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Exposure to stress hormones in the womb linked to mood disorders

May 15, 2013

ResearchBlogging.orgPregnancyStress hormones released by a pregnant mother can cause the placenta to shrink and can directly affect the developing brain of the foetus. Now, researchers have identified the mechanism through which stress may damage an unborn child in the womb. An enzyme in the placenta of the mother and the brain of the foetus acts as a barrier to protect the unborn baby from chemicals released in times of stress. But during periods of prolonged stress – such as anxiety and depression or due to a traumatic event such as abuse – levels of the hormones can soar and are believed to overwhelm the protective barrier, resulting in a host of problems. The damage may make the child more likely to develop mood disorders such as depression, anxiety, and even schizophrenia.

Professor Megan Holmes of the University of Edinburgh has been looking into the mechanisms involved. She identified that an enzyme in the mother and baby, called 11-β HSD2, works by mopping up stress hormones called glucocorticoids (GCCs) and converting them to their inactive form. Using pregnant mice genetically engineered to lack the enzyme, her team showed that the increased exposure to GCCs (like cortisol) resulted in smaller pups, which went on to exhibit the signs of mood disorders. The mothers also had smaller placentas which meant a reduced flow of nutrients to pups in the womb – which could directly contribute to their mental condition.

When the team blocked the enzyme in the brains of the developing pups, but left the enzyme barrier in the placenta, the baby mice still showed some signs of damage. This indicates that both sites, the placenta and the foetal brain, play a role. The team are looking to see if one of the two sites has an overriding effect, although it’s thought to be a combination of the two.

This enzyme barrier is crucial during pregnancy as it maintains the difference between the relatively high levels of stress hormones in the mother and the low levels in the foetus. If too much GCC reaches the foetus it can affect the development of growing tissues. For instance, if the developing brain is exposed to cortisol it can cause the young cells to stop dividing and to start maturing instead. Although this is a key step in the normal developmental process, if it happens too early things can go wrong and it can result in faulty wiring of the brain. “The neurons may not be in right place yet and may be differentiating too soon” says Holmes.

But Holmes’ work suggests that stress exposure doesn’t just impact the brain in the womb, it can have an effect in adolescence too. Puberty is another key point in the timeline of the brain’s development, as it’s when existing connections and networks are strengthened or weakened. It’s a time when the brain is particularly sensitive to environmental factors, including stress.

In experiments, adolescent rats were conditioned to associate a flashing light with an electric shock and then had their brains scanned using functional MRI (fMRI). When they were shown the cue of a flashing light their emotional fear pathways were activated. In rats that had been stressed, the amygdala – the part of the brain which deals with fear and emotion – was overactive compared with rats that hadn’t been stressed. This indicated that the way in which the brain processed emotional stimuli had been changed.

The results suggest that the early teenage years are another critical period in the brain’s development in which stress could have an impact on the network of connections. The rewiring of emotional response pathways in the brain could result in long-term problems with mood disorders and emotional behaviour.

Presenting these findings at the British Neuroscience Association’s Festival of Neuroscience conference in London last month, Professor Holmes said that she hopes to use the animal models to uncover more about the pathways involved and to find more accessible targets for treatment. “We think this a really good translational model, so we can do the same tests or comparative tests to what are done in patient populations.”

It’s not all just mice and rats either, the damaging effect of stress hormones on the developing brain has demonstrated in human studies. Trials showed that the children of women who suffered from anxiety or depression during the pregnancy were more likely to develop the mood disorders themselves. In a telephone interview, Professor Vivette Glover, of Imperial College London, explained to me that in pregnant mothers with anxiety, production of the enzyme 11-β HSD2 decreases and this could expose the unborn baby to more cortisol. “The first thing is to look after pregnant women better,” said Glover. Although whether or not it’s a case for drug treatment isn‘t clear at this stage, “it’s an interesting idea”, she added.

Although genetic predisposition and environmental factors play a strong role in influencing the risk of developing mood disorders, this research hints at the potential for early therapeutic intervention. Currently, targeting 11-β HSD2 directly for drug treatment is difficult, so clinical trials may not be on the horizon just yet. “At the moment our intention is to use our models to see exactly which pathways are changing through development,” said Holmes, “and to try and find an alternative target that’s more easily targetable therapeutically.”

References:

  • Holmes M (2013). Perinatal programming of stress-related behaviour by glucocorticoids. Abstract presented at BNA 2013, London.
  • O’Donnell, K., Bugge Jensen, A., Freeman, L., Khalife, N., O’Connor, T., & Glover, V. (2012). Maternal prenatal anxiety and downregulation of placental 11β-HSD2 Psychoneuroendocrinology, 37 (6), 818-826 DOI: 10.1016/j.psyneuen.2011.09.014
  • Giedd, J., Blumenthal, J., Jeffries, N., Castellanos, F., Liu, H., Zijdenbos, A., Paus, T., Evans, A., & Rapoport, J. (1999). Brain development during childhood and adolescence: a longitudinal MRI study Nature Neuroscience, 2 (10), 861-863 DOI: 10.1038/13158
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