F H Gage

Torrey Pines Institute for Molecular Studies, Port St. Lucie, Florida, United States

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Publications (701)6165.26 Total impact

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    ABSTRACT: Adult animals continue to modify their behavior throughout life, a process that is highly influenced by past experiences. To shape behavior, specific mechanisms of neural plasticity to learn, remember, and recall information are required. One of the most robust examples of adult plasticity in the brain occurs in the dentate gyrus (DG) of the hippocampus, through the process of adult neurogenesis. Adult neurogenesis is strongly upregulated by external factors such as voluntary wheel running (RUN) and environmental enrichment (EE); however, the functional differences between these two factors remain unclear. Although both manipulations result in increased neurogenesis, RUN dramatically increases the proliferation of newborn cells and EE promotes their survival. We hypothesize that the method by which these newborn neurons are induced influences their functional role. Furthermore, we examine how EE-induced neurons may be primed to encode and recognize features of novel environments due to their previous enrichment experience. Here, we gave mice a challenging contextual fear-conditioning (FC) procedure to tease out the behavioral differences between RUN-induced neurogenesis and EE-induced neurogenesis. Despite the robust increases in neurogenesis seen in the RUN mice, we found that only EE mice were able to discriminate between similar contexts in this task, indicating that EE mice might use a different cognitive strategy when processing contextual information. Furthermore, we showed that this improvement was dependent on EE-induced neurogenesis, suggesting a fundamental functional difference between RUN-induced neurogenesis and EE-induced neurogenesis. © 2014 Wiley Periodicals, Inc.
    Hippocampus 10/2014; · 5.49 Impact Factor
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    ABSTRACT: Adult neurogenesis in the hippocampus is a notable process due not only to its uniqueness and potential impact on cognition but also to its localized vertical integration of different scales of neuroscience, ranging from molecular and cellular biology to behavior. This review summarizes the recent research regarding the process of adult neurogenesis from these different perspectives, with particular emphasis on the differentiation and development of new neurons, the regulation of the process by extrinsic and intrinsic factors, and their ultimate function in the hippocampus circuit. Arising from a local neural stem cell population, new neurons progress through several stages of maturation, ultimately integrating into the adult dentate gyrus network. The increased appreciation of the full neurogenesis process, from genes and cells to behavior and cognition, makes neurogenesis both a unique case study for how scales in neuroscience can link together and suggests neurogenesis as a potential target for therapeutic intervention for a number of disorders.
    Physiological reviews. 10/2014; 94(4):991-1026.
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    ABSTRACT: This study investigated human-induced pluripotent stem cell (hiPSC) -derived neurons for their ability to secrete neurotransmitters in an activity-dependent manner, the fundamental property required for chemical neurotransmission. Cultured hiPSC neurons showed KCl stimulation of activity-dependent secretion of catecholamines-dopamine (DA), norepinephrine (NE), and epinephrine (Epi)-and the peptide neurotransmitters dynorphin and enkephlain. hiPSC neurons express the biosynthetic enzymes for catecholamines and neuropeptides. Because altered neurotransmission contributes to schizophrenia (SZ), we compared SZ to control cultures of hiPSC neurons and found that SZ cases showed elevated levels of secreted DA, NE, and Epi. Consistent with increased catecholamines, the SZ neuronal cultures showed a higher percentage of tyrosine hydroxylase (TH)-positive neurons, the first enzymatic step for catecholamine biosynthesis. These findings show that hiPSC neurons possess the fundamental property of activity-dependent neurotransmitter secretion and can be advantageously utilized to examine regulation of neurotransmitter release related to brain disorders.
