Gene-environment interactions modulating

cognitive and affective endophenotypes in mice

Anthony Hannan

Florey Institute of Neuroscience and Mental Health

University of Melbourne

12th International Conference on Cognitive Neuroscience, Brisbane, 29th July 2014

ENVIRONMENTAL

FACTORS

mental/physical activity

stressors, toxins, diet…

(‘Envirome’)

GENETIC FACTORS

monogenic

polygenic

(Genome)

Disorders with high

genetic loads

(e.g. HD)

Disorders with

complex polygenic &

environmental loads

(e.g. schizophrenia,

depression, autism,

dementia)

Disorders with high

environmental loads

(e.g. stroke)

Tandem repeat polymorphisms and mutations

Hannan, 2010

Huntington’s Disease

• Fatal neurodegenerative disorder with autosomal dominant inheritance

• Psychiatric symptoms (e.g. depression), cognitive deficits (culminating in dementia), and a movement disorder (e.g. chorea)

• Caused by a CAG/glutamine repeat expansion in huntingtin (HD Collab.

Research Group, 1993, Cell) which is most toxic to specific neuronal populations in the cerebral cortex and striatum (Wang et al., 2014, Nature Med.)

(CAGCAGCAGCAGCAG)n+x

huntingtin gene

Abnormal protein

cleavage, folding,

multimerization

Altered gene expression,

trafficking, signaling,

homeostasis, etc.

Toxic gain-of-function,

abnormal molecular

interactions

(QQQQQ)n+x

huntingtin protein

PATHOLOGICAL

PLASTICITY?

COGNITIVE & PSYCHIATRIC

SYMPTOMS

CELLULAR

DYSFUNCTION

MOTOR

SYMPTOMS

huntingtin

mRNA

Transgenic HD mice • R6/1 mice expressing human exon 1 transgene

encoding expanded polyglutamine in the huntingtin

N-terminal fragment (Mangiarini et al., 1996, Cell)

• Progressive neurodegenerative phenotype, including

affective, cognitive and motor deficits

WT HD

Somatosensory discrimination learning test

Mazarakis et al., 2005, J. Neurosci.

Motor presymptomatic HD mice have a deficit in

somatosensory discrimination learning

Trials

191715131197531

Nu

mb

er

of

co

rre

ct

ch

oic

es

20

18

16

14

12

10

8

Genotype

Positive HD

Negative HD

Mazarakis et al., 2005, J. Neurosci.

2DG

Barrel Cortex

Histology Right/Left

Areas

Motor presymptomatic HD mice have a deficit in

experience-dependent barrel cortex plasticity

Mazarakis et al., J. Neurosci. (in press)

WT HD

Mazarakis et al., 2005, J. Neurosci.

Spatial learning and memory in the Morris water maze

•Spatial navigation task

•Repeated daily trials to locate platform

•Probe trial: no platform present

Frequency, duration and

latency to the quadrant and

platform can be used as

measures of memory

acquisition

A GSK-3b signaling abnormality in the cerebral cortex

of HD mice correlates with cognitive deficits

Lim et al., 2014, Hum. Mol. Genet.

WT HD WT HD

(CAG)n+x

Huntingtin gene

(Q)n+x

Huntingtin protein

COGNITIVE DEFICITS & DEMENTIA

Abnormal protein

interactions (toxic

gain of function)

GSK-3b

Gene expression

(e.g. GluRs, BDNF, etc.)

b-Catenin,

CREB

Cellular plasticity deficits

(adult neurogenesis & synaptic plasticity)

Molecular and cellular mediators of cognitive deficits

HD mice develop a sexually dimorphic depression-like

behavioural endophenotype by 12 weeks of age

Novelty suppressed feeding test (NSFT)

Antidepressants with clinical efficacy rescue this behavioural sign

Pang et al., 2009, Hum. Mol. Genet.

NSFT - Latency to feed

0

50

100

150

200

Female Male

Tim

e (

sec)

*

CHD

WT

Depression-like behaviour in female HD mice is

rescued by chronic administration of an SSRI

Sacharin-preference test (SPT) of anhedonia

*

Ɨ

Renoir et al., 2012, BJP

Disease onset and progression in the R6/1

transgenic mouse model of HD

End-stage

disease/death (Mangiarini et al., 1996, Cell)

Age (weeks)

Onset of motor

deficits

(van Dellen et al., 2000, Nature)

Onset of affective and

cognitive abnormalities (Mazarakis et al., 2005, J. Neurosci.

