Abstract
Background
Exposure to maternal immune activation (MIA) in utero is a risk factor for neurodevelopmental
disorders later in life. The impact of the gestational timing of MIA exposure on downstream
development remains unclear.
Methods
We characterized neurodevelopmental trajectories of mice exposed to the viral mimetic
poly I:C (polyinosinic:polycytidylic acid) either on gestational day 9 (early) or
on day 17 (late) using longitudinal structural magnetic resonance imaging from weaning
to adulthood. Using multivariate methods, we related neuroimaging and behavioral variables
for the time of greatest alteration (adolescence/early adulthood) and identified regions
for further investigation using RNA sequencing.
Results
Early MIA exposure was associated with accelerated brain volume increases in adolescence/early
adulthood that normalized in later adulthood in the striatum, hippocampus, and cingulate
cortex. Similarly, alterations in anxiety-like, stereotypic, and sensorimotor gating
behaviors observed in adolescence normalized in adulthood. MIA exposure in late gestation
had less impact on anatomical and behavioral profiles. Multivariate maps associated
anxiety-like, social, and sensorimotor gating deficits with volume of the dorsal and
ventral hippocampus and anterior cingulate cortex, among others. The most transcriptional
changes were observed in the dorsal hippocampus, with genes enriched for fibroblast
growth factor regulation, autistic behaviors, inflammatory pathways, and microRNA
regulation.
Conclusions
Leveraging an integrated hypothesis- and data-driven approach linking brain-behavior
alterations to the transcriptome, we found that MIA timing differentially affects
offspring development. Exposure in late gestation leads to subthreshold deficits,
whereas exposure in early gestation perturbs brain development mechanisms implicated
in neurodevelopmental disorders.
Keywords
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Article info
Publication history
Published online: March 22, 2021
Accepted:
March 15,
2021
Received in revised form:
February 23,
2021
Received:
January 4,
2021
Identification
Copyright
© 2021 Society of Biological Psychiatry.
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- Maternal Immune Activation During Pregnancy and Offspring Brain DevelopmentBiological PsychiatryVol. 90Issue 5
- PreviewOne of the principles of fetal programming is that organs undergoing rapid developmental changes are especially vulnerable to organizing and disorganizing influences of environmental conditions. Because the brain is a prominent target for such influences, the prenatal environment may shape mental health across the lifespan. Among gestational conditions that have been extensively studied and shown to increase the risk for neurodevelopmental and psychiatric disorders is maternal infection and maternal immune activation (MIA) (1).
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