Gene-Environment Interplay on Behaviour
Marla B. Sokolowski, PhD, FRSC
University ProfessorCanada Research Chair in Genetics and Behavioural Neurology,
Academic Director Institute for the Fraser Mustard Human Development.Co-director of Canadian Institutes for Advanced Research (CIFAR)
Experience Based Brain and Biological Development Programme (EBBD),
Early adversity sets developmental trajectories for health, learning and social
functioning across the life-time.
How?
a) Gene-Environment Interactions
b) Epigenetics
For most traits:• It’s not just nature (genes)• It’s not just nurture
(environment)• It’s not nature plus nature
(genes + environment).
It is their interaction!
G x E
Sokolowski and Wahlsten 2001
Example of Gene by Environment Interaction in Human Mothering Behavior (serotonin transporter gene variants LL, SS and LS)
Mileva-Seitz et al 2011
Why?
Conservation of DNA Sequence Conservation of a Gene’s Behavioural
Function
Candidate Genes Model Organisms to Humans
Almost all organisms have the gene including humans!
The gene affects energy balance: food intake, food related movement, fat, learning and memory
Different individuals have different forms of the gene –rover or sitter
The gene makes an enzyme found in the brain called PKG. Rovers have more of it than sitters
How much enzyme the gene makes depends on the environment. (G x E)
Example 2: G x E: The foraging (for) gene
(Osborne et al 1997 Science; Ben Shahar et al 2002 Science; Mery et al 2007 PNAS; Fitzpatrick et al 2007 Nature;Kaun et al 2007 J Exp Biol; Lucas and Sokolowski 2009 PNAS; Sokolowski 2010 Neuron).
The rover/sitter natural variants are due to variation in a single gene called foraging which makes a cGMP-dependent protein kinase (PKG) enzyme
Rover heads and larval CNSs have more foraging enzyme than sitter heads and larval CNSs.
Osborne et al. 1997 Science 277: 834-836.
Honey Bee
Ant
Forager or defender
Nematode Worm
Roamer or dweller
Nurse or forager
Fruit Flies
Rover or sitter
The foraging gene responds to the environment
BenShahar et al 2002 Science
Lucas & Sokolowski 2009 PNAS
Fujiwara et al.2002 Neuron
Osborne et al 1997Science
Sokolowski 2010 Neuron
Example 2: Rovers change into sitters when chronically food deprived (the gene is responsive to the early rearing
environment) Fo
od In
take
5
10
15
100% 15%
*
Food Quality
RoverSitter
Enzy
me
Activ
ity
4
8
12
100% 15%
Food Quality
RoverSitter
Kaun et al 2007 J Exp Biol
Chronic nutritional deprivation in the larval period affects adult exploratory behaviour
Burns et al 2012 PNAS
High ‘darting exploration’
Low ‘darting exploration’
Darting Exploration (darting is stop and go motion)
Burns et 2012 PNS
G-E interplay: sitter adults exhibit a more plastic response to modifications
in the larval nutritional environment
*** p<0.001
***
***
*** p<0.001, ** p<0.01, * p<0.05
Increasing foraging gene expression in the mushroom bodies changes exploratory behavior from sitter to rover (reared in 100%
food)
Burns et al 2012 PNAS
UAS-forT1a + - + - + - -Gal4 30Y 201Y 739Y None
foraging affects learning and memory: the gene is responsive to the environment
Rovers have better short term memory. foraging acts in the mushroom bodies for olfactory based aversive learning and memory
Mery et al 2007 PNAS
STM: sitters are sensitive to the learning context(rovers and sitters are trained alone or in groups)
P = 0.20
P = 0.005
Kohn, Reaume, Burns, Sokolowski, Mery (submitted)
Increasing foraging enables sitter to learn when alone
PKG activator (8-Bromo-cGMP) on flies trained and tested alone
Rover Sitter S20.5
0.55
0.6
0.65
0.7
0.75
Sham Control8-Bromo-cGMP
Prop
ortio
n m
akin
g th
e co
rrec
t cho
ice
141 120 162 154 150 154
Treatment
S2
P = 0.01
P < 0.001
Rover Sitter S2
0.45
0.5
0.55
0.6
0.65
0.7
0.75
Sham Control
KT5823
Prop
ortio
n m
akin
g th
e co
rrec
t cho
ice
111 112135 136 139 139
S2
Treatment
P = 0.01
Decreasing PKG decreases learning in roversPKG inhibitor (KT5823) on individuals trained and tested alone
Early adversity sets developmental trajectories for health and behaviour across the life-time.