    Stem Cell Reports. 09/2014;
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    ABSTRACT: Proneurogenic compounds have recently shown promise in some mouse models of Alzheimer's pathology. Antagonists at Group II metabotropic glutamate receptors (Group II mGluR: mGlu2, mGlu3) are reported to stimulate neurogenesis. Agonists at those receptors trigger γ-secretase-inhibitor-sensitive biogenesis of Aβ42 peptides from isolated synaptic terminals, which is selectively suppressed by antagonist pretreatment. We have assessed the therapeutic potential of chronic pharmacological inhibition of Group II mGluR in Dutch APP (Alzheimer's amyloid precursor protein E693Q) transgenic mice that accumulate Dutch amyloid-β (Aβ) oligomers but never develop Aβ plaques. BCI-838 is a clinically well-tolerated, orally bioavailable, investigational prodrug that delivers to the brain BCI-632, the active Group II mGluR antagonist metabolite. Dutch Aβ-oligomer-forming APP transgenic mice (APP E693Q) were dosed with BCI-838 for 3 months. Chronic treatment with BCI-838 was associated with reversal of transgene-related amnestic behavior, reduction in anxiety, reduction in levels of brain Aβ monomers and oligomers, and stimulation of hippocampal neurogenesis. Group II mGluR inhibition may offer a unique package of relevant properties as an Alzheimer's disease therapeutic or prophylactic by providing both attenuation of neuropathology and stimulation of repair.Molecular Psychiatry advance online publication, 12 August 2014; doi:10.1038/mp.2014.87.
    Molecular psychiatry. 08/2014;
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    ABSTRACT: Mobile elements are DNA sequences that can change their position (retrotranspose) within the genome. Although its biological function is largely unappreciated, DNA derived from mobile elements comprises nearly half of the human genome. It has long been thought that neuronal genomes are invariable; however, recent studies have demonstrated that mobile elements actively retrotranspose during neurogenesis, thereby creating genomic diversity between neurons. In addition, mounting data demonstrate that mobile elements are misregulated in certain neurological disorders, including Rett syndrome and schizophrenia.
    Nature reviews. Neuroscience. 07/2014;
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    ABSTRACT: Neural stem cells have been adopted to model a wide range of neuropsychiatric conditions in vitro. However, how well such models correspond to in vivo brain has not been evaluated in an unbiased, comprehensive manner. We used transcriptomic analyses to compare in vitro systems to developing human fetal brain and observed strong conservation of in vivo gene expression and network architecture in differentiating primary human neural progenitor cells (phNPCs). Conserved modules are enriched in genes associated with ASD, supporting the utility of phNPCs for studying neuropsychiatric disease. We also developed and validated a machine learning approach called CoNTExT that identifies the developmental maturity and regional identity of in vitro models. We observed strong differences between in vitro models, including hiPSC-derived neural progenitors from multiple laboratories. This work provides a systems biology framework for evaluating in vitro systems and supports their value in studying the molecular mechanisms of human neurodevelopmental disease.
    Neuron 07/2014; 83(1):69-86. · 15.77 Impact Factor
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    ABSTRACT: Granule neurons in the hippocampal dentate gyrus (DG) receive their primary inputs from the cortex and are known to be continuously generated throughout adult life. Ongoing integration of newborn neurons into the existing hippocampal neural circuitry provides enhanced neuroplasticity, which plays a crucial role in learning and memory; deficits in this process have been associated with cognitive decline under neuropathological conditions. In this Primer, we summarize the developmental principles that regulate the process of DG neurogenesis and discuss recent advances in harnessing these developmental cues to generate DG granule neurons from human pluripotent stem cells.
    Development (Cambridge, England). 06/2014; 141(12):2366-75.
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    ABSTRACT: While motor neuron diseases are currently incurable, induced pluripotent stem cell research has uncovered some disease relevant phenotypes. We will discuss strategies to model different aspects of motor neuron disease and the specific neurons involved in the disease. We will then describe recent progress to investigate common forms of motor neuron disease: amyotrophic lateral sclerosis, hereditary spastic paraplegia, and spinal muscular atrophy.
    Human Molecular Genetics 05/2014; · 7.69 Impact Factor
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    ABSTRACT: Successful memory involves not only remembering information over time but also keeping memories distinct and less confusable. The computational process for making representations of similar input patterns more distinct from each other has been referred to as ‘pattern separation’. Although adult-born immature neurons have been implicated in this memory feature, the precise role of these neurons and associated molecules in the processing of overlapping memories is unknown. Recently, we found that BDNF in the dentate gyrus is required for the encoding/consolidation of overlapping memories. In this work we provide evidence that consolidation of these “pattern-separated” memories requires the action of BDNF on immature neurons specifically. © 2014 Wiley Periodicals, Inc.
