity and cognitive stimulation have been widely addressed in adult rodents. However, the pro-neurogenic potential of the social aspect of EE has been less explored to date. Here we tackled this question by specifically focusing on the effects of a prolonged period of social enrichment (SE) in adult female C57BL6 mice. To this end, 7-week-old mice were housed in groups of 12 per cage for 8 weeks. These mice were compared with others housed under control housing (2-3 mice per cage) or EE (12 mice per cage plus running wheels and toys) conditions during the same period.
We analyzed the number and morphology of Doublecortin-expressing (DCX+) cells. Moreover, using RGB retroviruses that allowed the labeling of three populations of newborn DGCs of different ages in the same mouse, we performed morphometric, immunohistochemical, and behavioral determinations. Both SE and EE increased the number and maturation of DCX+ cells, and caused an increase in dendritic maturation in certain populations of newborn DGCs. Moreover, both manipulations increased exploratory behavior in the Social Interaction test. Unexpectedly, our data revealed the potent neurogenesis-stimulating potential of SE in the absence of any further cognitive stimulation or increase in physical activity. Given that an increase in physical activity is strongly discouraged under certain circumstances, our findings may be relevant in the context of enhancing AHN via physical activity-independent mechanisms.
d
Maturation Dynamics of the Axon Initial Segment (AIS) of Newborn Dentate Granule Cells in Young Adult C57BL/6J Mice. Bolós M, Terreros-Roncal J, Perea JR, Pallas-Bazarra N, Ávila J, Llorens-Martín M. (2019) Journal of Neuroscience 39(9):1605-1620. doi: 10.1523/JNEUROSCI.2253-18.2019.
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Expand Abstract: Newborn dentate granule cells (DGCs) are generated in the hippocampal dentate gyrus (DG) of rodents through a process called adult hippocampal neurogenesis, which is subjected to tight intrinsic and extrinsic regulation. The use of retroviruses encoding fluorescent proteins has allowed the characterization of the maturation dynamics of newborn DGCs, including their morphological development and the establishment and maturation of their afferent and efferent synaptic connections. However, the study of a crucial cellular compartment of these cells, namely, the axon initial segment (AIS), has remained unexplored to date. The AIS is not only the site of action potential initiation, but it also has a unique molecular identity that makes it one of the master regulators of neural plasticity and excitability.
Here we examined the dynamics of AIS formation in newborn DGCs of young female adult C57BL/6J mice in vivo Our data reveal notable changes in AIS length and thickness throughout cell maturation under physiological conditions and show that the most remarkable structural changes coincide with periods of intense morphological and functional remodeling. Moreover, we demonstrate that AIS development can be modulated extrinsically by both neuroprotective (environmental enrichment) and detrimental (lipopolysaccharide from Escherichia coli) stimuli.
Invited talks and conferences
María Llorens-Martín
Eurogenesis, Bordeaux (France), 12 June 2019.
María Llorens-Martín
AGE2021 (Madison, USA), 21 July 2021.
María Llorens-Martín
IBRO2019 (Tsukuba, Japan), 21 July 2021.
Press
Ciberned
Miguel Flor-García. CIBERNED Young Investigator National Award. 19 Oct 2020.
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CSIC
Press release: “Logran “reconectar” un grupo de neuronas dañadas por una enfermedad neurodegenerativa”. 28 May 2019.
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Cadena Ser
“Logran 'reconectar' neuronas dañadas”. 28 May 2019.
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Diario Salud
“Logran “reconectar” un grupo de neuronas dañadas por una enfermedad neurodegenerativa”. 6th June 2019.
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Centro de Biología Molecular Severo Ochoa (CBMSO) Universidad Autónoma de Madrid (Campus de Cantoblanco)
C/ Nicolás Cabrera 1 - 28049 Madrid (Spain)
María Llorens-Martín (PI)
m.llorens@csic.es
+34 911964632