Fred H Gage

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

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Publications (750)6660.84 Total impact

  • Biological psychiatry 04/2015; 77(8). DOI:10.1016/j.biopsych.2015.02.021 · 9.47 Impact Factor
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    ABSTRACT: Neurons utilize mitochondrial oxidative phosphorylation (OxPhos) to generate energy essential for survival, function, and behavioral output. Unlike most cells that burn both fat and sugar, neurons only burn sugar. Despite its importance, how neurons meet the increased energy demands of complex behaviors such as learning and memory is poorly understood. Here we show that the estrogen-related receptor gamma (ERRγ) orchestrates the expression of a distinct neural gene network promoting mitochondrial oxidative metabolism that reflects the extraordinary neuronal dependence on glucose. ERRγ(-/-) neurons exhibit decreased metabolic capacity. Impairment of long-term potentiation (LTP) in ERRγ(-/-) hippocampal slices can be fully rescued by the mitochondrial OxPhos substrate pyruvate, functionally linking the ERRγ knockout metabolic phenotype and memory formation. Consistent with this notion, mice lacking neuronal ERRγ in cerebral cortex and hippocampus exhibit defects in spatial learning and memory. These findings implicate neuronal ERRγ in the metabolic adaptations required for memory formation. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell metabolism 04/2015; 21(4):628-636. DOI:10.1016/j.cmet.2015.03.004 · 16.75 Impact Factor
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    ABSTRACT: Newborn granule neurons generated from neural progenitor cells (NPCs) in the adult hippocampus play a key role in spatial learning and pattern separation. However, the molecular mechanisms that control activation of their neurogenic program remain poorly understood. Here, we report a novel function for the pluripotency factor sex-determining region Y (SRY)-related HMG box 2 (SOX2) in regulating the epigenetic landscape of poised genes activated at the onset of neuronal differentiation. We found that SOX2 binds to bivalently marked promoters of poised proneural genes [neurogenin 2 (Ngn2) and neurogenic differentiation 1 (NeuroD1)] and a subset of neurogenic genes [e.g., SRY-box 21 (Sox21), brain-derived neurotrophic factor (Bdnf), and growth arrest and DNA-damage-inducible, beta (Gadd45b)] where it functions to maintain the bivalent chromatin state by preventing excessive polycomb repressive complex 2 activity. Conditional ablation of SOX2 in adult hippocampal NPCs impaired the activation of proneural and neurogenic genes, resulting in increased neuroblast death and functionally aberrant newborn neurons. We propose that SOX2 sets a permissive epigenetic state in NPCs, thus enabling proper activation of the neuronal differentiation program under neurogenic cue.
    Proceedings of the National Academy of Sciences 03/2015; DOI:10.1073/pnas.1421480112 · 9.81 Impact Factor
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    ABSTRACT: In the mammalian hippocampus, canonical Wnt signals provided by the microenvironment regulate the differentiation of adult neural stem cells (NSCs) toward the neuronal lineage. Wnts are part of a complex and diverse set of signaling pathways and the role of Wnt/Planar cell polarity (PCP) signaling in adult neurogenesis remains unknown. Using in vitro assays on differentiating adult NSCs, we identified a transition of Wnt signaling responsiveness from Wnt/β-catenin to Wnt/PCP signaling. In mice, retroviral knockdown strategies against ATP6AP2, a recently discovered core protein involved in both signaling pathways, revealed that its dual role is critical for granule cell fate and morphogenesis. We were able to confirm its dual role in neurogenic Wnt signaling in vitro for both canonical Wnt signaling in proliferating adult NSCs and non-canonical Wnt signaling in differentiating neuroblasts. Although LRP6 appeared to be critical for granule cell fate determination, in vivo knockdown of PCP core proteins FZD3 and CELSR1-3 revealed severe maturational defects without changing the identity of newborn granule cells. Furthermore, we found that CELSR1-3 control distinctive aspects of PCP-mediated granule cell morphogenesis with CELSR1 regulating the direction of dendrite initiation sites and CELSR2/3 controlling radial migration and dendritic patterning. The data presented here characterize distinctive roles for Wnt/β-catenin signaling in granule cell fate determination and for Wnt/PCP signaling in controlling the morphological maturation of differentiating neuroblasts. Copyright © 2015 the authors 0270-6474/15/354983-16$15.00/0.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 03/2015; 35(12):4983-98. DOI:10.1523/JNEUROSCI.4130-14.2015 · 6.75 Impact Factor
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  • Proceedings of the National Academy of Sciences 01/2015; DOI:10.1073/pnas.1504393112 · 9.81 Impact Factor
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    Wei Deng, Fred H Gage
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    ABSTRACT: The neurogenesis hypothesis of depression is based on the correlation between the rate of adult hippocampal neurogenesis and the affective status of rodents. However, studies investigating the role of neurogenesis in the causation of mood regulation have reported inconsistent results. Here, we explored whether the affective state can be affected differentially by adult-born neurons with distinctive physiological characteristics at different maturation stages. We revealed that reducing the immature newborn neuron population had no effect on anxiety- or depression-like behaviors in an array of tests; however, it enhanced hyponeophagia in a novelty suppressed feeding test, but only when the novel environment was drastically different from the home cage. We further demonstrated that reducing the immature newborn neuron population led to delayed habituation to a novel environment and impaired contextual learning. Hence, rather than being directly involved in mood regulation, our studies raise the possibility that adult neurogenesis may influence hyponeophagia through its role in mnemonic processing.
    Frontiers in Systems Neuroscience 01/2015; 9:34. DOI:10.3389/fnsys.2015.00034
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  • Sebastian Jessberger, Fred H. Gage
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    ABSTRACT: Neural stem/progenitor cells (NSPCs) generate new neurons in the mammalian brain throughout life. Over the past two decades, substantial progress has been made in deciphering the cellular and molecular mechanisms underlying adult neurogenesis and in understanding the role played by new neurons in brain function in animal models of health and disease. By contrast, knowledge regarding the extent and relevance of neurogenesis in the adult human brain remains scant. Here we review new concepts about how new neurons shape adult brain circuits, discuss fundamental, unanswered questions about stem cell-associated neural plasticity, and illustrate how the gap between the animal-based basic research and current efforts to analyze life-long neuronal development of the human brain may be overcome by using novel experimental strategies.
    Trends in Cell Biology 10/2014; DOI:10.1016/j.tcb.2014.07.003 · 12.31 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. DOI:10.1152/physrev.00004.2014 · 29.04 Impact Factor
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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; 25(3). DOI:10.1002/hipo.22380 · 4.30 Impact Factor
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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.
    09/2014; 3(4). DOI:10.1016/j.stemcr.2014.08.001
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    ABSTRACT: New neurons are continuously added to the hippocampus of adult mammals. Their survival and integration into the circuitry are highly dependent on experience. Here we show that mushroom spine formation in newborn granule cells was modulated by experience and that dendritic segments in different areas of the molecular layer were differentially regulated. Specifically, spines of new neurons in the outer molecular layer of the dentate gyrus were more readily influenced by non-spatial features in the living environment. Those in the middle molecular layer were more likely to be influenced by the size of the living environment. Therefore, the activity of cortical inputs into newborn granule cells may be reflected in the formation of mushroom spines in different dendritic segments in the molecular layer. J. Comp. Neurol., 2014. © 2014 Wiley Periodicals, Inc.
    The Journal of Comparative Neurology 08/2014; 522(12). DOI:10.1002/cne.23581 · 3.51 Impact Factor
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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; 19(11). DOI:10.1038/mp.2014.87 · 15.15 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 08/2014; DOI:10.1002/hipo.22304 · 4.30 Impact Factor
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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; DOI:10.1038/nrn3730 · 31.38 Impact Factor
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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. DOI:10.1016/j.neuron.2014.05.035 · 15.98 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 06/2014; 141(12):2366-75. DOI:10.1242/dev.096776 · 6.27 Impact Factor
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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; DOI:10.1093/hmg/ddu205 · 6.68 Impact Factor
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Publication Stats

