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Antidepressants during pregnancy: underlying mechanisms associated with neurodevelopmental outcome

Periodic Reporting for period 1 - depreg (Antidepressants during pregnancy: underlying mechanisms associated with neurodevelopmental outcome)

Reporting period: 2015-06-01 to 2017-05-31

Problem being addressed
About 20% of the current pregnant women are depressed or suffer from depressive symptoms during pregnancy. Up to 5% percent of these women suffer from major depression and cannot operate without antidepressant treatment. Both depressive symptoms during pregnancy as well as using antidepressants during pregnancy can negatively impact the behavioral development and health of the child. It is difficult to tell whether taking antidepressants during pregnancy increases the risk for the developing child, and if so whether we can unravel the mechanisms that are involved in these risks and use this information for new therapeutic applications. Therefore the overall aim of this project is to identify molecular mechanisms and behavioral alterations in the offspring due to antenatal depression, antidepressant treatment during pregnancy, and their combination.

Importance for society
Currently, little information is available about the underlying mechanisms contributing to the critical implications for the health of the child due to depression during pregnancy, antidepressant treatment during pregnancy and their combination. The current project focused especially on the molecular mechanisms (gene expression and epigenetics in the brain) underlying the behavioral alterations in the offspring. So far, genetic studies have not revealed new targets for the treatment of depression. As this project focuses on epigenetic modulations of altered genes due to depression or antidepressant use during pregnancy, new targets for therapeutic applications may be discovered.

Overall objectives
The objectives of the proposal were to identify the effects of depression during pregnancy, antidepressant treatment use during pregnancy, and their combination on:

1. behavior of the offspring,
2. gene expression patterns of the fetal brain (offspring), and
3. epigenetic profile adult brain and blood plasma (offspring) of candidate genes found in objective 2.

Because it is difficult to discern between the effects of the drug and the effects of the depression itself in humans, we used a rat model for depression. These rats were treated with an antidepressant drug or a placebo during pregnancy and the lactation period. This period was chosen to mimic the developmental stages of the human brain. Besides these rats, also healthy rats were treated with antidepressants to find out what the effect of only antidepressant use during pregnancy was on the offspring.
We investigated the behavioral alterations and molecular mechanism in the offspring from mothers that were:
A) Healthy rats treated with placebo
B) Healthy rats treated with antidepressants
C) Depressed treated with placebo
D) Depressed treated with antidepressants (mimicking the human situation)
Breeding and treatment of the animals took much more time than was anticipated for. The treatment of rats with antidepressants caused a higher mortality rate in both mothers and offspring than expected. This was an interesting observation on itself and will be published in our first experimental publication. Our first batch was born in June 2016 and our final batch of animals was born in January 2017. However in the 4 offspring batches we tested animals 1) for social-emotional behavior (juvenile play behavior and social interaction during adulthood); 2) Anxiety- and depression-related behavior, and 3) externalizing behaviors (aggression).

Social-emotional behavior
Both male and female offspring exposed to antidepressants during pregnancy spent less time in social play behavior. Maternal depression did not affect social play behavior. When studying the specific characteristic form of social play behavior “pouncing” it was found that male offspring was not affected by the maternal depression, while female offspring showed increased pouncing behavior when maternal stress was combined with exposure to antidepressant treatment. These results indicate that antidepressant use in healthy mothers show negative effects on social play behavior, but suggest a positive (female), or no effect (males) of antidepressant treatment during pregnancy when a mother is depressed. Retested during adulthood showed that male offspring exposed to antidepressants displayed decreased social behavior. However male offspring exposed to maternal depression and antidepressants did not show this decrease in social behavior. Interestingly, females displayed increased social behavior was increased due to maternal depression. Antidepressants did not influence the female social behavior during adulthood.
The manuscript of these data is in preparation to be submitted for publication in September 2017. These data have also been presented at the Dutch Neuroscience meeting 2017 in Lunteren the Netherlands, at the ECNP meeting 2015 (Amsterdam, the Netherlands), 2016 (Vienna, Austria) and 2017 (Paris, France).

Anxiety- and depression-related behavior
Offspring exposed to antidepressants spent less time in the center of a novel open arena suggesting increased anxiety in these animals. Offspring exposed to maternal depression had higher sucrose preference when concentrations of sucrose were low, but lower sucrose preference when a higher dose of sucrose was presented. These results indicate that both antidepressants and maternal depression can influence the affective behavior of the offspring.
The behavioral tests and analysis were finished in July 2017. The manuscript is in preparation and will be submitted for publication in the autumn of 2017.

Externalizing behaviors
Only male offspring were tested for aggressive behavior. Offspring exposed to antidepressants showed less aggressive behavior, and latency to attack other males was increased. Maternal depression did not affect aggressive behavior in males.
We are extending this research by studying sexual behavior in these males as well. Experiments are finished and analysis are ongoing. The manuscript will be prepared as soon as the data are available and submitted for publication in the winter of 2017.

Gene expression patterns and epigenetic profile
All rats have been bred and brains dissected. In the autumn of 2017 DNA and RNA samples will be isolated from these samples and microarray will be performed in the autumn 2017. Once results are analyzed (winter 2017/2018) DNA will be investigated for epigenetic alterations. This process is ongoing and is finished in 2018.
The H2020-MSCA-IF-2014 finished in May 2017, but research is still in full progress. Together with two PhD students we hope to have all results published in 2018. We also executed a microbiome study on the fecal and vaginal samples and the behavior of depressed mothers (two manuscripts in preparation). Moreover when the rats were exposed to maternal separation, to induce depression-like behavior, we also studied the fecal microbiome and published it in Frontiers of Cellular Neuroscience (https://doi.org/10.3389/fncel.2017.00222). We also published a review on the rat model for depression in Frontiers of Cellular Neuroscience in April 2017 (https://doi.org/10.3389/fncel.2017.00117). Unfortunately due to the delay in breeding the genetic and epigenetic studies are not finished but the materials have been gathered to execute the experiments (2018). The data of the behavioral experiments were presented at the ECNP meeting in Paris in September 2017.
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