1. Mouse BIRN
CORE 4: Applications
Background test slide.

2. Extend out from growing strengths in multi- modal multi-scale imaging of the mouse CNS to link up with numerous molecular and genetic resources. ADD LINKAGE to GENOMICS.
Provide a TRANSLATIONAL BRIDGE between mouse and human neurological disease that relies on common disease progression, shared behavior and phenotypes and MOLECULAR SIGNATURES.
VALIDATE models on two or more genetic backgrounds. What features are robust? What generalizes well between mouse and human populations?
University of Tennessee, Institute of Neuroscience Jan 21, 2003.

3. Three models of neurodegeneration
Multiple sclerosis (Voskuhl, MOG EAE model)
Alzheimer’s disease (Jankowsky, Human Tg line)
Parkinson’s disease (Masliah, Human Tg line)

4. General Design
Three stages of progression + control Males and females Two fully sequenced strains (C57BL/6J and DBA/2J) Three replicates (± 2) As many modalities as possible
Diana Price

5. New Modality: mRNA expression level
~40,000 transcript assays
Often use a split design (histo<–>array)
Lumping vs splitting (whole brain)
Will generate modulated transcript sets
Then what?
Analysis of signature lists
Mediation with WebQTL

6. Analysis of disease signature lists with
What is the network connectivity of list members?
What are the mechanistic common denominators of lists?
Are there final common pathways?
How do we ensure high quality lists? (Partial answer: replicate on two genetic backgrounds)

7. Genetic Correlations
with Ken Manly

8. Group A Group B Vamp8 Vamp5 Rapsn Syngr4 Snap23 Syt3 Rnp24 Sybl1 Syt8
Acv1
Syt7
Syt10
Sycp1
Syt5
Group B
Snpa91
Synj2
Sybl1
Syt4
Syt5
Vdp
Vti1b
Rnp24
Vamp3
Sec22l1
Syn2
Syn1
Vapa
Vamp1
Syt11
Vamp4

9. The Two Strains: C57BL/6J and DBA/2J
First two inbred strains made at TJL
Very extensive phenotype and CNS data
Disease susceptibility well characterized
1.8 million defined SNPs
Large RI set
We really want to get down to Levels 3 and 4, but we should work down from higher levels. Variation in cell number may actually be due to a global variation: whole body size differences or whole brain differences. We need the basic data before we can explore the more refined phenotypes.
In this slide on the right side I illustrate on line of research supported by the NIMH in which we are mapping and characterizing the genes (or gene loci) that modulate the size of different cell populations in the brain. Here is red we are interested in the population of dentate granule cells in the hippocampus. These are the only cortical cell population of neurons that are generated at a low level even in adult humans. Virtually all other neuron populations have no renewal capacity. The question we are asking is what genes make this cell population or and brain region so unusual. Can we discover the gene that modulate the proliferation of these neurons using a model such as the mouse?

10. 20 generations brother-sister matings
What are recombinant inbred strains (RI)
female
male
C57BL/6J (B)
DBA/2J (D)
BXD
fully
inbred
chromosome pair
isogenic F1
hetero-
geneous F2
20 generations brother-sister matings
BXD RI
Strain set
Recombined chromosomes are needed for mapping
Inbred
Isogenic
siblings
+ … +
BXD2
BXD80
BXD1

11. Mediation with the MBL
with Glenn Rosen

12. Mouse Brain Library

13. Low-res serial Nissl stain for stereology

14. Mediation with the iScope

15. Clique analysis: Mike Langston, Elissa Chesler

16. Collaborators Lu Lu Ken Manly Jintao Wang Elissa Chesler
David Airey
Jing Gu
Shuhua Qi
Hong Tao Zhang
Arthur Centeno
Yanhua Qu
Ken Manly
Jintao Wang
Michael Langston
Michele Baldwin
Glenn Rosen
National Institute of Mental Health, National Institute on Drug Abuse, and the National Science Foundation (P20-MH 62009)