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Brain Deveopment

Mom's immune system shapes baby's brain

The state of a woman's immune system during pregnancy may shape the connectivity of her child's brain...

The state of a woman's immune system during pregnancy may shape the connectivity of neurons in her child's brain, suggests a study of teenage mothers published in the Journal of Neuroscience.

Marisa Spann, Bradley Peterson and colleagues studied thirty-six teenagers (ages 14 to 19) pregnant with their first child, to examine the relationship between two proteins: interleukin-6 (IL-6) and C-reactive protein (CRP).

C-reactive protein (CRP) is found in blood plasma and its levels rise in response to inflammation. It binds to phosphocholine which is produced on the surface of dead or dying cells (even some bacteria). Phosphocholin acts to suppress an immune response by attracting phagocyte cells to come and 'eat' dead, dying or just unneeded cells. So when a cell is damaged, CRP binds to phosphocholine, beginning the phagocytotic immune response.

IL-6 helps regulate fever in response to inflammation. It can cross the blood-brain barrier to initiate chemical compounds in reaction to PGE2 in the hypothalamus of the brain — thereby changing the body's temperature setpoint. In muscle and fatty tissue, IL-6 mobilizes energy which in turn leads to increased body temperature. IL-6 can be secreted by macrophages (a type of white blood cell that also 'eats' cell debris and anything else without proteins specific to healthy cells) in response to specific microbial triggers, referred to as pathogen-associated molecular patterns (PAMPs). PAMPs bind to an important group of detection molecules produced by our innate immune system, called pattern recognition receptors (PRRs). These include Toll-like receptors (TLRs) present on the cell surface and within cellular compartments that induce intracellular signaling cascades which initiate an inflammatory cytokine response.

The mothers' examinations included electrocardiograms to measure fetal heart rate variability (FHRV), at 34-37 weeks gestation. Resting-state images were also collected of infants at 40-44 weeks post-menstrual age (PMA). The researchers found that higher maternal levels of the two proteins are associated with greater connectivity of the infants' brain regions and with higher cognitive ability at 14 months of age.

The relationship between Il-6 and CRP proteins released by the mothers' immune systems during her third trimester of pregnancy influences her infant's brain development network which is involved in disorders such as autism, schizophrenia and attention deficit-hyperactivity disorder. This research emphasizes maternal health as an influence on her child's susceptibility to psychiatric disorders later in life.
The researchers found that higher maternal levels of the IL-6 and CRP proteins are associated with greater connectivity of the infants' brain regions — and with higher cognitive ability at 14 months of age.

Activation of the mother's immune system was also associated with lower fetal heart rate at the end of her gestation/pregnancy. This might indicate delayed development of the autonomic nervous system of her infant. Such results suggest that the final weeks of pregnancy have an important influence on a child's brain development.

Prenatal maternal immune activation (MIA) is associated with altered brain development and risk of psychiatric disorders in offspring. Translational human studies of MIA are few in number. Alterations of the salience network has been implicated in the pathogenesis of the same psychiatric disorders associated with MIA. If MIA is pathogenic, then associated abnormalities in the salience network should be detectable in neonates immediately after birth. We tested the hypothesis that 3rd trimester MIA of adolescent women who are at risk for high stress and inflammation, is associated with the strength of functional connectivity in the salience network of their neonate. Thirty-six women underwent blood draws to measure interleukin-6 (IL-6) and C-reactive protein (CRP), and electrocardiograms to measure fetal heart rate variability (FHRV), at 34-37 weeks gestation. Resting-state imaging data were acquired in the infants at 40-44 weeks post-menstrual age (PMA). Functional connectivity was measured from seeds placed in the anterior cingulate cortex and insula. Measures of cognitive development were obtained at 14-months PMA using the Bayley Scales of Infant and Toddler Development—Third Edition (BSID-III). Both sexes were studied. Regions in which the strength of the salience network correlated with maternal IL-6 or CRP levels included the medial prefrontal cortex, temporoparietal junction, and basal ganglia. Maternal CRP level correlated inversely with FHRV acquired at the same gestational age. Maternal CRP and IL-6 levels correlated positively with measures of cognitive development on the BSID-III. These results suggest that MIA is associated with short- and long-term influences on offspring brain and behavior.

Significance Statement
Preclinical studies in rodents and non-human primates and epidemiological studies in humans suggest that MIA alters the development of brain circuitry and associated behaviors, placing offspring at risk for psychiatric illness. Consistent with preclinical findings, we show that maternal 3rdtrimester IL-6 and CRP levels are associated with neonatal functional connectivity and with both fetal and toddler behavior. MIA-related functional connectivity was localized to the salience, default mode, and frontoparietal networks, which have been implicated in the pathogenesis of psychiatric disorders. Our results suggest that MIA alters functional connectivity in the neonatal brain, that those alterations have consequences for cognition, and that these findings may provide pathogenetic links between preclinical and epidemiological studies associating MIA with psychiatric risk in offspring.

Authors: Marisa Spann, Catherine Monk, Dustin Scheinost, Bradley Peterson.(Children's Hospital Los Angeles, CA, USA)

The authors declare no competing financial interests.

We wish to thank the women who participated in this study, our research assistants, Michelle Gilchrest, Alida Davis, Ashley Rainford, and Kirwan Walsh for dedicated help with participant engagement and data collection.

Article: Maternal immune activation during the third trimester is associated with neonatal functional connectivity of the salience network and fetal to toddler behavior DOI: https://doi.org/10.1523/JEUROSCI.2272-17.2018

This work was supported by the National Institute of Mental Health MH093677-05, the National Center for Advancing Translational Sciences KL2 TR001874 and 000081, and the and Marilyn and James Simons (MJS) Foundation (Whitaker Scholar Developmental Neuropsychiatry program).

About the Journal of Neuroscience
JNeurosci, the Society for Neuroscience's first journal, was launched in 1981 as a means to communicate the findings of the highest quality neuroscience research to the growing field. Today the journal remains committed to publishing cutting-edge neuroscience that will have an immediate and lasting scientific impact while responding to authors' changing publishing needs, representing breadth of the field and diversity in authorship.

About The Society for Neuroscience
The Society for Neuroscience is the world's largest organization of scientists and physicians devoted to understanding the brain and nervous system. The nonprofit organization, founded in 1969, now has nearly 37,000 members in more than 90 countries and over 130 chapters worldwide.

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Mar 2, 2018   Fetal Timeline   Maternal Timeline   News   News Archive

This is the neonatal salience (important) network connectivity. A) Regions of interest used for seed connectivity. The right and left insula and dACC seeds are shown in green. B) Left and C) right insula connectivity. The insula is functionally connected primarily to the contralateral insula, bilateral amygdala (Amyg), ipsilateral hippocampus (Hippo), ipsilateral basal ganglia (BG), ipsilateral IFG, ipsilateral temporal gyrus (TG), and the dACC. D) Dorsal ACC connectivity. The dACC connectivity is primarily to dlPFC, mPFC, SMA, and bilateral anterior insula. Image credit: Spann et al., JNeurosci

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