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  • Work by Eric Nestler at UT southwestern and others is examining the genetic, cellular and molecular mechanisms associated with chronic drug use. This research is showing that With initial drug use such as cocaine use Neurons emanating from the ventral tegmental area release dopamine on medium spiny neurons in the NAC. Repeated cocaine use and dopamine release there is an up regulation in the gene transcription factor delta fos B that is believed to result in morphological changes to dendrites and dendritic spines on these neurons.
  • In fact research conducted by Terry Robinson at the university of Michigan shows that that repeated exposure to cocaine in rats leads to increased number of dendritic spines in the nucleus accumbens neurons and increased in dendritic branching. Taken as a whole this research shows that repeated exposure to drugs of abuse causes a cascade of events involving increased gene transcription in regions such as the nucleus accumbens that is believed to be responsible for actual morphological changes in dendrites and synaptic connections and plasticity leading to drug addiction.
  • But, what we do not understand is why some people become addicted and others do not. We know from NIDA supported Twin studies that there is a heritable component to drug addiction. And now with the sequencing of the human genome we are able to ask what are the gene variants associated with drug addiction and what is their functional significance? We have taken a two-pronged approach to begin to answer this question: First NIDA’s intramural program is looking at genetic variants in heterogeneous populations of drug addicted individuals. Second our extramural research program through NIDA’s Genetic consortium and a contract with Perlegen Sciences has just completed a whole genome wide association study to uncover genetics variations associated with Tobacco dependence. A similar approach to uncover the genetic basis of disease now also moving forward under the NIH GAIN (Genetic Association Information Network) and GEI (Genes and Environment Initiative)
  • So what this genome-wide association study is telling us is that Genes associated with drug addiction are those involved with many different aspects of synaptic function and synaptic plasticity and neuronal signaling. For example neurexin is a presynaptic cell adhesion protein that binds with neuroligin in synaptic formation and SYNAP-TO-TAG-MIN is involved in vesicle trafficking and neurotransmitter release.
  • From this research we are now showing that addiction is a complex behavioral, neurobiological and genetic Disorder.
  • New Pathways: This theme of the NIH Roadmap addresses the need to advance our understanding of the daunting complexity of biological systems. Future progress in medicine will require a quantitative understanding of the many interconnected networks of molecules that comprise our cells and tissues, their interactions, and their regulation Research Teams of the Future: NIH wants to stimulate new ways of combining skills and disciplines in both the physical and biological sciences Re-engineering the Clinical Research Enterprise is intended to address these pressing needs by promoting the better integration of existing clinical research networks, encouraging the development of technologies to improve the assessment of clinical outcomes, harmonizing regulatory processes, and enhancing training for clinical researchers. A major goal is to more fully involve and empower the public in the research process.

www.nida.nih.gov/researchtraining/Presentations/Sh... www.nida.nih.gov/researchtraining/Presentations/Sh... Presentation Transcript

  • Research Training Director’s Meeting November 3, 2006 Division of Basic Neuroscience and Behavioral Research (DBNBR ) David Shurtleff, Ph.D. Director
  • DBNBR Goals
      • Identify antecedents and consequences of drug abuse and addiction
      • Develop and exploit new technologies, models, paradigms
      • Identify genetic & developmental vulnerabilities for drug abuse
      • Foster transdisciplinary/integrative research and training
  • Division of Basic Neuroscience and Behavioral Research Office of the Director David Shurtleff, PhD - Director Paul Schnur, PhD - Deputy Director Joni Rutter, PhD- Assoc Director Population & Applied Genetics Christie Baxter, BA – Program Analyst Amira Debbas, BA – Program Analyst Joyce Williams – Program Analyst Technology Development Karen Skinner, PhD Deputy Director for Science and Technology Development
    • Training
    • Charles Sharp, PhD
      • Special Assistant &
      • Training Coordinator
    • Beth Babecki, MA
      • Deputy Training
      • Coordinator
    • Diane Lawrence, PhD
    Functional Neuroscience Research Branch Nancy Pilotte, PhD, Chief Jerry Frankenheim, PhD Diane Lawrence, PhD Geraline Lin, PhD Yu (Woody) Lin, PhD Genetics and Molecular Neurobiology Research Branch Jonathan Pollock, PhD, Chief Christine Colvis, PhD John Satterlee, PhD Da Yu Wu, PhD Behavioral and Cognitive Science Research Branch Minda Lynch, PhD, Chief Tom Aigner, PhD Allison Chausmer, PhD Susan Volman, PhD Cora Lee Wetherington, PhD (Women’s Health Coordinator) Chemistry and Physiological Systems Research Branch Rao Rapaka ,PhD, Chief Paul Hillery, PhD Kevin Gormley Hari Singh, PhD Pushpa Thadani, PhD Dave Thomas, PhD
  • Drug Addiction: A Complex Behavioral and Neurobiological Disorder DRUGS BRAIN MECHANISMS ADDICTION ENVIRONMENT HISTORY - previous history - expectation - learning - social interactions - stress - conditioned stimuli - genetics - circadian rhythms - disease states - gender BIOLOGY
  • Dopamine Dendritic Spines Repeated Drug Abuse Increases Genetic Transcription Resulting in Long-term Structural Changes Adapted from Nestler E.J. Science & Practice Perspectives , 5(1) 2005.