    Hippocampus 05/2014; · 5.49 Impact Factor
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    ABSTRACT: The adult dentate gyrus produces new neurons that morphologically and functionally integrate into the hippocampal network. In the adult brain, most excitatory synapses are ensheathed by astrocytic perisynaptic processes that regulate synaptic structure and function. However, these processes are formed during embryonic or early postnatal development and it is unknown whether astrocytes can also ensheathe synapses of neurons born during adulthood and, if so, whether they play a role in their synaptic transmission. Here, we used a combination of serial-section immuno-electron microscopy, confocal microscopy, and electrophysiology to examine the formation of perisynaptic processes on adult-born neurons. We found that the afferent and efferent synapses of newborn neurons are ensheathed by astrocytic processes, irrespective of the age of the neurons or the size of their synapses. The quantification of gliogenesis and the distribution of astrocytic processes on synapses formed by adult-born neurons suggest that the majority of these processes are recruited from pre-existing astrocytes. Furthermore, the inhibition of astrocytic glutamate re-uptake significantly reduced postsynaptic currents and increased paired-pulse facilitation in adult-born neurons, suggesting that perisynaptic processes modulate synaptic transmission on these cells. Finally, some processes were found intercalated between newly formed dendritic spines and potential presynaptic partners, suggesting that they may also play a structural role in the connectivity of new spines. Together, these results indicate that pre-existing astrocytes remodel their processes to ensheathe synapses of adult-born neurons and participate to the functional and structural integration of these cells into the hippocampal network.
    Brain Structure and Function 04/2014; · 7.84 Impact Factor
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    ABSTRACT: Prenatal exposure of the developing brain to various environmental challenges increases susceptibility to late onset of neuropsychiatric dysfunction; still, the underlying mechanisms remain obscure. Here we show that exposure of embryos to a variety of environmental factors such as alcohol, methylmercury, and maternal seizure activates HSF1 in cerebral cortical cells. Furthermore, Hsf1 deficiency in the mouse cortex exposed in utero to subthreshold levels of these challenges causes structural abnormalities and increases seizure susceptibility after birth. In addition, we found that human neural progenitor cells differentiated from induced pluripotent stem cells derived from schizophrenia patients show higher variability in the levels of HSF1 activation induced by environmental challenges compared to controls. We propose that HSF1 plays a crucial role in the response of brain cells to prenatal environmental insults and may be a key component in the pathogenesis of late-onset neuropsychiatric disorders.
    Neuron 04/2014; · 15.77 Impact Factor
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    ABSTRACT: Consistent with recent reports indicating that neurons differentiated in vitro from human-induced pluripotent stem cells (hiPSCs) are immature relative to those in the human brain, gene expression comparisons of our hiPSC-derived neurons to the Allen BrainSpan Atlas indicate that they most resemble fetal brain tissue. This finding suggests that, rather than modeling the late features of schizophrenia (SZ), hiPSC-based models may be better suited for the study of disease predisposition. We now report that a significant fraction of the gene signature of SZ hiPSC-derived neurons is conserved in SZ hiPSC neural progenitor cells (NPCs). We used two independent discovery-based approaches-microarray gene expression and stable isotope labeling by amino acids in cell culture (SILAC) quantitative proteomic mass spectrometry analyses-to identify cellular phenotypes in SZ hiPSC NPCs from four SZ patients. From our findings that SZ hiPSC NPCs show abnormal gene expression and protein levels related to cytoskeletal remodeling and oxidative stress, we predicted, and subsequently observed, aberrant migration and increased oxidative stress in SZ hiPSC NPCs. These reproducible NPC phenotypes were identified through scalable assays that can be applied to expanded cohorts of SZ patients, making them a potentially valuable tool with which to study the developmental mechanisms contributing to SZ.Molecular Psychiatry advance online publication, 1 April 2014; doi:10.1038/mp.2014.22.
