ISSVS · Immune system involvement in sex-specific vulnerability to prenatal stress
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2015-07-01 → 2017-10-21
- EU contribution
- €177,599
- Participants
- 1
- Scheme
- MSCA-IF-EF-RI
Lines connect the coordinator with its partners.
Results in brief
Immune system involvement in sex-specific vulnerability to prenatal stress
Substantial psychological or immunological stress in pregnant women can have consequences for the unborn offspring. Animal models have shown that fetal males are more vulnerable to stress than fetal females. And research in humans corroborate the finding that prenatal stress has different effects in males than in females. Furthermore, evidence is accumulating that prenatal stress may play an important role in the development of neurodevelopmental disorders with a complex multifactorial etiology, which often show a male bias in incidence. The mechanisms underlying the sex-specific effects of prenatal stress are largely unknown, but recent evidence implicates a crucial role for microglia, the resident immune cells of the brain. Although in the adult brain microglia are activated only after infection or injury, in the developing neonate microglia show a structurally activated pattern, especially in males. This time period of male specific microglia activation coincides with the critical period for hormonal action that causes sexual differentiation of the brain. And these observations are not merely a coincidence; recently microglia were found to play a pivotal role in the process of sexual differentiation of the male brain. In this project we investigated whether this male-specific neonatal activation of microglial cells makes males more vulnerable to the effects of stress than females, since we know that overactivation of microglia is detrimental and associated with a wide range of neurological disorders. These experiments contribute to important novel insights into the sex-specific sensitivity to the prenatal environment, and help understand the male predominance in many neurodevelopmental disorders.
Data: CORDIS, © European Union
Project objective
Prenatal stress (PS) is more detrimental to males than to females. Evidence is accumulating that PS may play an important etiological role in the incidence of neurodevelopmental disorders, which often show a male bias in incidence. The mechanisms underlying the sex-specific effects of PS are still unknown, but recent evidence implicates a crucial role for microglia, the resident immune cells of the central nervous system. Although in the adult brain microglia are activated only after infection or injury, in the developing neonate microglia show a structurally activated pattern, especially in males, which coincides with the critical period for hormonal action that cause sexual differentiation of the brain. Very recently the immune system, with a central role for microglia cells, was found to play a pivotal role in the masculinizing pathway. I hypothesize that the sex-specific behavioral vulnerability to PS is caused by sex-specific activation of neonatal microglia, leading to deficits in synaptic pruning, through epigenetic alterations in microglia, most notable in the COX2 promoter. COX2 is pivotal in the feed-forward mechanism of microglia activation and implicated in neurodevelopmental disorders. I will induce or block neonatal microglia activation to study whether PGE2 is both necessary and sufficient to induce the sex-specific vulnerability to PS and its mechanisms. These experiments may give important novel insights into the sex-specific sensitivity to the prenatal environment, and help understand the male predominance in many neurodevelopmental disorders. Coming from a world-leading lab with the main focus on sex differences in the brain I will bring important new knowledge and techniques to the host institute, while I will be thoroughly trained in state-of-the-art techniques at the interface of neuroscience and immunology at the country’s best research university, creating a novel niche in the field and preparing me for a professorship position in the EU.
Original text from CORDIS.
Participants
- UNIVERSITAIR MEDISCH CENTRUM UTRECHT · UtrechtCoordinatorNetherlands
Links
Data: CORDIS, © European Union