Sex Specific Threshold Effects of Prenatal Stress on Striatal Microglia and Relevant Behaviors in Mice

Prenatal stress, a neurodevelopmental disorder (NDD) risk factor, induces neurobehavioral alterations, including offspring neuroimmune cells. Variable offspring outcomes may arise from the extent to which prenatal stress crosses "thresholds" for specific effects. Therefore, we sought to determine offspring outcomes using models with different extents of prenatal stress. We focused on striatal outcomes, because of their relevance for NDDs.

Pregnant CD1 mice were assigned to four groups (each: n = 6): no stress ("NoS") or stressors administered three times daily: i.p. saline injections (low prenatal stress, LoS), interleukin-6 injections as a component of prenatal stress (immune prenatal stress; ImS), or restraint stress + saline injections (high prenatal stress, HiS), embryonic days 12-18. Behavioral (open field, rotarod, amphetamine-induced stereotypy, water T-maze) and brain and placental immunohistochemical (Iba1, Ki67) assessments of offspring were performed.

In adult offspring, HiS altered behaviors across males and females, while ImS induced fewer behavioral changes, and LoS did not affect behavior. Adult striatal microglia morphologies were mostly unchanged across groups, with only HiS altering striatal density of minimally-ramified cells. However, embryonic striatal microglia were affected by all stressors in distinct ways. The HiS model, and to a lesser extent LoS, also influenced immune components of the maternal-fetal interface: placental macrophages.

High and immune stress affected adult striatal-dependent behavior, exceeding the threshold necessary for persistent impacts mostly in males, but all stress models affected embryonic microglia, suggesting a lower threshold for early neuroimmune impacts. Distinct severities and aspects of prenatal stress may therefore underlie different NDD-relevant outcomes.