Caring Mothers Reduce Response to Stress for Life

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> 7 Sep 2004 19:05:58 -0000

 

> Caring Mothers Reduce Response to Stress

> for Life

> press-release

>

>

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>

> Life after the Central Dogma

>

> The biotech industry was launched on the scientific

> myth

> that organisms are hardwired in their genes, a myth

> thoroughly exploded by scientific findings

> accumulating

> since the mid 1970s and especially so since genome

> sequences

> have been accumulating (see Living with the Fluid

> Genome

> http://www.i-sis.org.uk/fluidGenome.php, by Mae-Wan

> Ho ). We

> bring you the latest surprises that tell you why our

> health

> and environmental policies based on genetic

> engineering and

> genomics are completely misguided; and more

> importantly, why

> the new genetics demands a thoroughly ecological

> approach.

>

> Death of the Central Dogma

> http://www.i-sis.org.uk/DCD.php

> Caring Mothers Reduce Response to Stress for Life

> http://www.i-sis.org.uk/MCDIRTS.php

>

>

>

> ISIS Press Release 07/09/04

> Caring Mothers Reduce Response to Stress for Life

> *********************************

>

> How a rat responds to stress depends on whether its

> mother

> cared for it properly as a pup, which marks its

> genes for life.

> Dr. Mae-Wan Ho reports

>

> References (

> http://www.i-sis.org.uk/full/MCDIRTSFull.php )

> for this article are posted on ISIS members'

> website.

> Details here

> (http://www.i-sis.org.uk/membership.php)

>

> Maternal effects in the spotlight

>

> Maternal effects on the development of offspring are

> well

> known. But they are thought to be due to nutritional

> and

> physiological factors affecting the foetus in the

> womb; and

> within the past few years, geneticists have

> discovered that

> diet and stress can profoundly change the pattern of

> gene

> expression in the offspring, affecting their health

> prospects as adults (see Diet trumping genes, SiS 20

>

> http://www.i-sis.org.uk/isisnews/sis20.php).

>

> A team of researchers from the Douglas Hospital

> Research

> Centre and McGill University in Montreal Canada, and

> the

> Molecular Medicine Centre, in Edinburgh University

> Western

> General Hospital in the UK, now report a remarkable

> experiment in which the behaviour of the mother

> nursing her

> pups not only affects the pups' response to stress

> as

> adults, but are correlated with changes in gene

> expression

> states in brain cells that persist into adult life.

> Such

> changes are referred to as 'epigenetic' as they do

> not

> involve alterations in the base sequence of DNA in

> the

> genome, only their off and on states; but they can

> persist

> in the brain cells and are passed on to all the

> daughter

> cells.

>

> Caring mothers reduces stress response of pups

>

> In the nest, the mother rat licks and grooms her

> pups, and

> while nursing, arches her back to groom and lick her

> pups.

> Some mothers (high performers) tend to do these more

>

> frequently than others (low performers). As adults,

> the

> offspring of high performers are less fearful and

> show more

> modest responses to stress in the

> hypothalamus-pituitary-

> adrenal (HPA) neuro-endocrine pathway.

>

> Cross-fostering studies showed that the biological

> offspring

> of low-performers reared by high-performers,

> resemble the

> offspring of high performers, and vice versa.

> Maternal

> behaviour, therefore, alters the development of the

> HPA

> responses to stress. The magnitude of the HPA

> response is a

> function of the corticotropin-releasing factor (CRF)

>

> secreted by the hypothalamus, which activates the

> pituitary-

> adrenal system. This is modulated by glucocorticoid,

> which

> feeds back to inhibit CRF synthesis and secretion,

> thus

> dampening the HPA responses to stress. The adult

> offspring

> of high-versus low performer mothers show increased

> glucocorticoid expression the hippocampus, and

> enhanced

> sensitivity to glucocorticoid feedback. If this

> difference

> is eliminated, so is the difference in HPA responses

> to

> stress.

>

> Maternal care and gene expression

>

> Previous studies indicate that the maternal

> behaviour of

> licking and grooming and arching her back to do so

> while

> nursing increased the expression of glucocorticoid

> receptor

> (GR), accompanied by, among other things, an

> increased

> expression of a special transcription factor,

> NGF1-A, which

> binds to the promoter of the GR gene to increase its

>

> transcription and expression. But how could this be

> transmitted from the neonate to the adult?