How? a) Gene-Environment Interactions
b) Epigenetics
DNA is like books in a library. Limitless potential to inform and inspire…….But they need to be read.
Individual differencesin neural and endocrine responses to stress brain development, Immune system
Prevention
Health Risks Associated with Early Adversity and Low SES
Early Experience
AbuseFamily strifeEmotional neglectHarsh discipline
Health Risks
DepressionDrug abuseAnxietyDiabetesHeart diseaseObesity
A New Science = EPIGENETICS
Epigenetics
the study of those environmental factors that alter whether DNA will be “expressed” without altering the DNA sequence
Factors that change the likelihood that a book will be read.
Champagne and Mashoodh, 2009
Epigenetic Variation
nutritionstress
drug usesocial
interactions
Environmental toxins hormones
smoking
What factors induce epigenetic changes?
When the DNA is read it is said to be “expressed”
Early adversity makes some genes difficult to read. Those involved in: 1) how we cope with stress, 2) how our brain develops and works and, 3) how we fight disease.
hard to read
easier to read
epigenetics
Social Interactions: Natural Variations in Maternal Care in the Rat: High and Low Lickers and Groomers. Differential Methylation of Glucocorticoid Receptor in rats (and humans)
Michael Meaney, McGill University
High/High High/Low Low/High Low/Low
0.0
0.2
0.4
0.6
0.8G
Rir (
ROD
)
Biological Mom / Foster Mom
* *
Epigenetics: Cross-fostering shows direct effects of maternal care on the expression of genes in the brain
(i.e. glucocorticoid receptor) involved with coping with stress!
Gl
Early Abuse in Victims of Suicide
GR
-1F m
RN
A/G
AP
DH
(lo
g
con
c.)
Control Suicide Suicide- Abuse + Abuse
0.0
0.5
1.0
1.5
*
GR
1-F
Cp
G M
eth
yla
tion
(%
)
Control Suicide Suicide- Abuse + Abuse
0
20
40
60*
McGowan et al 2009 Nature Neuroscience
Changes to the epigenome are a cellular memory of an
environmental event
New Era of Research on the Origins of our “Uniqueness”
Consequences?• The mom’s behaviour (social context) affects the
lifelong health of the infants via later stress reactivity
• The mom’s behaviour is transferred to the pups in an epigenetic manner
• Is this epigenetic effect is reversible, how?
Early adversity sets developmental trajectories for health and behaviour across the life-time.
How: mechanisms? Gene by Environment Interaction and Epigenetics
When: sensitive periods?What: early adversities?
(individual differences)
Drosophila foraging gene project:Amsale Belay Ralph GreenspanKate Osborne Joel LevineMark Fitzpatrick Chris ReaumeLocke Rowe Tony SoKarla Kaun Tad KaweckiCraig Riedl Bertam Gerber Clement KentThomas Hendel Bryon HughsonAaron Allen Hiwote Belay
Bee foraging gene project:Yehuda Ben-Shahar Alain RobichonGene Robinson
Ant foraging gene project:Christophe Lucas
Human foraging gene project James Kennedy Robert Levitan Hiwote Belay Sam BidnurRoger Ferreira
Torry Higgins
Learning and Memory
Fred Mery
Nancy Kohn
Hypothesis: Epigenetic modification of foraging by EHMTeuchromatin histone methyltransferases afamily of evolutionarily conserved proteins that write part of theepigenetic code through methylation of histone 3 at lysine 9(H3K9).
EHMT is a a key epigenetic regulator of neuronal genes and processes.
How does the foraging gene respond to food deprivation?
USCS genome browser “LOMB” track
Loss of methylation peak in EHMT mutants
foraging gene
transcripts
Kramer et al in prep
EHMT in the transcriptional control of foraging (Mutations in EHMT affect larval foraging behaviour and adult cognition)
Kramer et al in prep
FORAGING protein levels are reduced in response to food deprivation. This does not
occur in EHMT mutants EHMT(-)
forR fors fors2 forR fors fors2wild type EHMT EHMT mutants
0
2
4
6
8
10
12
EHMT modulates food dependent plasticity in rover and sitter larval foraging behaviour
FedFood Deprived
Path
leng
th (c
m)
I. Anreiter, J. Kramer, M.B. Sokolowski
forR fors forR forswild type EHMT EHMT mutants
0
0.5
1
1.5
2
2.5
Adult Foraging Behaviour: Number of drops consumed in 10 min
no o
f dro
ps c
onsu
med
in 1
0 m
in
I. Anreiter, B. Hughson, J. Kramer, M.B. Sokolowski
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