john crabbe, ph.d. portland alcohol research center department of behavioral neuroscience oregon...
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John Crabbe, Ph.D.Portland Alcohol Research Center
Department of Behavioral Neuroscience
Oregon Health & Science University
VA Medical Center
Genetic Animal ModelsNeurobiology of Disease Toolbox
May 2, 2007
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Collaborators
PortlandPam MettenKari BuckJohn BelknapDeb FinnTamara PhillipsJeanna WheelerHelen Kamens
University of Windsor)Doug Wahlsten
Monell Chemical Senses InstituteAlex Bachmanov
University of TexasSue Bergeson
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G X E Interaction
Risk Factors for Substance Abuse
GENETIC ENVIRONMENTAL
Specific genes
FamilyPeersWorkComorbidityEarly onset
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Alcoholism
Depression Anxiety
Substance Abuse is Comorbid with Many Psychiatric Diagnoses and Personality Traits
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Alcoholism
ADHD Impulsivity
Substance Abuse is Comorbid with Many Psychiatric Diagnoses and Personality Traits
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Behaviors are Usually Complex Genetic Traits
MULTIGENIC: Several genes contribute
POLYGENIC: Each gene exerts only a small influence
Such traits are quantitative (distributed continuously) rather than qualitative (all-or-none) in populations
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Genes A,B,C, and D converge to influence Trait X, and may interact (epistasis)
Genes B,C, and D all influence both Traits X and Y (pleiotropy)
Genetic influences on traits depend on the environment, and differentially so throughout lifespan
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Thanks to Kathleen Merikangas
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Data Supporting Genetic Influences
• 4-fold increased in risk in 1o relatives
• Adopted away children have 4-fold increased risk
• Identical vs fraternal twins (2:1 risk ratio)
• Work with genetic animal models
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What Behaviors do We Currently Model in Animals?
• Self-administration
• Intoxication
• Tolerance and/or sensitization
• Withdrawal severity
• Reinforcement
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DSM-IV Diagnostic Criteria for Substance Dependence
• Tolerance
• Withdrawal
• Use greater than intended
• Loss of control
• Much time spent…,
• at expense of important activities
• Persistence despite problems
(4 symptoms within a year)
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Courtesy of Russ Fernald
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Advantages of the Mouse for Genetic Studies
• A dense map of the mouse genome now exists
• The mouse and human genetic maps are very similar (~ 80%)
• Mice are a reasonably intelligent mammalian species
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Inbred Strains
• Within an inbred strain, all same-sex animals are essentially clones
• Within a strain, individual differences are largely due to environmental effects.
• Across inbred strain mean responses, genetic differences are the most likely influence.
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Uses of Inbred Strains
• “Quiet” genetic background on which to explore targeted gene effects
• Identify genetically correlated traits (i.e., pleiotropic gene effects)
• Explore environmental dependence of genetic effects (i.e., GXE interaction), i.e., the instability of genetic correlations across tasks and/or environmental conditions
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McClearn & Rodgers, Q J Stud Alc 20:691 (1959)
Two-bottle Preference for 10% EtOH vs Water in 3 Inbred Mouse Strains
C57BL/6 DBA/2
C3H/NT
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Wahlsten, et al, PNAS 103:16364 (2006)
Two-bottle Preference, 10% EtOH vs Water
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How Not to Use Inbred Strains
Low progesterone leads to high sensitivity to sigma1 receptor ligands which leads to increased cocaine reward, and cocaine dependence
C57SW
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Brain progesterone content (ng/g)
Co
ndi
tion
ed p
lace
pre
fere
nce
sco
re a
fter
20
mg/
kg c
oca
ine
SW
C57
Brain progesterone is negatively correlated with cocaine CPP
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Brain progesterone content (ng/g)
Co
ndi
tion
ed p
lace
pre
fere
nce
sco
re a
fter
20
mg/
kg c
oca
ine
SW
C57
Brain progesterone is negatively correlated with cocaine CPP
r = -1.00
df = n - 2
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Brain progesterone content (ng/g)
Co
ndi
tion
ed p
lace
pre
fere
nce
sco
re a
fter
20
mg/
kg c
oca
ine
SW
C57
Brain progesterone is negatively correlated with cocaine CPP
r = -1.00
df = n - 2
Each strain is essentially many clones of one individual
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Brain progesterone content (ng/g)
Co
ndi
tion
ed p
lace
pre
fere
nce
sco
re a
fter
20
mg/
kg c
oca
ine
SW
C57
Brain progesterone is negatively correlated with cocaine CPP
DBA
r = -.95
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Brain progesterone content (ng/g)
Co
ndi
tion
ed p
lace
pre
fere
nce
sco
re a
fter
20
mg/
kg c
oca
ine
SW
C57
Brain progesterone is negatively correlated with cocaine CPP
DBA
C3H
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Brain progesterone content (ng/g)
Co
ndi
tion
ed p
lace
pre
fere
nce
sco
re a
fter
20
mg/
kg c
oca
ine
SW
C57
Brain progesterone isn't correlated with cocaine CPP
DBA
C3H
r = -.07
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Logue et al, Alcohol Clin Exp Res 22:1919 (1998)
Animals with high alcohol preference have low scores on an impulsivity task
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Letwin et al. J Neurosci. 20:5277 (2006)
Strain differences in expression patterns of 188 genes in specific brain regions
CR = cerebellum
PG = peri-acqueductal gray
TL = temporal lobe
PF = prefrontal cortex
VS = ventral striatum
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Letwin et al. J Neurosci. 20:5277 (2006)
41 genes increased expression
28 genes decreased expression
Strain (genetic) correlation of gene expression with ethanol-stimulated activity
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The Mouse Phenome Project
• Data are being collected from 40 inbred mouse strains
• 679 biochemical, physiological and behavioral variables are in this database as of April 18, 2007
• Genetic correlations can be explored with archived data, or your own data
http://aretha.jax.org/pub-cgi/phenome/mpdcgi?rtn=docs/home
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Issues with Null Mutant Mice
• Developmental compensation
• Genetic background effects
• Intrinsic limitations of background strain
• Limited generalizability of phenotypes
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The real issue with null mutant mice is that the addictions are not single gene disorders
• 1996 saw the first paper reporting an effect of a null mutation on an alcohol response
• By 2006, 141 papers had reported effects of manipulating nearly 100 genes on various alcohol responses
• 76 genes have been studied for effects on alcohol preference drinking
¼ increased, 1/3 decreased, 40% had no effect
Crabbe, Phillips, Harris, Arends & Koob, Addiction Biol 11:195 (2006)
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This polygenicity is not just a problem with alcohol due to its peculiar pharmacology
• 1991 saw the first paper reporting an effect of a null mutation on response to an amphetamine-like drug
• By 2007, ~150 papers had reported effects of manipulating 80 genes on various responses
• 115 papers have studies effects on acute locomotor stimulation
Phillips, Kamens & Wheeler, In: Crusio, Sluyter & Gerlai (Eds), Handbook of Behavioral Genetics of the Mouse. In press.