>

> The answer is: through the structure of chromatin

> (complex

> of protein and DNA in the chromosomes), and the

> methylation

> of DNA. DNA methylation is a stable chemical

> modification of

> the cytosine in the cytosine-guanine (CpG)

> dinucleotides,

> often associated with stable variations in gene

> transcription. Under-methylation of CpG

> dinucleotides is

> associated with active transcription. The

> researchers

> decided to look at the methylation state of the GR

> promoter

> around the binding region of the NGF1-A

> transcription factor

> in the hippocampus of adult offspring from high and

> low

> performers. Sure enough, they found highly

> significant

> differences in methylation, with low methylation in

> offspring from high-performing mothers and high

> methylation

> in offspring from low-performing mothers,

> corresponding to

> high and low expression respectively of the GR.

>

> Cross-fostering results in methylation patterns

> associated

> with the adoptive mother, as consistent with the

> change in

> the adult offspring's responses to stress. Moreover,

> these

> epigenetic differences due to maternal behaviour

> during the

> first week of life persisted into adulthood.

>

> A clean slate at birth

>

> Amazingly, the pups of both high and low-performing

> mothers

> start out life genetically the same. Just before

> birth, the

> entire region of the GR promoter was unmethylated in

> both

> groups; and day one after birth, methylation is

> found in the

> region in both groups to the same extent.

>

> The changes in methylation pattern then develops

> within the

> first week according to the behaviour of the mother,

> and

> thereafter remain for the rest of their lives. This

> finding

> is consistent with earlier studies showing that the

> first

> week of postnatal life is a 'critical period' for

> the

> effects of early experiences on hippocampus GR

> expression.

> The hippocampus is the 'emotion centre' of the

> brain, and is

> believed to be responsible for transferring memory

> to the

> rest of the brain. It is vulnerable to stress and

> richly

> supplied with receptors for the sex hormones [2, 3].

>

>

> Additional markings of the gene

>

> Next, the researchers looked at the structure of

> chromatin

> around the GR gene, as chromatin structure

> determines

> whether a gene is transcribed or not. Chemical

> modification

> of the histones (major chromatin protein) by adding

> an

> acetyl- group is a well-established marker for

> 'active'

> chromatin around transcribed genes, which makes it

> accessible for the transcription enzyme complex.

> Again, they

> found highly significant changes in acetylation

> between the

> two groups of pups. There was greater acetylation

> and

> threefold greater binding of the NGF1-A

> transcription factor

> to the GR promoter in the adult offspring of high-

> compared

> with low-performing mothers.

>

> Marked for life?

>

> Now, a critical question is, are these gene-marking

> changes

> reversible? Is the adult doomed to conditioning by

> the

> mother's behaviour towards it as a pup? The general

> belief

> is that one is marked for life. DNA methylation

> pattern is

> irreversible. However, recent data from in vitro

> experiments

> suggests that under certain circumstances, it is

> possible to

> demethylate DNA by increasing histone acetylation

> through a

> chemical inhibitor of the deacetylating enzyme,

> trichostatin

> A (TSA). The researchers, rather crudely, infused

> the adult

> brain with TSA by applying the solution into the

> ventricle

> (space inside the brain), and obtained more than

> 3-fold

> binding of the NGF1-A protein to the GR promoter in

> the

> adult offspring of low-performers, and as expected,

> no

> change in the adult offspring of high-performers.

> Simultaneously correlated changes in DNA methylation

> pattern

> of the GR promoter was found in the adults reared by

> low-

> performing mothers treated with TSA, but not those

> reared by

> high-performing mothers. In other words, those

> epigenetic

> changes were reversed.

>

> The next question is, are the reversal of epigenetic

> changes

> associated with reversal in HPA responses to stress?

> The

> answer, incredibly, is yes. The TSA treatment, crude

> as it

> was, appeared to significantly decreased plasma

> corticosterone in the offspring of low-performer in

> response

> to stress.

>

> This is all grist to the mill of the fluid and

> adaptive,

> adaptable genome [4] that makes nonsense of the

> Central

> Dogma. mail message here

>

>

>

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>

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> http://www.i-sis.org.uk/MCDIRTS.php

>

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