NEWS: Medical Life Sciences

September 5, 2013

A stressful pregnancy might be the last thing a future mother needs, but it is to her unborn baby that this stress spells real trouble. All because stress hormones (called glucocorticoids or GCs) can disturb normal foetal brain development, leading to behavioural and/or emotional problems later in life. Despite this danger we are still far from understanding how GCs work. But now a study in rats by a Portuguese team has discovered that the prenatal (before birth) effects of GCs on behaviour are linked to low dopamine (a brain messenger) in the brain areas linked to pleasure, but also that this could be treated.

Sonia Borges and Barbara Coimbra from the University of Minho found that rats exposed to prenatal stress developed emotional and social behavioural problems and that this was linked to reduced levels of dopamine, but also that once dopmaine levels were restored to normal (what was very easy to do) there was a complete reversion of the social problems. This supports the idea that changes in the brain by early life trauma can be reversed.

The study, that is coming out in the September issue of the journal Neuropsychopharmacology, could have implications for neuropsychiatric disorders associated with dopamine and early neurodevelopmental problems such as depression, anxiety, attention-deficit hyperactivity disorder (ADHD), schizophrenia and autism. Ana João Rodrigues, one of study leaders (together with Nuno Sousa) warns for the need to be very cautious though ” Although there are some clues that prenatal stress may affect emotional and social behaviour in humans, our work is still at very early stage. All we can really say” – she points – “is that dopamine is able to improve deficiencies in social behaviour and this might have important implications for diseases characterised by social impairment”

While GCs mediate the negative effects of stress, they are also of crucial importance for the normal functioning of the body; from controlling the immune system to help the maturation of foetal organs, GCs are indispensable to life. In fact, even if prenatal stress can provoke problems in the brain, GCs are still routinely given to pregnant women with danger of premature births for foetal lung maturation. So it is urgent to understand better how GCs work to be able to make better crucial, even life dependent,  decisions

In the study soon to be published Borges, Coimbra and colleagues exposed rats still in the uterus to high levels of GCs (the equivalent of having a very stressed mother), and found that these animals go to develop signs of depression and lack of motivation later in life like previously reported, but, surprisingly, they also found they developed social impairments. Animals exposed to prenatal stress played less, interacted awkwardly with others and had less “happy” calls (“happy” and “sad” calls can be differentiated by their sound frequencies).

” Since our group had seen before that exposure to prenatal GCs affected a neural circuit important for the feelings of reward and pleasure (the mesolimbic system) ” – explains Rodrigues – “and in juvenile rats rough tumble and play is one of the most rewarding behaviours, we wondered if the problem could be dopamine, a key molecule in this system.”

And in fact, it was found found that “prenatal stress” rats lacked dopamine in both the amygdala and the nucleus accumbens (NAc), which are regions of the mesolimbic system.

But what was remarkable was the finding that by simply adding L-dopa (a precursor of dopamine given to Parkinson’s patients who also lack it) to the water of the affected animals, their social and emotional abnormalities disappeared turning them indistinguishable from those rats that went through normal pregnancies.

So the new study reveals that high GC levels/prenatal stress can lead to social impairments, as well as the emotional problems, by reducing dopamine levels in the brain areas linked to pleasure perception. But also that once these dopamine levels are corrected, the problems disappear completely.

So could things work similarly in humans?  In diseases like depression, autism and schizophrenia, which are characterised by emotional and social inadequacies and have already been linked to prenatal stress? Rodrigues alerts “To transfer these results to humans requires caution. These results do not mean that L-dopa is a miraculous drug to treat lack of motivation or depression, although it certainly appears that the mesolimbic dopamine system is critical in these problems. For now the most important thing is that we are starting to unveil GCs’ induced molecular changes in specific neuronal circuits, which will help in the understanding of some of these problems”.

What is most interesting about Borges and Coimbra’s study too is the fact that it “links the dots” – prenatal stress has already been associated to an increased incidence of several neurologic diseases and some of these to problems in dopamine. Social impairments like those seen autism and ADTH, for example, are more common in individuals that went through stressful prenatal periods. The new study now reveals the “underneath story” (or a version of it at least).

But the study had another interesting result: when the social behaviour of the animals was tested, and while two “prenatal stress” rats put together didn’t play, surprisingly, the interaction of a “prenatal stress” rat in the presence of a normal one was very different. This because the normal animal would incite and provoke the “stressed” rat to play until it responded and started interacting. This supports the idea that interaction with other individuals can make a vital difference to revert the negative effects of pre-natal or early life stress on the brain. It also reveals an interesting degree of empathy between the animals, an idea that recently has started to receive much attention.