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  3. Fakultät für Biologie - Digitale Hochschulschriften der LMU - Teil 05/06 Podcast
  4. Interaction of genetic predisposition and epigenetic factors in the development of anxiety
It is becoming increasingly clear by current research that the
continuum of physiological anxiety up to psychopathology is not
merely dependent on genes, but is orchestrated by the interplay of
genetic predisposition, gene x environment and epigenetic
interactions. To consider this interplay, we here took advantage of
the rigid genetic predisposition of a selectively bred mouse model
exhibiting high anxiety-related behavior (HAB) and tested whether
and how enriched environment, a manipulation of housing conditions,
is capable of rescuing the genetically driven high anxiety
phenotype via gene x environment and/or epigenetic interactions.
Indeed, enriched environment exerts a significant anxiolytic effect
on HABs of both sexes indicating for the first time that even a
rigid genetic predisposition of high anxiety can be rescued by
beneficial environmental stimuli. Thereby, a reduced neophobia and
a bigger behavioral repertoire of HABs (e.g. social interactions)
have been observed with a stronger anxiolysis in males than in
females. The behavioral shift is accompanied by an attenuated
release of corticosterone after application of a mild stressor. A
hyperreactive hypothalamic-pituitary-adrenal (HPA) axis and
amygdala constitute the most common symptoms of anxiety disorders,
and decreased corticosterone release seems to entail a reduced
release of noradrenaline from locus caeruleus (LC) to the medial
prefrontal cortex (mPFC), thereby increasing the top-down control
of mPFC on amygdala. This would entail less activation of amygdala
and thus HPA axis, a consequence we indeed can observe as decreased
neuronal activity flow through the amygdala of enriched housed (EE)
compared to standard housed (SE) HABs. We suggest that
corticotropin-releasing hormone receptor 1 (Crhr1) is critically
involved in this phenomenon since (i) HABs compared to low
anxiety-related behavior (LAB) mice exhibit higher Crhr1 mRNA in
the basolateral amygdala (BLA), (ii) this overexpression can be
significantly reduced when HABs are housed in enriched environment
and (iii) a bilateral application of a CRHR1 antagonist in the BLA
of SE HABs induced a significant anxiolytic effect. Subsequent
pyrosequencing identified that enriched environment increased
methylation at a CpG site in the promoter of Crhr1, which is
located next to a transcription factor binding site (TFB) of the
epigenetic transcription factor Yin Yang 1 (YY1), whose mRNA levels
are indeed decreased in EE HABs. In silico analysis identified
Nr4a1 and D3Ertd300e as critical co-transcription factors, whereas
Nr4a1 seems to be regulated by the quantity of available
glucocorticoid receptor (GR) and D3Ertd300e positively regulates
YY1. Thus, we hypothesize that reduced corticosterone release
decreases the availability and thus binding of corticosterone to GR
in the BLA. This, in turn decreases the binding affinity of Nr4a1
to D3Ertd300e, which then cannot positively regulate YY1 to
decrease or even prevent methylation at the identified CpG site of
Crhr1. This would finally result in a differentially methylated
region (DMR) with higher methylation levels in EE HABs, which
underlies the observed gene expression differences. The identified
DMR might therefore be used as a biomarker for high or pathological
anxiety. This hypothesized mechanism highlights the possibility
that even a rigid genetic predisposition modeling pathological
anxiety might be rescued by an epigenetic process that seems to be
triggered by beneficial environmental stimuli, thereby raising the
exciting possibility for new treatment strategies, which can be
utilized complementary to already existing ones.

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