The Role of HIF-1 in Neurogenic and Behavior Responses to Antidepressants.


Principal Investigator: W TIMOTHY O'BRIEN
Abstract: DESCRIPTION (provided by applicant): Major Depressive Disorder (MDD) is a debilitating mood disorder associated with significant morbidity and mortality. Different classes of antidepressants act through unique mechanisms on specific, yet distinct neurotransmitter systems. It is a noteworthy coincidence that inhibition of glycogen synthase kinase-3 (GSK-3) is a common molecular consequence of treatment with diverse classes of antidepressants as well as mood stabilizers. We have forwarded the hypothesis that GSK-3 is the molecular target of lithium, a mood stabilizer, and modulates several antidepressant-sensitive behaviors. GSK-3 participates in multiple intracellular pathways including Wnt and insulin signaling. In the context of active Wnt signaling, GSK-3 is inhibited, resulting in the accumulation of the transcription factor [unreadable]-catenin. Thus lithium recapitulates Wnt/[unreadable]-catenin signaling by inhibiting GSK-3. During the course of our studies, we found several antidepressant-sensitive behaviors that were similarly affected by lithium. It is an intriguing parallel that lithium and antidepressants inhibi GSK-3 and affect mouse behaviors similarly. Indeed, heterozygous loss of GSK-3b mimicked the effect of antidepressants on these tests. The critical molecular effectors(s) downstream of GSK-3, relevant to the behavioral effects of antidepressant treatment have yet to be identified. This proposal will test the hypothesis that hypoxia-induced factor 1[unreadable] (Hif-1a), recently discovered as a modulator of Wnt/[unreadable]-catenin signaling, is required for the effects of lithium and the antidepressants, imipramine and fluoxetine on behavior. Remarkably, lithium and antidepressants also enhance adult neurogenesis as a common cellular correlate! Enhanced hippocampal neurogenesis has been proposed as an integral component of the response to antidepressant and mood stabilizing therapy, yet little is known regarding the effect of antidepressants on neurogenesis. Wnt/[unreadable]-catenin signaling is critical for adult neurogenesis in the hippocampus. In a recent collaboration we found that Hif-1a regulates Wnt/[unreadable]-catenin transcription in embryonic stem cells and neural stem/progenitor cells but not in differentiated neurons. Neuron-specific deletion of Hif-1a in mice results in a severe adult neurogenesis defect in the hippocampus. Remarkably, the neurogenesis defect in Hif-1a KO mice can be rescued by inhibition of GSK-3 or stabilization of [unreadable]-catenin, both of which activate downstream Wnt signaling. These novel findings demonstrate a requirement for Hif-1a in neurogenesis and a novel mechanism of regulating Wnt/[unreadable]-catenin mediated transcription unique to NSCs. This proposal will test the hypothesis that Hif1a is required for antidepressant-induced enhancement of neurogenesis and that antidepressants act directly on NSCs. This proposal will determine the impact of Hif-1a deletion on Wnt/[unreadable]-catenin signaling and the ability antidepressants to rescue Hif-1a KO phenotypes at the molecular, cellular and behavior level. A new connection between hypoxia signaling and the actions of mood stabilizers and antidepressants could lead to a better understanding of and new approaches for the treatment of affective disorders. PUBLIC HEALTH RELEVANCE: Major Depressive Disorder (MDD) is a debilitating mood disorder associated with significant morbidity and mortality. Enhancement of neurogenesis is required for the effect of antidepressants on several pre-clinical behaviors. However, the mechanisms through which antidepressants act on neural stem/progenitor cells are not fully understood. We recently found that the stem cell niche in the adult hippocampus is relatively hypoxic and mice lacking the hypoxia-induced factor-1[unreadable] (Hif-1a) gene have a profound defect in adult neurogenesis. This proposal explores the hypothesis that Hif-1a regulates adult neurogenesis and plays a central role in the neurogenic and behavioral responses to antidepressants. A new connection between hypoxia signaling and the actions antidepressants could lead to a better understanding of and new approaches to the treatment of affective disorders.
Funding Period: 2012-09-24 - 2014-07-31
more information: NIH RePORT