    Molecular Psychiatry 04/2014; · 15.15 Impact Factor
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    ABSTRACT: In Parkinson's disease and dementia with Lewy bodies, α-synuclein aggregates to form oligomers and fibrils; however, the precise nature of the toxic α-synuclein species remains unclear. A number of synthetic α-synuclein mutations were recently created (E57K and E35K) that produce species of α-synuclein that preferentially form oligomers and increase α-synuclein-mediated toxicity. We have shown that acute lentiviral expression of α-synuclein E57K leads to the degeneration of dopaminergic neurons; however, the effects of chronic expression of oligomer-prone α-synuclein in synapses throughout the brain have not been investigated. Such a study could provide insight into the possible mechanism(s) through which accumulation of α-synuclein oligomers in the synapse leads to neurodegeneration. For this purpose, we compared the patterns of neurodegeneration and synaptic damage between a newly generated mThy-1 α-synuclein E57K transgenic mouse model that is prone to forming oligomers and the mThy-1 α-synuclein wild-type mouse model (Line 61), which accumulates various forms of α-synuclein. Three lines of α-synuclein E57K (Lines 9, 16 and 54) were generated and compared with the wild-type. The α-synuclein E57K Lines 9 and 16 were higher expressings of α-synuclein, similar to α-synuclein wild-type Line 61, and Line 54 was a low expressing of α-synuclein compared to Line 61. By immunoblot analysis, the higher-expressing α-synuclein E57K transgenic mice showed abundant oligomeric, but not fibrillar, α-synuclein whereas lower-expressing mice accumulated monomeric α-synuclein. Monomers, oligomers, and fibrils were present in α-synuclein wild-type Line 61. Immunohistochemical and ultrastructural analyses demonstrated that α-synuclein accumulated in the synapses but not in the neuronal cells bodies, which was different from the α-synuclein wild-type Line 61, which accumulates α-synuclein in the soma. Compared to non-transgenic and lower-expressing mice, the higher-expressing α-synuclein E57K mice displayed synaptic and dendritic loss, reduced levels of synapsin 1 and synaptic vesicles, and behavioural deficits. Similar alterations, but to a lesser extent, were seen in the α-synuclein wild-type mice. Moreover, although the oligomer-prone α-synuclein mice displayed neurodegeneration in the frontal cortex and hippocampus, the α-synuclein wild-type only displayed neuronal loss in the hippocampus. These results support the hypothesis that accumulating oligomeric α-synuclein may mediate early synaptic pathology in Parkinson's disease and dementia with Lewy bodies by disrupting synaptic vesicles. This oligomer-prone model might be useful for evaluating therapies directed at oligomer reduction.
    Brain 03/2014; · 10.23 Impact Factor
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    ABSTRACT: Despite therapeutic advancement, pulmonary disease still remains a major cause of morbidity and mortality around the world. Opportunities to study human lung disease either in vivo or in vitro are currently limited. Using induced pluripotent stem cells (iPSCs), we generated mature multiciliated cells in a functional airway epithelium. Robust multiciliogenesis occurred when notch signaling was inhibited and was confirmed by (i) the assembly of multiple pericentrin-stained centrioles at the apical surface, (ii) expression of transcription factor forkhead box protein J1, and (iii) presence of multiple acetylated tubulin-labeled cilia projections in individual cells. Clara, goblet, and basal cells were all present, confirming the generation of a complete polarized epithelial-cell layer. Additionally, cAMP-activated and cystic fibrosis transmembrane regulator inhibitor 172-sensitive cystic fibrosis transmembrane regulator currents were recorded in isolated epithelial cells. Our report demonstrating the generation of mature multiciliated cells in respiratory epithelium from iPSCs is a significant advance toward modeling a number of human respiratory diseases in vitro.
