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…