Genomic Mapping of Hippocampus

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This was a presentation I gave to a journal club seminar on how neurogenomics can be used to accurately map the regions of the brain.

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Genomic Mapping of Hippocampus

  1. 1. Genomic Anatomy of the Hippocampus Carol Thompson 1 , Sayan Pathak 1 , Andreas Jeromin 1 , Lydia Ng 1 , Cameron MacPherson 2 , Marty Mortrud,1 Allison Cusick,1 Zackery Riley 1 , Susan Sunkin 1 , Amy Bernard 1 , Ralph Puchalski 1 , Fred Gage 3 , Allan Jones 1 , Vladimir Bajic 2 , Michael Hawrylycz, 1 and Ed Lein 1 1 Allen Institute for Brain Science, Seattle, WA 98103, USA 2 South African National Bioinformatics Institute, University of the Western Cape, Bellville 7535, Cape Town, South Africa 3 Salk Institute for Biological Studies, La Jolla, CA 92037, USA
  2. 2. Authors <ul><li>Allen Institute for Brain </li></ul><ul><li>Science, Washington </li></ul><ul><li>Carol L. Thompson </li></ul><ul><li>Sayan D. Pathak </li></ul><ul><li>Andreas Jeromin </li></ul><ul><li>Lydia L. Ng </li></ul><ul><li>Marty T. Mortrud </li></ul><ul><li>Allison Cusick </li></ul><ul><li>Zackery L. Riley </li></ul><ul><li>Susan M. Sunkin </li></ul><ul><li>Amy Bernard </li></ul><ul><li>Ralph B. Puchalski </li></ul><ul><li>Allan R. Jones </li></ul><ul><li>Michael J. Hawrylycz </li></ul><ul><li>Ed S. Lein </li></ul>Allan R. Jones, Chief Scientific Officer Michael J. Hawrylycz, Director of Informatics Ed S. Lein, Director in Neuroscience Ralph B. Puchalski, Research Alliance Manager Susan M. Sunkin, Research Alliance Manager
  3. 3. Authors Continued <ul><li>South African National Bioinformatics Institute, University of the Western Cape, South Africa </li></ul>Salk Institute for Biological Studies, California Vladimir B. Bajic, Director Cameron R. MacPherson, PhD Student Fred H. Gage, Chair for Research on Age-Related Neurodegenerative Diseases
  4. 4. What is the Hippocampus? Temporal lobe Hippocampus
  5. 5. Why do we care? <ul><li>The Hippocampus is a major part of the limbic system – involved in long-term memory and spatial navigation. </li></ul><ul><li>Codes for context – the “when” and “where” of memory (experience). </li></ul>
  6. 6. No Hippocampus = Anterograde Amnesia <ul><li>Anterograde amnesia is the inability to form new memories (still able to remember things before damage, and to function in all other ways). </li></ul><ul><li>The case of HM </li></ul>HM Interview
  7. 7. Other Famous Cases <ul><li>EP – Discovered procedural memory (took the same test over and over again for three weeks and got better, but had no idea why… each time he thought it was the first time taking the test). </li></ul><ul><li>Memento </li></ul>
  8. 8. Discovery of LTP <ul><li>Primary Messenger system (NMDA receptors ‘recruit’ more AMPA receptor activation </li></ul><ul><li>Secondary Messenger System – Genetic changes (New synapse structures) </li></ul>
  9. 9. How does it work? <ul><li>Entorhinal cortex -> Dentate Gyrus (DG) -> CA3 -> CA1 -> Cortex </li></ul>Cajal’s Hippocampus (1911)
  10. 10. A Conceptual Model: EC DG CA3 CA1 ParaHp- Sensory components of “where” Perirhinal-Sensory components of object identity = “what” Other sensory inputs
  11. 11. How do we study it? <ul><li>Mice/Rats </li></ul><ul><li>Birds </li></ul>
  12. 12. How do we study it? Histology – slice up the brain into fine slices and examine them under the microscope Nissl Stains of the hippocampus
  13. 13. Problems with what we know <ul><li>Different studies tend to yield different results about the how… where do these ‘memories’ go when they leave the hippocampus? </li></ul><ul><li>Maybe subregions of the hippocampus can be isolated with unique functions? </li></ul>
  14. 14. Genomic Anatomy <ul><li>Brodmann’s map of cortex based on differences in cellular morphology </li></ul><ul><li>By mapping out hundreds/thousands of genes, you can do even better! </li></ul>
  15. 15. Allen Brain Atlas (ABA) List of In Situ Hybridization data for entire genome!
  16. 16. In Situ Hybridization
  17. 17. Nonnegative Matrix Factorization x This is a way to break down huge data sets into workable amounts that you can then compare against each other. 98 59 112 73 34 91 64 33 78 7 8 9 6 7 2 5 6 3 8 0 9 3 4 5 2 3 1
  18. 18. Hierarchical clustering of voxel-based hippocampal gene expression data <ul><li>Used a measure of expression “energy” between voxels in a data grid. </li></ul>
  19. 19. What Happened?
  20. 20. NMF Data Matches our Known Anatomy!
  21. 21. Can we do better?
  22. 22. 9 Subregions of CA3
  23. 23. Can we do better? <ul><li>Using genes that code for ‘border’ proteins (between two genes), map out boundaries for the regions. </li></ul><ul><li>Identify what types of gene products are at these boundaries -- Cell Adhesion Molecules (cam), ion channel regulators, and transcriptional regulators = Determine axonal growth. </li></ul>
  24. 24. 3-D Models of Hippocampus <ul><li>Segregated brain into ‘voxels’ (computer generated pixels), then combined them into a 3D structure. </li></ul>
  25. 25. Retrograde Tracing <ul><li>Goes in from the synapse to the cell body </li></ul>
  26. 26. Subregions = Functionally Different? <ul><li>Layers of path-specific neurons </li></ul><ul><li>If where they go is different, they should be functionally different </li></ul>
  27. 27. Conclusion <ul><li>The Hippocampus is split into 4 major areas (DG, CA1, CA3, and temporal area ~ CA2) </li></ul><ul><li>CA1 and DG are uniform, but CA3 has multiple subregions. Some connect into septum. </li></ul>EC DG CA1 CA3
  28. 28. Future Research <ul><li>Find out where they go – Determine function from the entire network. </li></ul><ul><li>Learn molecular function for each of the genes </li></ul><ul><li>Build a brain… </li></ul>

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