    Proceedings of the National Academy of Sciences 03/2014; · 9.81 Impact Factor
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Publication Stats

77k Citations
6,165.26 Total Impact Points

Institutions

  • 1998–2014
    • Torrey Pines Institute for Molecular Studies
      Port St. Lucie, Florida, United States
    • Université de Montpellier 1
      Montpelhièr, Languedoc-Roussillon, France
    • The Ohio State University
      • Department of Physiology and Cell Biology
      Columbus, OH, United States
    • Sahlgrenska University Hospital
      Goeteborg, Västra Götaland, Sweden
  • 1970–2014
    • Salk Institute
      • Laboratory of Genetics
      La Jolla, California, United States
  • 2013
    • Nagasaki University
      Nagasaki, Nagasaki, Japan
  • 1996–2013
    • Howard Hughes Medical Institute
      Ashburn, Virginia, United States
    • University of Kentucky
      Lexington, Kentucky, United States
    • Simon Fraser University
      Burnaby, British Columbia, Canada
  • 1986–2013
    • University of California, San Diego
      • • Department of Pediatrics
      • • Department of Cellular and Molecular Medicine (CMM)
      • • Department of Neurosciences
      • • Department of Medicine
      San Diego, CA, United States
  • 2012
    • Massachusetts General Hospital
      • Department of Psychiatry
      Boston, Massachusetts, United States
    • Center of Regenerative Medicine in Barcelona
      Barcino, Catalonia, Spain
  • 2003–2011
    • Stony Brook University
      • Department of Neurobiology and Behavior
      Stony Brook, NY, United States
  • 2009
    • ETH Zurich
      • Department of Biology
      Zürich, ZH, Switzerland
    • National University (California)
      San Diego, California, United States
  • 2005–2009
    • National Institute of Advanced Industrial Science and Technology
      • Research Center for Stem Cell Engineering
      Tsukuba, Ibaraki-ken, Japan
    • Universität Bremen
      Bremen, Bremen, Germany
  • 2006–2008
    • University of New Mexico Hospitals
      Albuquerque, New Mexico, United States
    • University of Texas Southwestern Medical Center
      • Department of Molecular Biology
      Dallas, TX, United States
  • 2003–2008
    • University of Wisconsin, Madison
      • • Department of Animal Sciences
      • • Department of Zoology
      Madison, MS, United States
  • 1982–2008
    • Lund University
      • Division of Neurology
      Lund, Skåne, Sweden
  • 2004–2006
    • Fundación Instituto Leloir
      Buenos Aires, Buenos Aires F.D., Argentina
    • Charité Universitätsmedizin Berlin
      • Department of Neurology with Chair in Experimental Neurology/BNIC
      Berlin, Land Berlin, Germany
    • Yale University
      • Department of Neurobiology
      New Haven, CT, United States
    • University of California, Berkeley
      Berkeley, California, United States
  • 2002–2003
    • Max-Delbrück-Centrum für Molekulare Medizin
      Berlín, Berlin, Germany
    • Humboldt-Universität zu Berlin
      Berlín, Berlin, Germany
    • University of Washington Seattle
      • Department of Neurological Surgery
      Seattle, WA, United States
  • 2000–2001
    • Stanford University
      • Department of Neurosurgery
      Palo Alto, California, United States
    • Princeton University
      Princeton, New Jersey, United States
    • Schepens Eye Research Institute
      Boston, Massachusetts, United States
    • Spokane VA Medical Center
      Spokane, Washington, United States
  • 1999
    • Universität Regensburg
      • Department of Neurology
      Regensburg, Bavaria, Germany
  • 1993–1998
    • Kyoto University
      • • Department of Neurosurgery
      • • Department of Neurology
      Kyoto, Kyoto-fu, Japan
    • Georgetown University
      • Department of Pharmacology
      Washington, D. C., DC, United States
  • 1995
    • California Institute of Technology
      • Division of Biology
      Pasadena, CA, United States
  • 1994
    • Monash University (Australia)
      • Monash Medical Centre
      Melbourne, Victoria, Australia
  • 1991–1994
    • University of California, San Francisco
      • Department of Neurology
      San Francisco, CA, United States
    • Neuropsychiatric Research Institute
      Fargo, North Dakota, United States
  • 1990–1991
    • Naval Medical Center San Diego
      San Diego, California, United States
  • 1989
    • University of Utah
      • Department of Psychiatry
      Salt Lake City, UT, United States
    • Johns Hopkins University
      Baltimore, Maryland, United States
    • University of Rochester
      • Department of Neurobiology and Anatomy
      Rochester, NY, United States
  • 1988
    • Karolinska Institutet
      • Institutionen för neurovetenskap
      Solna, Stockholm, Sweden
  • 1987
    • University of Pécs
      • Department of Plant Physiology
      Fuenfkirchen, Baranya county, Hungary
  • 1984
    • Texas Christian University
      Fort Worth, Texas, United States