Neurobiology of resilience

A role for epigenetics in linking psychological and biological aspects?

Bart P.F. Rutten, M.D. PhD., July 2nd, 2014

Maastricht University Medical Centre, Maastricht, the Netherlands

Content

• Resilience

• Genetic moderation of sensitivity to stress by DNMT3a

• DNMT3a and neuroplasticity

• DNMT3a and (un)susceptibility to severe chronic stress

• Conclusions

trauma

Well being

Psychopathology

time

trauma

Well being

Psychopathology

time

A

B

MODEL OF RESILIENCE

TRAJECTORIES OF RISK & RESILIENCE

Rutten et al. Acta Psych. Scan, 2014

Integrating Nurture and Nature

Van Os, Kenis, Rutten. Nature 2010

DNA

RNA

Protein

promoter exon 1 exon 2

SNP/mutation

quantity quality

Cell functions

gene

GTCATTAAACAGGTGTCATTACACAGGT

Genes related to (un)susceptibility to stress

Wu, Feder, et al. Front Behav Neurosci 2013

Epigenetics & the environmentEN

VIR

ON

MEN

Tchanges in phenotype and/or gene expression by

mechanisms other than changes in the DNA sequence itself

Maternal care during early life has persistent influence on later-life behaviourand molecules in the stress-system via the epigenetic mechanism of DNA methylation

(team of Michael Meaney and others)

I. blocks transcription factors

DNA Methylation ↓Gene Transcription

promoter exon 1 exon 2

quantity

genemethyl

DNA methylation is performed by DNA methyltransferases

promoter exon 1 exon 2

genemethyl

DNMT1DNMT3aDNMT3b

We determined the genetic variability in these genes

29 genetic variant in genes of DNMT1, DNMT3a and DNMT3b

Pishva et al. PlosOne 2014

Stress sensitivity

= increases in negative affect after unpleasant activities or events

Daily Life Stress Sensitivity

eventHigh stress sensitivity

Low stress sensitivity

eventeventevent

Pishva et al. PlosOne 2014

10 times a day

6 consecutive days

at random moments

multiple assessments

real world, no lab

in the moment, not retrospective

Evaluation of the context

The Experience Sampling Method (ESM)

Stress sensitivity and DNMT3a genotype

a multistep replication study

Pishva et al. PlosOne 2014

Cohort 1 Cohort 2 Cohort 3

However, no influence of the genetic variants on reward experience,i.e. the experience of positive affect after pleasant stimuli

Psychotic reactivity

= increases in paranoid ideations after socially unpleasant events

High psychotic reactivity

Low psychotic reactivity

socialevent

Pishva et al. PlosOne 2014

socialevent

socialevent

socialevent

Gene SNP Sample I(healthy)

Sample II(twins)

Sample III(Patients)

Sample IV(Siblings)

Sample V(Depress.)

Dnmt3a rs13401241 p=0.0000 p=0.0373 - p=0.0010 -

Expression of DNMT3a in the mouse brain

1) subgranular zone dentate gyrus of the hippocampus

DNMT3a protein

Distinct cells are highly immunoreactive, these cells are found in:

2) subventricular zone

3) olfactory bulb

4) rostral migratory stream

Hammels et al. in review

GFAP DCX

Nestin, Ki-67 NeuN

DNMT3a involved in neurogenesis?

Establishment of methylation patterns?

High levels of DNMT3a in newborn neurons

GFAP DCX

Nestin, Ki-67 NeuNDnmt3a DCXDnmt3a NeuNDnmt3a GFAP

** p<0.01; (*) p=0.05

control susceptible resilient0

10000

20000

30000

40000

50000

**

ce

ll d

en

sity

(ce

lls/m

m3

)

(*)

Hammels et al. under review

(same genetic background in all mice)

Mice unsusceptible to severe stress have more cells with high levels of DNMT3a

Conclusions• Deep phenotyping with experience sampling

methodology allows for– studying dynamics in positive and negative affect

– dissection of genetic influences on emotional reactivity in daily life

• A gene involved in DNA methylation (i.e. DNMT3a) moderates stress-sensitivity

• DNMT3a is highly expressed in newborn neurons in the adult brain (at least in mice)

• Thus, DNA methylation seems to be relevant for active adaptation to stressors

Many thanks for your attention

Acknowledgments