Emotional behavior of adults could be triggered in the womb
Research links hormonal imbalance in the placenta to anxiety and possible vulnerability to poor mental health in mice
Adults could be at greater risk of becoming anxious and vulnerable to poor mental health if they were deprived of certain hormones while developing in the womb according to new research by scientists at Cardiff and Cambridge universities.
New research in mice has revealed the role of the placenta in long-term programming of emotional behaviour and the first time scientists have linked changes in adult behaviour to alterations in placental function.
Insulin-like growth factor-2 has been shown to play a major role in foetal and placental development in mammals, and changes in expression of this hormone in the placenta and foetus are implicated in growth restriction in the womb.
“The growth of a baby is a very complex process and there are lots of control mechanisms which make sure that the nutrients required by the baby to grow can be supplied by the mother,” according to Professor Lawrence Wilkinson, a behavioural neuroscientist from Cardiff University’s School of Psychology who led the research.
“We were interested in how disrupting this balance could influence emotional behaviours a long time after being born, as an adult,” he added.
In order to explore how a mismatch between supply and demand of certain nutrients might affect humans, Professor Wilkinson and his colleagues Dr Trevor Humby, Mikael Mikaelsson – both also from Cardiff University – and Dr Miguel Constancia of Cambridge University, examined the behaviour of adult mice with a malfunctioned supply of a vital hormone.
Dr Humby added: “We achieved this by damaging a hormone called Insulin-like growth factor-2, important for controlling growth in the womb. What we found when we did this was an imbalance in the supply of nutrients controlled by the placenta, and that this imbalance had major effects on how subjects were during adulthood – namely, that subject became more anxious later in life.
“These symptoms were accompanied by specific changes in brain gene expression related to this type of behaviour. This is the first example of what we have termed ‘placental-programming’ of adult behaviour. We do not know exactly how these very early life events can cause long-range effects on our emotional predispositions, but we suspect that our research findings may indicate that the seeds of our behaviour, and possibly vulnerability to brain and mental health disorders, are sown much earlier than previously thought.”
Although these studies were carried out in mice, the findings may have wider implications for human development. Further studies are planned to investigate the brain mechanisms linking early life events, placental dysfunction and the emotional state of adults.
The role of Insulin Like Growth Factor (IGF) has been the focus of research in autism at many differing institutes.
Activation of the maternal immune system induces endocrine changes in the placenta via IL-6.
Activation of the maternal immune system in rodent models sets in motion a cascade of molecular pathways that ultimately result in autism- and schizophrenia-related behaviors in offspring.
The finding that interleukin-6 (IL-6) is a crucial mediator of these effects led us to examine the mechanism by which this cytokine influences fetal development in vivo. Here we focus on the placenta as the site of direct interaction between mother and fetus and as a principal modulator of fetal development.
We find that maternal immune activation (MIA) with a viral mimic, synthetic double-stranded RNA (poly(I:C)), increases IL-6 mRNA as well as maternally-derived IL-6 protein in the placenta. Placentas from MIA mothers exhibit increases in CD69+ decidual macrophages, granulocytes and uterine NK cells, indicating elevated early immune activation. Maternally-derived IL-6 mediates activation of the JAK/STAT3 pathway specifically in the spongiotrophoblast layer of the placenta, which results in expression of acute phase genes. Importantly, this parallels an IL-6-dependent disruption of the growth hormone-insulin-like growth factor (GH-IGF) axis that is characterized by decreased GH, IGFI and IGFBP3 levels. In addition, we observe an IL-6-dependent induction in pro-lactin-like protein-K (PLP-K) expression as well as MIA-related alterations in other placental endocrine factors. Together, these IL-6-mediated effects of MIA on the placenta represent an indirect mechanism by which MIA can alter fetal development.