Pang et al., 2008, Hum. Mol. Genet.)

Decreased cortical

and striatal volume (van Dellen et al., 2000, Nature)

10 15 20 30 25

Onset of neuronal

cell death (Turmaine et al., 2000, PNAS)

35

Onset of molecular

and cellular deficits?

Environmental enrichment enhances activity levels

Nithianantharajah & Hannan, 2006, Nature Rev. Neurosci.

Environmental enrichment delays disease onset

Van Dellen et al., 2000, Nature

Age (days)

40 60 80 100 120 140 160

Per

cent

age

with

phe

noty

pe (

faili

ng r

od te

st)

0

20

40

60

80

100

aStandard

housed HD

Environmentally

enriched HD

Wild-type

Subsequent studies exploring environmental enrichment, cognitive and/or motor stimulation in HD mice:

Hockly et al., 2002 (‘minimal enrichment’); Spires et al., 2004; Schilling et al., 2004; Lazic et al., 2006;

Pang et al., 2006, 2009; Kohl et al., 2007; van Dellen et al., 2008; Nithianantharajah et al., 2008;

Benn et al., 2010; Zajac et al., 2010; Renoir et al., 2011; Wood et al., 2011; Du et al., 2012

Evidence for environmental modifiers in clinical HD

• Wexler et al.; US-Venezuela Collaborative Research Project, 2004, PNAS

- Analysis of large Venezuelan kindreds showing that the remaining variance not explained by CAG repeat length has a major environmental component

• Trembath et al., Delatycki, 2010, Mov. Disorders

- Retrospective study of Australian & New Zealand families indicating that ‘passivity’ (reduced activity) is a risk factor contributing to earlier age of HD onset

• Twin studies provide further evidence (although somatic CAG repeat instability and stochastic epigenetic variability may also play a role)

MOLECULAR

MEDIATORS

(CAG)n+x

huntingtin gene

SELECTIVE CELLULAR DYSFUNCTION

(Q)n+x

huntingtin protein

ENVIRONMENTAL

MODULATORS

?

?

MOTOR, COGNITIVE & PSYCHIATRIC SYMPTOMS

?

Cellular plasticity? (neurogenesis & synaptic plasticity)

Gene expression? (experience-dependent regulation)

huntingtin (Qn+x)

Abnormal protein

interactions

EE

Hypothesised mechanisms mediating the

beneficial effects of environmental enrichment

?

? ?

Altered gene expression

Epigenetics?

Environmental enrichment delays onset of

hippocampal-dependent cognitive deficits in HD mice

***

0

2

4

6

8

10

12

14

16

18

20

1st 2nd 2nd to last Last

Block of 5 trials

Mean

# e

rro

rs

WTNE

WTE

HDNE

HDE**

ERRORS

Nithianantharajah et al., 2008, Neurobiol. Dis. Barnes circular maze

A depressive-like behavioural endophenotype

is rescued by environmental enrichment

FST performance of female mice

0

50

100

150

200

Standard housed Environmental Enrichment

Tim

e (

sec)

HD

WT

***

*A

Pang et al., 2009, Hum. Mol. Genet.

Performance in the forced-swim test (FST) responds to clinically effective antidepressants

Parsing the components of environmental enrichment:

Can enhanced voluntary physical exercise alone

induce beneficial effects?

Nithianantharajah & Hannan, 2006, Nature Rev. Neurosci.

Abnormal stress response in female HD mice

is ameliorated by increased voluntary exercise

Renoir et al., 2013, J. Physiol.

***

Wheeling running delays onset of cognitive, affective

and motor deficits in HD mice: Pang et al., 2006;

van Dellen et al., 2008; Renoir et al., 2012

GR

Assessing short-term spatial memory in the

Y-maze

TRAINING TRIAL TEST

Inter-trial interval

(e.g.