96k Citations
6,660.84 Total Impact Points

Institutions

  • 1999–2014
    • Torrey Pines Institute for Molecular Studies
      Port St. Lucie, Florida, United States
  • 1986–2014
    • University of California, San Diego
      • • Department of Neurosciences
      • • Department of Medicine
      San Diego, California, United States
    • Colorado State University
      Fort Collins, Colorado, United States
  • 1970–2014
    • Salk Institute
      • Laboratory of Genetics
      لا هویا, California, United States
  • 2008
    • University of Wisconsin, Madison
      • Department of Animal Sciences
      Madison, MS, United States
  • 1996–2008
    • Howard Hughes Medical Institute
      Ashburn, Virginia, United States
  • 1982–2008
    • Lund University
      • • Division of Neurology
      • • Department of Surgery
      Lund, Skåne, Sweden
  • 2005
    • Università degli Studi di Sassari
      Sassari, Sardinia, Italy
    • National Institute of Advanced Industrial Science and Technology
      • Research Center for Stem Cell Engineering
      Tsukuba, Ibaraki-ken, Japan
  • 2004
    • Fundación Instituto Leloir
      Buenos Aires, Buenos Aires F.D., Argentina
    • Kumamoto University
      Kumamoto, Kumamoto, Japan
  • 2003
    • Humboldt-Universität zu Berlin
      Berlín, Berlin, Germany
  • 2002
    • University of Washington Seattle
      • Department of Neurological Surgery
      Seattle, Washington, United States
  • 2001
    • Stanford University
      Palo Alto, California, United States
  • 2000
    • Universität Regensburg
      Ratisbon, Bavaria, Germany
    • University of California, Davis
      Davis, California, United States
  • 1998
    • Sahlgrenska University Hospital
      • Department of Cardiology
      Goeteborg, Västra Götaland, Sweden
  • 1995
    • California Institute of Technology
      • Division of Biology
      Pasadena, CA, United States
  • 1994
    • Massachusetts Institute of Technology
      • Department of Biology
      Cambridge, Massachusetts, United States
  • 1991–1994
    • University of California, San Francisco
      • Department of Neurology
      San Francisco, CA, United States
    • University of Utah
      • Department of Pharmacology and Toxicology
      Salt Lake City, Utah, United States
    • Neuropsychiatric Research Institute
      Fargo, North Dakota, United States
  • 1993
    • Kyoto University
      • Department of Neurology
      Kyoto, Kyoto-fu, Japan
  • 1990–1991
    • Naval Medical Center San Diego
      San Diego, California, United States
    • University of San Diego
      San Diego, California, United States
  • 1974–1991
    • Johns Hopkins University
      • Department of Neuroscience
      Baltimore, Maryland, United States
  • 1989
    • Harvard University
      Cambridge, Massachusetts, United States
    • CSU Mentor
      Long Beach, California, United States
    • Case Western Reserve University
      Cleveland, Ohio, United States
  • 1984
    • University of Glasgow
      Glasgow, Scotland, United Kingdom
  • 1978–1984
    • Texas Christian University
      • Department of Psychology
      Fort Worth, Texas, United States