  • Branches 60 55 50 45 11 10 9 8 CTL COC CTL COC Chronic cocaine increases density of dendritic spines and neuronal branching in the nucleus accumbens CTL COC CTL COC Robinson, T.E. & Kolb, B. Eur. J. of Neuro. 1999. Ferrario, C.R. et al. Biol. Psychiatry, 2005.
  • Drug Addiction is a Developmental Disease with High Prevalence in Adolescence NIAAA National Epidemiologic Survey on Alcohol and Related Conditions, 2003 Age 0.0% 0.2% 0.4% 0.6% 0.8% 1.0% 1.2% 1.4% 1.6% 1.8% 5 10 15 21 25 30 35 40 45 50 55 60 65 Percentage in each age group who develop first - time dependence THC ALCOHOL TOBACCO
  • Highly Rewarding Effect of Nicotine/Acetaldehyde During Adolescence Belluzzi, et al., Neuropsychopharmacology, 2005 Apr;30(4):705-12. * ** ** ** ** 0 10 20 30 40 0 1 2 3 4 5 Test Day Mean Self-Injections (Nose-pokes in 3 hr) Nic/Acet 30/16 µg (N=11) Acet 16 µg (N = 8) Nic 30 µg (N=9) Saline 100 µl (N=7) P27 Males
  • Drug Addiction Is Influenced by Interactions of Genes and Environment Twin studies consistently show that there is a heritable component to drug abuse and addiction . What are the gene variants? Extramural Study NIDA/Perlegen/WashU Whole Genome Scan for Nicotine Addiction Intramural Study NIDA Affymetrix 500K screen for Drug Addiction
  • Many of These Genes Have Synaptic Functions Dean and Dresbach, TINS, 2006 CELL ADHESION NEURO- TRANSMISSION SIGNAL TRANSDUCTION TRANSCRIPTION FACTORS { presynaptic postsynaptic { De Camilli et al, 2001 Dendritic Spines
    • Need: Functional validation of gene variant
    • Capitalize on:
      • NIH Knockout Mouse Project
      • High-throughput genetic and RNAi methods
      • Research in GEI (FY11&12)
    • Use genetic models to:
      • Investigate mechanisms of drug dependence
      • Test potential therapeutics
    Genome-wide association scans Gene variants What is the functional significance? Functional Genomics
  • Addiction is a Complex Behavioral, Neurobiological, and Genetic Disorder ENVIRONMENT & DRUG EXPOSURE SYNAPTIC PLASTICITY BRAIN CHANGES GENETIC VARIANTS
  • DBNBR Research Training
    • Framework to enhance cooperative activities among 16 NIH Institutes and Centers
    • Take on challenges in neuroscience that are best met collectively
    • Develop research tools and infrastructure that will serve the entire neuroscience community
    • Research Training Programs
      • Training in Neuroscience Imaging (Steve Grant, PO)
      • Computational Neuroscience (Susan Volman, PO)
      • Neurobiology of Disease (Beth Babecki, PO)
      • Jointly Sponsored Predoctoral Program in the Neurosciences (JSPTPN )
      • (Beth Babecki, PO)
  • NIH Roadmap FOR Medical Research
    • TransNIH initiative for a more efficient and productive system of medical research
    • Identifies themes in three main areas for support:
      • New pathways to discovery
      • Research teams of the future
      • Re-engineering the clinical research enterprise
    • NIDA lead on Interdisciplinary Research Training initiative
      • Support didactic and research experiences designed to provide students with the knowledge and research experiences necessary to develop interdisciplinary solutions
      • Allison Chausmer (lead program officer)
  • Career Development Plan Yes Do I have pilot data? No No Apply for R03, BSTART or ISTART Do I need more training or changing career emphasis? Institutional Pre-Doctoral Fellowship-T32 Pre-Doctoral Fellowship-F31 Post-Doctoral Fellowship-F32 Institutional Post-Doctoral Fellowship-T32 R01 Yes Apply for Mentored K * Contact Program * * *
  • Mentored Career Development Awards
    • Mentored Research Scientist Development Award (K01)
    • NIH Pathway to Independence (PI) Award (K99/R00)
    • Mentored Clinical Scientist Development Award (K08)
    • Mentored Quantitative Research Career Development Award (K25)
    • Mentored Patient-Oriented Research Career Development Award (K23)
  • Progress Review of T32s
    • Trainee progress (publications, placement, mentors)
    • Program features and changes (breadth, student diversity, scientific diversity)
    • Interactions
      • Scientific
      • Career development
    • Use of slots (level, length, throughput, transition to independence)
    • Contingency planning for gaps in funding (last year of T32)- Looking beyond supplements
  • Enhancing the Training Experience
    • Scientific Meetings
      • NIDA/SfN Mini-convention
        • Poster presentation
        • Travel awards
    • Networking
      • CPDD/ INRC/ SNIP etc. training mixers
      • NIDA/SfN Mini-convention/NIDA exhibit
    • Grantsmanship
      • CPDD Grant writing workshop/tutorial
      • SFN NIH Professional “Survival” Skills Workshop
    • NIDA-supported Scientific Training
      • Cold Spring Harbor
      • Summer Institute
      • Woods Hole
  • DBNBR Training Coordinators Charles Sharp: [email_address] - - 301-443-1887 Beth Babecki : [email_address] 301-443-1887 Diane Lawrence : [email_address] 301-443-1887