Drug dependence is linked to decreased volume of limbic-related structures and to altered hippocampal morphology. Clinically, drug dependence is associated with limbic- and hippocampal-related symptoms, such as alterations in affect and emotion, and deficits in learning and memory. Clarification of the time course, extent, and cause of the changes in hippocampal structure and function will likely improve our understanding and treatment of addiction. One aspect of hippocampal plasticity potentially important for addiction research is the ability of the hippocampus to make new neurons throughout adulthood. Evidence suggests that the new hippocampal neurons are functionally integrated into hippocampal circuitry, and are involved in aspects of learning and memory. While much has been learned about what increases and decreases the number of new cells in the hippocampus, little progress has been made in identifying the cellular mechanisms underlying the regulation of adult hippocampus neurogenesis. This proposal is designed to explore how opiates regulate adult neurogenesis, and to explore the potential consequences of opiate-induced alterations in adult neurogenesis. There are three aspects to this proposal: a) We have shown that chronic, but not acute, opiate exposure inhibits the birth of new neurons in the adult hippocampus (Eisch et al., 2000). We will characterize the opiate-induced inhibition of adult neurogenesis by examining the time course of inhibition and alterations in the cell cycle. We also present data that a subset of newly born cells in the adult hippocampus express mu-opioid receptors. We will explore if mu-opioid receptor expression fluctuates across the cell cycle. b) We present data that certain cytokines and growth factors are decreased in the hippocampus after chronic morphine. To understand how morphine-induced changes in these factors alter adult neurogenesis, we will determine the time course of these changes relative to morphine exposure and explore if newly born hippocampal cells express receptors for these cytokines and growth factors. c) We present data that the morphine-induced decrease in adult hippocampal neurogenesis correlates with decreased hippocampal function. We will fully explore the deficit in hippocampal functioning caused by chronic morphine, particularly in relation to morphine-induced changes in adult neurogenesis and hippocampal levels of certain cytokines and growth factors. Examination of opiate-induced alterations of adult neurogenesis holds significant potential for testing the hypothesis that new neurons are important for learning and memory. In addition, comprehension of how opiates act to inhibit new neurons in the adult hippocampus will likely shed light on the basic mechanisms regulating neural stem cells. Importantly, such studies will improve our understanding of the complex mechanisms by which opiates affect brain function.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA016765-02
Application #
6891354
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Pilotte, Nancy S
Project Start
2004-05-01
Project End
2009-03-31
Budget Start
2005-04-01
Budget End
2006-03-31
Support Year
2
Fiscal Year
2005
Total Cost
$312,000
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Psychiatry
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
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Whoolery, Cody W; Walker, Angela K; Richardson, Devon R et al. (2017) Whole-Body Exposure to 28Si-Radiation Dose-Dependently Disrupts Dentate Gyrus Neurogenesis and Proliferation in the Short Term and New Neuron Survival and Contextual Fear Conditioning in the Long Term. Radiat Res 188:532-551
Yun, Sanghee; Donovan, Michael H; Ross, Michele N et al. (2016) Stress-Induced Anxiety- and Depressive-Like Phenotype Associated with Transient Reduction in Neurogenesis in Adult Nestin-CreERT2/Diphtheria Toxin Fragment A Transgenic Mice. PLoS One 11:e0147256
Petrik, David; Latchney, Sarah E; Masiulis, Irene et al. (2015) Chromatin Remodeling Factor Brg1 Supports the Early Maintenance and Late Responsiveness of Nestin-Lineage Adult Neural Stem and Progenitor Cells. Stem Cells 33:3655-65
Cho, Kyung-Ok; Lybrand, Zane R; Ito, Naoki et al. (2015) Aberrant hippocampal neurogenesis contributes to epilepsy and associated cognitive decline. Nat Commun 6:6606
Latchney, Sarah E; Jaramillo, Thomas C; Rivera, Phillip D et al. (2015) Chronic P7C3 treatment restores hippocampal neurogenesis in the Ts65Dn mouse model of Down Syndrome [Corrected]. Neurosci Lett 591:86-92
Latchney, Sarah E; Jiang, Yindi; Petrik, David P et al. (2015) Inducible knockout of Mef2a, -c, and -d from nestin-expressing stem/progenitor cells and their progeny unexpectedly uncouples neurogenesis and dendritogenesis in vivo. FASEB J 29:5059-71
Rivera, Phillip D; Raghavan, Ramya K; Yun, Sanghee et al. (2015) Retrieval of morphine-associated context induces cFos in dentate gyrus neurons. Hippocampus 25:409-14
Walker, A K; Rivera, P D; Wang, Q et al. (2015) The P7C3 class of neuroprotective compounds exerts antidepressant efficacy in mice by increasing hippocampal neurogenesis. Mol Psychiatry 20:500-8
DeCarolis, Nathan A; Rivera, Phillip D; Ahn, Francisca et al. (2014) 56 Fe Particle Exposure Results in a Long-Lasting Increase in a Cellular Index of Genomic Instability and Transiently Suppresses Adult Hippocampal Neurogenesisin Vivo. Life Sci Space Res (Amst) 2:70-79

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