LPS, lipopolysaccharide, or better lipopolysaccharides are a
group of large molecules consisting of a lipid attached to a polysaccharide.
They are found on the outer cell membrane of Gram-negative bacteria and act as
an endotoxin. It binds to the CD14/TLR4/MD2 receptor complex that can be found
on the membrane of several immune cells (monocytes, dendritic cells,
macrophages and B cells). Like PolyI:C, prenatal LPS, while not crossing the
blood placental barrier, activates the maternal immune system which ultimately
affect the foetus.
We currently have two projects aimed at investigating the long-term consequences of prenatal LPS treatment. In the first project, we specifically investigate how the timing of the maternal immune activation affects behaviour. Specifically, we have exposed pregnant rats to two consecutive injections of LPS on gestational days 10 and 11, 15 and 16 or 18 and 19. We have found that exposure on gestational days 10 and 11 (but not 15/16 or 18/19) leads to cognitive deficits in, among others, working memory capacity and selective attention. Additionally, we found that exposure of gestational days 15 and 16 (but not 10/11 and 18/19) leads to emotional deficits in, among others, reward sensitivity anticipatory pleasure and social interaction.
In the second project, we investigate the epigenetic changes
induced by LPS. Specifically, we aim to perform both a targeted and a genome wide
methylation approach. DNA methylation involves the addition of a methyl group
on specific DNA nucleotides, typically (though not exclusively) cytosines. In
most situations, DNA methylation leads to transcriptional repression, and thus
to a reduction in protein production. By investigating different brain regions
after LPS administration on gestational days 10 and 11 or 15 and 16, we hope to
gain more insight into the neurobiological basis of the cognitive and emotional
deficits induced by prenatal LPS.
This research is in part sponsored by a grant from the
acid (PolyI:C) is an immunostimulant that simulates viral infections. Like
viruses, it does not see to cross the blood placental barrier but activates the
maternal immune system by stimulating the TLR3 receptor (which is found on
several immune cells, such as B-cells, macrophages and dendritic cells). Components
of the maternal immune system, such as interleukin-6 and others are known to cross
the blood placental barrier to reach the foetal brain. Interleukins are known
to activate microglia (the brain’s immune system) and during development can
cause, what is known as a cytokine storm. This is then thought to subsequently
alter the connectivity between different brain regions as well as neurotransmitter
functioning, such as serotonin.
We currently have
two different projects investigating the long-term consequences of polyI:C, one
focussing on behaviour, one on the neurobiological changes in the brain.
In the behavioural
project, we are investigating whether polyI:C exposure on gestational day 15 leads
to changes in social behaviour throughout the lifetime of the rat. Specifically,
we study changes in maternal separation induced ultrasonic vocalizations, social
approach avoidance and empathy, using a helping behaviour paradigm in which
rats can help a trapped rat escape. In addition, we will investigate whether
environmental enrichment from very early on reverses some of these behavioural
behavioural experiments, the brains of the animals exposed to polyi:C and/or
environmental enrichment will be investigated. In this project, we will be
using a variety of standard immunohistochemical and molecular techniques and
will focus predominantly on oligodendrocytes and synaptic connectivity.
Oligodendrocytes are the glial cells that are principally involved in forming
the myelin sheet around axons of nerve cells and there is some clinical
evidence suggesting that the myelination is altered in for instance
schizophrenia and autism spectrum disorder. Likewise, both disorders have been
associated with altered synaptic connectivity, although interestingly in
opposite directions. Thus, while research has found an increased spine density
in autism spectrum disorder, a decrease has been reported in schizophrenia.
Given that prenatal polyI:C has been used as a model for both disorders, it
will be interesting to see how it affects spine density in rats.