1 hr)

e.g. 10 min e.g. 5 min

Stress as a modulator of pathogenesis:

Elevated stress hormone accelerates cognitive deficits

Y-maze

Mo et al., 2014, Neurobiol. Dis.

Experience-dependent HPA axis dysfunction

in HD mice: Du et al., 2012, Transl. Psychiatry

MOLECULAR

MEDIATORS

(CAG)n+x

huntingtin gene

SELECTIVE CELLULAR DYSFUNCTION

(Q)n+x

huntingtin protein

ENVIRONMENTAL

MODULATORS

MOTOR, COGNITIVE & PSYCHIATRIC SYMPTOMS

?

PHARMACOLOGICAL

MODULATORS

(e.g. ‘ENVIROMIMETICS’)

Sensory

stimulation

Physical

activity

Cellular mediators

• Neurogenesis

• Synaptic plasticity

• Synaptogenesis

• Gliogenesis

• Angiogenesis

Systems effects

• Network plasticity

• Efficiency of

information

processing and

storage

• Connectivity and

functional

redundancy

BCR Molecular mediators

• Epigenetics (e.g.

DNA methylation,

histone modifications,

regulatory RNA)

• Activity-dependent

gene expression (e.g.

neurotrophins)

• Protein processing

and trafficking

Genetic/

environmental

modifiers Cognitive

stimulation

Nithianantharajah & Hannan, 2009, Prog. Neurobiol.

Potential mechanisms mediating

brain and cognitive reserve (BCR)

GENETIC MEDIATORS

BRAIN MATURATION &

EXPERIENCE-DEPENDENT PLASTICITY

BRAIN DISORDER

SYMPTOMATOLOGY

DYSFUNCTION IN SPECIFIC NEURAL SYSTEMS

HEALTHY BRAIN

MATURATION & AGING

ENHANCED

MENTAL/PHYSICAL

ACTIVITY

OTHER

ENVIRONMENTAL

FACTORS (e.g. stress)

EMBRYONIC BRAIN DEVELOPMENT

NEUROPROTECTION VIA BCR

FAILURE TO COMPENSATE FUNCTIONAL COMPENSATION

THERAPEUTICS (e.g.

ENVIROMIMETICS) Nithianantharajah & Hannan,

2009, Prog. Neurobiol.

Florey Institute of Neuroscience and Mental Health, University of Melbourne Terence Pang Thibault Renoir Jess Nithianantharajah (Edinburgh) Xin Du Emma Burrows Caitlin McOmish (Columbia University) Michelle Zajac Mark Ransome Christina Mo (Chicago) Annabel Short Dean Wright Laura Gray (Deakin University) Jake Rogers Faith Lamont Mari Kondo (Johns Hopkins University) Shlomo Yushuren Lily Laskaris Elizabeth Manning (Pittsburgh) Andrew Argyropoulos Yanting Choong Chris Barkus (Oxford) Alex Eastwood Lavie Vo Ariel Zeleznikow-Johnston Pathology, Univ. Melb. Nastasia Lim, Peter Crouch INSERM, Paris Laurence Lanfumey University of Oxford Colin Blakemore

NHMRC, ARC

Environmental enrichment,

exercise, SSRIs

(e.g. fluoxetine, sertraline)

Genetic & environmental factors

(e.g. HD, 5-HT signaling, BDNF,

glucocorticoids, stress )

Increased neurogenesis

Antidepressant/Cognitive effects?

Decreased neurogenesis

Depression/Cognitive deficits?

Lazic et al., 2004

Grote et al., 2005

Gil et al., 2005

Philips et al., 2005

Pang et al., 2008

Kempermann et al.,

1997

Van Praag et al., 1999

Malberg et al., 2000

Lazic et al., 2006

Pang et al., 2006

Pang et al., 2008

Li et al., 2004

Gene-environment interactions and adult neurogenesis

Wheel running delays the onset of a short-term

spatial memory deficit in HD transgenic mice

14 week Y-maze Control and RW Duration

0

10

20

30

40

50

60

WT HD WT RW HD RW

Perc

en

tag

e d

ura

tio

n

Home

Familiar

Novel

*

* *

Pang et al., 2006, Neuroscience

Running delays onset of cognitive, affective and motor deficits in

HD mice: van Dellen et al., 2008; Renoir et al., 2012