Genomic Mapping of Hippocampus
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Transcript of Genomic Mapping of Hippocampus
Genomic Genomic Anatomy of the Anatomy of the HippocampusHippocampus
Carol ThompsonCarol Thompson11, Sayan Pathak, Sayan Pathak11, Andreas Jeromin, Andreas Jeromin11, Lydia , Lydia NgNg11, Cameron MacPherson, Cameron MacPherson22, Marty Mortrud,1 Allison , Marty Mortrud,1 Allison
Cusick,1 Zackery RileyCusick,1 Zackery Riley11, Susan Sunkin, Susan Sunkin11, Amy Bernard, Amy Bernard11, Ralph , Ralph PuchalskiPuchalski11, Fred Gage, Fred Gage33, Allan Jones, Allan Jones11, Vladimir Bajic, Vladimir Bajic22, Michael , Michael
Hawrylycz, Hawrylycz, 11 and Ed Lein and Ed Lein11
1 1 Allen Institute for Brain Science, Seattle, WA 98103, USAAllen Institute for Brain Science, Seattle, WA 98103, USA2 2 South African National Bioinformatics Institute, University of South African National Bioinformatics Institute, University of the the Western Cape, Bellville 7535, Cape Town, South AfricaWestern Cape, Bellville 7535, Cape Town, South Africa3 3 Salk Institute for Biological Studies, La Jolla, CA 92037, USASalk Institute for Biological Studies, La Jolla, CA 92037, USA
AuthorsAuthorsAllen Institute for BrainScience, Washington Carol L. Thompson Sayan D. Pathak Andreas Jeromin Lydia L. Ng Marty T. Mortrud Allison Cusick Zackery L. Riley Susan M. Sunkin Amy Bernard Ralph B. Puchalski Allan R. Jones Michael J. Hawrylycz Ed S. Lein
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
Authors ContinuedAuthors Continued
South African National Bioinformatics Institute, University of the Western Cape, South Africa
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
What is the What is the Hippocampus?Hippocampus?
Temporallobe
Hippocampus
Why do we care?Why do we care?
The Hippocampus is a major part of The Hippocampus is a major part of the limbic system – involved in long-the limbic system – involved in long-term memory and spatial navigation.term memory and spatial navigation.
Codes for context – the “when” and Codes for context – the “when” and “where” of memory (experience). “where” of memory (experience).
No Hippocampus = No Hippocampus = Anterograde AmnesiaAnterograde Amnesia
Anterograde amnesia is the inability Anterograde amnesia is the inability to form new memories (still able to to form new memories (still able to remember things before damage, remember things before damage, and to function in all other ways).and to function in all other ways).
The case of HMThe case of HM
HM Interview
Other Famous CasesOther Famous Cases
EP – Discovered procedural memory EP – Discovered procedural memory (took the same test over and over (took the same test over and over again for three weeks and got again for three weeks and got better, but had no idea why… each better, but had no idea why… each time he thought it was the first time time he thought it was the first time taking the test).taking the test).
MementoMemento
Discovery of LTPDiscovery of LTP Primary Messenger Primary Messenger
system (NMDA system (NMDA receptors ‘recruit’ receptors ‘recruit’ more AMPA more AMPA receptor activationreceptor activation
Secondary Secondary Messenger System Messenger System – Genetic changes – Genetic changes (New synapse (New synapse structures) structures)
How does it work?How does it work?
Entorhinal cortex -> Dentate Gyrus (DG) -Entorhinal cortex -> Dentate Gyrus (DG) -> CA3 > CA3 -> CA1 -> Cortex-> CA1 -> Cortex
Cajal’s Hippocampus (1911)
A Conceptual Model:A Conceptual Model:
ECDG
CA3CA1
ParaHp-Sensory components of “where”
Perirhinal-Sensory components of object identity = “what”
Other sensory inputs
How do we study it?How do we study it?
Mice/RatsMice/Rats BirdsBirds
How do we study it?How do we study it?
Histology – slice up the brain into fine slices and examine them under the microscope
Nissl Stains of the hippocampus
Problems with what we Problems with what we knowknow
Different studies tend to yield Different studies tend to yield different results about the how… different results about the how… where do these ‘memories’ go when where do these ‘memories’ go when they leave the hippocampus?they leave the hippocampus?
Maybe subregions of the Maybe subregions of the hippocampus can be isolated with hippocampus can be isolated with unique functions?unique functions?
Genomic AnatomyGenomic Anatomy
Brodmann’s map Brodmann’s map of cortex based on of cortex based on differences in differences in cellular cellular morphologymorphology
By mapping out By mapping out hundreds/thousandhundreds/thousands of genes, you s of genes, you can do even better!can do even better!
Allen Brain Atlas (ABA)Allen Brain Atlas (ABA)
List of In Situ Hybridization data for entire genome!
In Situ HybridizationIn Situ Hybridization
Nonnegative Matrix Nonnegative Matrix FactorizationFactorization
7878 3333 6464
9191 3434 7373
111122
5959 9898
33 66 55
22 77 66
99 88 77
x11 33 22
55 44 33
99 00 88
This is a way to break down huge data sets into workable amounts that you can then compare against each other.
Hierarchical clustering of voxel-based hippocampal gene expression data
Used a measure of expression “energy” Used a measure of expression “energy” between voxels in a data grid. between voxels in a data grid.
What Happened?What Happened?
NMF Data Matches our NMF Data Matches our Known Anatomy!Known Anatomy!
Can we do better?Can we do better?
9 Subregions of CA39 Subregions of CA3
Can we do better?Can we do better?
Using genes that code for ‘border’ Using genes that code for ‘border’ proteins (between two genes), map out proteins (between two genes), map out boundaries for the regions.boundaries for the regions.
Identify what types of gene products Identify what types of gene products are at these boundaries -- Cell are at these boundaries -- Cell Adhesion Molecules (cam), ion channel Adhesion Molecules (cam), ion channel regulators, and transcriptional regulators, and transcriptional regulators = Determine axonal growth.regulators = Determine axonal growth.
3-D Models of 3-D Models of HippocampusHippocampus
Segregated brain into ‘voxels’ Segregated brain into ‘voxels’ (computer generated pixels), then (computer generated pixels), then combined them into a 3D structure.combined them into a 3D structure.
Retrograde TracingRetrograde Tracing
Goes in from the synapse to the cell Goes in from the synapse to the cell bodybody
Subregions = Functionally Subregions = Functionally Different?Different?
Layers of path-specific neuronsLayers of path-specific neurons If where they go is different, they If where they go is different, they
should be functionally differentshould be functionally different
ConclusionConclusion
The Hippocampus is split into 4 The Hippocampus is split into 4 major areas (DG, CA1, CA3, and major areas (DG, CA1, CA3, and temporal area ~ CA2)temporal area ~ CA2)
CA1 and DG are uniform, but CA3 CA1 and DG are uniform, but CA3 has multiple subregions. Some has multiple subregions. Some connect into septum.connect into septum.
ECDG
CA1CA3
Future ResearchFuture Research
Find out where they go – Determine Find out where they go – Determine function from the function from the entireentire network. network.
Learn molecular function for each of Learn molecular function for each of the genesthe genes
Build a brain…Build a brain…