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Parental Population
Selection Generation
Maze-BrightMaze-Dull
Plomin, Nat Rev Neurosci (2001); adapted from Tryon, J Comp Psychol (1940)
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Advantages of Selection
• Gene frequencies for these affecting the trait increase to produce large cumulative changes in the trait
• Genes acting additively and interactively (epistasis) are captured
• Divergently selected lines can be used to explore biological underpinnings
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Withdrawal Seizure-Prone (WSP) and -Resistant (WSR) mice differ in handling induced convulsion
severity after 72 hr EtOH vapor inhalation
Withdrawal convulsions after 16 selected generations
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Responses Correlated with Ethanol Withdrawal in WSP vs WSR Mice
• WSP have more severe withdrawal from barbiturates, benzodiazepines, other sedative drugs
• During withdrawal, WSP has greater enhancement in sensitivity to NMDA, kainic acid, and corticosterone
• WSP shows large increases in L-type Ca++ channels
• WSP chows pronounced changes in GABA-A receptor subunit composition
• WSP shows greater sensitivity to modulators of Cl-
flux at GABA-A channels, including neurosteroids
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Quantitative Trait Loci (QTLs)
• Each QTL comprises a region of a chromosome containing a gene affecting the target trait
• Each such QTL indicates one or more genes
• Each QTL usually exerts a modest effect
• Collectively, the multiple QTLs affecting a trait can control a substantial proportion of individual differences in the trait
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Mapping QTLs in WSP x WSR F2 Mice
• 440 mice were made dependent and scored for withdrawal severity
• The highest and lowest scoring 20% were genotyped for 82 microsatellite markers spanning the genome
• Five significant associations were found, on chromosomes 1, 4, 8, 11 & 14
Bergeson et al, Mammalian Genome 14:454 (2003)
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Bergeson et al, Mammalian Genome 14:454 (2003)
Mapping QTLs in WSP x WSR F2 Mice
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DBA/2J (D2) inbred mice have more severe acute ethanol withdrawal than C57BL/6J (B6) inbreds
A single large dose of alcohol is given by injection (4.0 g/kg, i.p.). Handling induced convulsions are assessed 4-12 hours later. Peak withdrawal intensity is at 6-8 hrs post-injection.
0 2 4 6 8 10 12Hours post ethanol injection
0
1
2
3
4
D2
B6
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Combined data from RI strains, an F2 segregating population, and short-term selected lines [Buck et al., J. Neurosci 17:3946 (1997) ]
Location of significant QTLs for acute alcohol withdrawal
Boxes denote approximate 95% confidence intervals.
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Short term selective breeding for acute alcohol withdrawal severity from B6D2F2 mice
As withdrawal severity increases, frequency of the D2 allele at the b locus on Chr 4 increases.
Metten et al, Behavioural Brain Res. 95:113 (1998)
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A congenic strain is identical to its inbred, background strain, except for a small segment of a chromosome that has been introduced from another (donor) inbred strain by repeated backcrossing
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x x
x x
x
1
2
3
4
5-10
Two inbred strains F1 hybrid (backcross)
Congenic line
Additional backcross generations
Three chromosomes are shown
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Congenic Strains can be Used for QTL Mapping
Trait??
----+++++++++----
----
Introgressed QTL region
QTL is narrowed to the yellow interval
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Congenic strains for the Chromosome 4 alcohol withdrawal QTL
Fehr, et al, J. Neuroscience 22:3730 (2002)
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Fehr et al, J. Neuroscience 22:3730 (2002)
Capture of B6 alleles confers lower acute ethanol and pentobarbital withdrawal
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Additional backcrossing reduced the QTL interval until only two known genes remained, Mpdz and Nfib
Shirley et al., Nat. Neurosci. 7:699 (2004)
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Mpdz haplotypes and protein variants in 15 inbred strains, and their acute ethanol withdrawal scores
Fehr et al, J. Neurosci 22:3730 (2002)Metten & Crabbe, Behav. Pharmacol 5:533 (1994)
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Shirley et al., Nat. Neurosci. 7:699 (2004)
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Summary
• Inbred strains, selected lines, and mice with single genes manipulated are all powerful genetic animal models for exploring substance abuse
• Gene mapping efforts started with QTL mapping based on polymorphisms in gene sequence, and are increasingly using gene expression array methods
• Invertebrate models (Drosophila, C. elegans) and zebrafish have been little used thus far, with the exception of ethanol and a few studies with cocaine.