Detail Information

Research Grants30

  1. Role of sFRP3-Dependent Regulation of Adult Neurogenesis in Antidepressant Action
    Mi Hyeon Jang; Fiscal Year: 2013
    ..PHS 398 (Rev. 11/07) Page 1 Continuation Format Page ..
  2. Comprehensive NeuroAIDS Core Center
    Kamel Khalili; Fiscal Year: 2013
    ..abstract_text> ..
  3. Acute Inhibition of Adult-born Granule Cells and its Effect on Antidepressant Act
    LINDSAY ELSA TANNENHOLZ; Fiscal Year: 2013
    ..These studies will be the first to examine the acute contribution of adult-generated GCs in behavior, as well as determine the mechanism underlying the neurogenesis-dependent behavioral effects of chronic AD treatment. ..
  4. Cellular Mechanisms of Antidepressant Action
    Rene Hen; Fiscal Year: 2013
    ..However, only 25-50% of patients achieve remission. Therefore, there is a considerable need for new therapies. This proposal will lay the groundwork for a totally novel treatment strateav for these disorders...
  5. Harnessing Adult Hippocampal Neurogenesis to Enhance Learning and Modulate Mood
    Amar Sahay; Fiscal Year: 2013
    ..Therefore, the experiments proposed here will attempt to causally link discrete changes in cell-type properties with circuit functions and behavior. ..
  6. In vitro and in vivo study of simvastatin plus lithium in bipolar depression
    Roy H Perlis; Fiscal Year: 2013
  7. CRCNS: Computational Model for Neural Stem Cell Divisions in the Adult Brain
    Alexei Koulakov; Fiscal Year: 2013
    ..Because the lifetime incidence of depression in the US is more than 12% in men and 20% in women, our studies may substantially contribute to public health. ..
  8. Effect of Major Depression and antidepressants on human neurogenesis
    Maura Boldrini; Fiscal Year: 2013
    ..In an exploratory analysis we test the same effects for or lithium. These results have implications for understanding the pathophysiology of depression and the mode of action of antidepressants and lithium treatment. ..
  9. Role of The Circadian Clock in the Development and Treatment of Mood Disorders
    Colleen A McClung; Fiscal Year: 2013
    ..Furthermore, we will determine how the treatments for mania and depression affect behavioral and molecular rhythms, and if these changes are important for therapeutic efficacy. ..
  10. Memory and Mood Enhancing Therapies for Gulf War Illness
    Ashok K Shetty; Fiscal Year: 2013
    ..abstract_text> ..
  11. Interactions Between Depression, Neuroinflammation and Glycogen Synthase Kinase-3
    Eleonore Beurel; Fiscal Year: 2013
    ..Specific Aim 3 will test the hypothesis that GSK3 promotes depression-like behavioral responses to inflammatory and environmental stress. ..
  12. Regulation of CNS viral persistence
    Cornelia Bergmann; Fiscal Year: 2013
    ..Importantly, it will provide valuable information on the interactions of specific CNS cells involved in viral persistence and demyelination and the cellular and soluble mediators of the host immune response...
  13. Effects of lithium on cellular signaling
    Richard S Jope; Fiscal Year: 2013
    ..Altogether, this project will continue to address important problems concerning the causes and treatments of mood disorders. ..
  14. Neuropeptide VGF in Antidepressant-Induced Neurogenesis and Mood Disorders
    Janet Alder; Fiscal Year: 2013
    ..In addition, the neuropeptide VGF may represent a way to regulate proliferation of stem cells which has therapeutic potential. ..
  15. Necessity of Neurogenesis for Antidepressant Efficacy
    TARIQUE DHYAN PERERA; Fiscal Year: 2013
    ..Since we cannot study new neurons in humans we will conduct a project to test this hypothesis in monkeys because of their similarity to humans. ..
  16. Neural stem cells in the aging brain
    GRIGORI N ENIKOLOPOV; Fiscal Year: 2013
    ..Together, our results and genetic tools will provide a framework for studying division and differentiation of stem cells and tissue turnover as an integrated quantitative endeavor. ..
  17. Iowa Cochlear Implant Clinical Research Center Project VI
    Bruce Jay Gantz; Fiscal Year: 2013
    ..The five research projects are highly integrated and depend on data from each other to answer the experimental questions. ..
  18. Prepubertal Stress, Windows of Risk &Sex Bias for Affective Disturbance
    C NEILL NEILL EPPERSON; Fiscal Year: 2013
    ..The Center would provide an intellectual platform with important resources to encourage established investigators, and their mentees, to consider sex and gender as crucial factors in their research. ..
  19. Distinct Embryonic Origin for Postnatal Dentate Neural Stem Cells
    SAMUEL JEREMY PLEASURE; Fiscal Year: 2013
    ..Aim #1: Examine the contribution of the ventral hippocampal ventricular zone to the production of subgranular NSCs throughout the hippocampus. Aim #2: Characterize the roles of various sources of Shh in SGZ development. ..
  20. Substrate-selective inhibition of COX-2 to target affective disorders
    Sachin Patel; Fiscal Year: 2013
  21. Carbon-14 birth dating of Neurons in addiction
    Deborah C Mash; Fiscal Year: 2013
    ..The proposed studies will contribute to an understanding of the neurobiology of drug and alcohol addiction, and may have important implications for the development of novel therapeutic approaches targeted to these cell populations. ..
  22. The Effects of 5-HT Deficiency on Responses to Stress and Antidepressant Drugs
    Benjamin D Sachs; Fiscal Year: 2013
    ..e. neurogenic) consequences of hyposerotonergia in mice and will enhance our understanding of the mechanisms underlying depressive-like behaviors and antidepressant-like responses. ..
    Irwin Lucki; Fiscal Year: 2013
  24. Glutamatergic Mediators of Antidepressant Response in Major Depression
    Brian P Brennan; Fiscal Year: 2013
    ..Third, this study will likely provide additional insights into the role of glutamatergic dysfunction in mood disorders, expanding scientific knowledge of the pathophysiology and potential treatment of MDD. ..