Summary: Researchers discovered a critical role for the cytokine XCL1 in fetal brain development and the emotional behavior of offspring, challenging previous assumptions about its low impact due to minimal circulating levels during pregnancy. The study shows that a temporary spike in maternal XCL1 is essential for proper placental development and regulating fear behavior in male offspring.
Disruptions in this cytokine level were linked to increased anxiety and stress reactions due to neuronal abnormalities in the ventral hippocampus. These findings provide new insights into how maternal immune responses during pregnancy might influence psychiatric conditions in children.
Key Facts:
- Critical XCL1 Spike: A transient increase in XCL1 during pregnancy is crucial for healthy placental development and managing offspring emotional behavior, particularly fear responses.
- Neuronal Impact: Blocking or neutralizing this cytokine spike leads to neuronal abnormalities in the ventral hippocampus and increased anxiety behaviors in male offspring.
- Long-Term Effects: Although the immune and neuronal abnormalities observed in offspring normalize by adulthood, the early-life inflammatory state linked to XCL1 deficiency may set the stage for adult anxious behavior.
Source: Weill Cornell University
Researchers at Weill Cornell Medicine have discovered in a preclinical model that cytokines, proteins that control immune response, circulating in maternal blood during pregnancy may mitigate an offspring’s risk for psychiatric conditions.
The findings are surprising because circulating maternal cytokines are at such low levels that they were not implicated in fetal brain development and offspring behavior before.
The study published online in Brain, Behavior, and Immunity on Feb. 29, reported that cytokine XCL1 produced by maternal immune cells can function as a pregnancy hormone and is required for the proper development of placenta and male offspring fear behavior.
These results support epidemiological studies which have long suggested a link between human maternal infection and inflammation during pregnancy and offspring developing psychiatric disorders later life.
“Using mouse models, we found that circulating XCL1 normally remained at the same low pre-pregnancy level throughout gestation except for a short rise and fall in the middle period,” said corresponding author Dr. Miklos Toth, professor of pharmacology at Weill Cornell Medicine.
“This temporary rise is essential for the proper development of the placenta and offspring emotional behavior.” First author Dr. Rosa Chen was a graduate student in the Toth lab during the study, which was a collaboration with Dr. Heidi Stuhlmann, acting chair of Biochemistry and also of Cell and Developmental Biology and the Harvey Klein Professor of Biomedical Sciences, Cell and Developmental Biology at Weill Cornell Medicine.
When this spike in XCL1 in maternal blood was blocked genetically or neutralized by anti-XCL1 antibodies, the researchers found increased production of factors associated with tissue damage in the fetal placenta which led to increased innate anxiety and stress reactions in male mouse offspring.
The researchers also found a neuronal abnormality in the developing brains of these offspring, specifically in the ventral hippocampus, a region that has been linked to anxiety and anxious behavior.
The immune and neuronal abnormalities observed when the cytokine spike was blocked were normalized by adulthood, suggesting that the adult anxious behavior of the offspring could be related to the early life proinflammatory state caused by the absence of elevated XCL1.
Dr. Toth will explore other chemokines that may regulate placenta development and impact offspring emotional behavior. The team plans to collaborate with researchers who have access to blood samples from pregnant women to see if the profile of XCL1, a protein also found in humans, corresponds to the observations in mouse models.
Funding: This study was support by the National Institute of Mental Health, a part of the National Institutes of Health, grant R01MH113124 and 1R01MH117004.
About this neurodevelopment and mental health research news
Author: Krystle Lopez
Source: Weill Cornell University
Contact: Krystle Lopez – Weill Cornell University
Image: The image is credited to Neuroscience News
Original Research: Open access.
“The chemokine XCL1 functions as a pregnancy hormone to program offspring innate anxiety” by Miklos Toth et al. Brain, Behavior, and Immunity
Abstract
The chemokine XCL1 functions as a pregnancy hormone to program offspring innate anxiety
Elevated levels of cytokines in maternal circulation increase the offspring’s risk for neuropsychiatric disease.
Because of their low homeostatic levels, circulating maternal cytokines during normal pregnancies have not been considered to play a role in fetal brain development and offspring behavior.
Here we report that the T/NK cell chemotactic cytokine XCL1, a local paracrine immune signal, can function as a pregnancy hormone and is required for the proper development of placenta and male offspring approach-avoidance behavior.
We found that circulating XCL1 levels were at a low pregestational level throughout pregnancy except for a midgestational rise and fall.
Blunted elevation in maternal plasma XCL1 in dams with a genetic 5HT1A receptor deficit or following neutralization by anti-XCL1 antibodies increased the expression of tissue damage associated factors in WT fetal placenta and led to increased innate anxiety and stress reactivity in the WT male offspring.
Therefore, chemokines like XCL1 may act as pregnancy hormones to regulate placenta development and offspring emotional behavior.
