Link between pregnancy stress, immune activation, and postpartum depression

By Dr. Liji Thomas, MDOct 22 2019

A new study presented at the Society for Neuroscience meeting on October 19, 2019, at Chicago, shows for the first time how postpartum depression could actually be due to abnormal immune system activation within the brain, which in turn is set off by chronic pregnancy stress.  This is the earliest study to show this link in animals.

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The finding is important because it shows how stress can counter the normal relative immunosuppression of pregnancy in the brain while leaving it intact in the rest of the body. Researcher Benedetta Leuner says, “That suggests there's this disconnect between what's happening in the body and what's happening in the brain.”

Postpartum depression is a condition in which new mothers feel extremely sad, anxious and tired, to the point that they cannot care for themselves and for the baby properly.

How does chronic stress induce postpartum depression?

We already know that chronic stress causes a higher risk of postpartum depression. For one thing, stress is known to provoke inflammation, which in turn triggers an immune response that guards against the detrimental effects of inflammation on the body.

The researchers have been inducing postpartum depression in pregnant rats for the last few years through chronic exposure to stress, in order to look into the biological basis of the condition. Normally, pregnant rats show immunosuppression, typical of pregnancy, which persists until the child is born. While this was already known to occur in the systemic immune system, prior research by Leuner in tandem with Kathryn Katz showed that brain immune responses were also downregulated during pregnancy, as shown by a decrease in the number of microglia.

With long-term stress exposure, however, there is a disruption in the brain neurochemicals indicating the occurrence of a stress-induced immune response in the brain as well. In other words, the neurons and their environment appear to be inflamed in pregnant rats exposed to stress. This may be the background against which the mother shows a high vulnerability to depression. In stressed pregnant rats, immunosuppression persists in the rest of the body, however, which is an unusual state of affairs.

The study and its findings

In the current work, the pregnant rats face a variety of uncomfortable and unpredictable occurrences throughout the period of gestation, thus experiencing psychological stress without any direct physical harm to either mother or offspring.

The mother rats showed a range of proinflammatory markers when exposed to this type of stress. This indicated to the researchers that the microglial cells within the brain, which are the immune cells for this organ, were reacting to the stress by increased activity and proliferation. In the process, the brain cells were being programmed in different ways by microglial signals.

One such change is the lack of the normal pregnancy-associated increase in hair-like neuronal cell projections called dendritic spines, which promote the exchange of information between neurons. Rats that failed to show this normal pregnancy-linked change became anxious mothers, unable to interact physically with their brood as much as normal rats, and appearing to be depressed.

The researchers think that this neuroinflammation may be related to, and occurring side-by side with, the abnormal brain signals that they observed as an accompaniment to chronic stress in earlier research. This could help explain another phenomenon they observed in these stressed pregnant rats – the microglial cells’ increased phagocytic activity, where they tend to gulp up more matter than they normally would.

Leuner explains: “By layering gestational stress onto a normal pregnancy, we're finding evidence of inflammatory signaling in the brain that could be bad for dendritic spines and synapses. But we've also found changes in the microglia's appetite. Every characteristic we've looked at in these cells has changed as a result of this stress.”

Future directions

The focus of their future study will be to find out whether microglial activation causes both altered immune signaling and excessive phagocytosis, which could be part of the underlying reason for the absence of dendritic spines – perhaps, they think, by removing the synapse-associated cellular substance normally found on dendrites. Currently they are trying to image microglia in the act of ‘eating’, to catch them possibly engulfing synaptic material. They also want to reduce the levels of specific inflammatory brain markers to see what change that produces on postpartum rats showing symptoms similar to depression.

The current study thus indicates that the absence of dendritic spines is associated with changes in the brain environment. These in turn are linked to depressive-like symptoms. The latest findings show that these physical changes could be due to microglial abnormalities, and thus this could be the fundamental reason for post-partum depression.