Chronic prenatal corticosterone exposure alters postpartum maternal behavior and shapes sex-specific offspring outcomes

Technical Summary: Chronic Prenatal Corticosterone Exposure Alters Postpartum Maternal Behavior and Shapes Sex-Specific Offspring Outcomes

Problem Statement
Prenatal maternal stress is a widespread phenomenon associated with increased risks for cardiometabolic dysfunction and psychiatric disorders in offspring. While the concept of "fetal programming" suggests that prenatal stress alters offspring development, the specific mechanisms remain unclear. It is hypothesized that maternal glucocorticoids (corticosterone in rodents) play a critical role, potentially by suppressing placental enzymes that normally protect the fetus, or by altering the postnatal maternal environment. However, distinguishing between direct fetal programming effects and indirect effects mediated by altered maternal caregiving behavior remains a challenge. This study aims to test the hypothesis that long-lasting behavioral and neurobiological changes in offspring prenatally exposed to elevated maternal glucocorticoids are mediated, at least in part, by maternal caregiving.

Methodology
The study utilized C57BL/6J mice with a specific focus on the late gestational window (Gestational Days 12–18), a sensitive period for hippocampal and cortical neurogenesis.

• Prenatal Exposure: Pregnant dams received daily subcutaneous injections of corticosterone (20 mg/kg) or vehicle (sesame oil) from GD12 to GD18.
• Maternal Assessment: Dams were monitored for physiological parameters (weight, food/fluid intake), anxiety-like behavior (open-field test), and appetitive maternal behaviors (pup retrieval, grooming, odor preference) on postnatal days (PND) 9–18.
• Offspring Assessment: Offspring were tested in separate cohorts at adolescence (PND 33–36) and adulthood. Behavioral assays included open-field exploration, novel object recognition, and elevated plus maze. Physiological measures included serum corticosterone levels.
• Cross-Fostering: To disentangle fetal programming from postnatal care, pups were swapped between vehicle- and C-CORT-treated dams within 24 hours of birth.
• Neurobiological Analysis: Fluorescence in situ hybridization (FISH) was used to quantify the expression of mineralocorticoid receptors (MR), glucocorticoid receptors (GR), and corticotropin-releasing factor receptor 1 (CRFR1) in specific brain regions (perifornical area Ucn3 neurons in dams; dorsal hippocampus in offspring).

Key Results

• Maternal Effects: Dams treated with chronic prenatal corticosterone (C-CORT) exhibited increased anxiety-like behavior (reduced center time in open field) and elevated circulating corticosterone levels at weaning (PND 22), despite a transient reduction during the treatment course. Behaviorally, C-CORT dams showed delayed pup retrieval, increased time investigating pups, and a specific preference for male pup odor over female pup odor. Neurobiologically, these dams displayed increased mineralocorticoid receptor (MR) expression in perifornical area Ucn3-expressing neurons.
• Offspring Effects (Adolescence vs. Adulthood):
  • Adolescence: Female offspring of C-CORT dams showed enhanced novel object recognition compared to controls, while males were unaffected.
  • Adulthood: Adult female offspring of C-CORT dams exhibited a depression-like phenotype, characterized by increased immobility and reduced locomotion in the open field. They also lacked the typical female elevation in basal circulating corticosterone and showed upregulated CRFR1 expression in the hippocampus (specifically CA1). Male offspring were largely unaffected in these specific measures at the time points studied.
• Cross-Fostering Findings:
  • Normalization: Cross-fostering normalized the increased immobility, basal corticosterone levels, and hippocampal CRFR1 expression in adult female offspring, suggesting these outcomes are heavily dependent on the postnatal maternal environment.
  • Persistence: However, cross-fostering did not reverse hypoactivity (reduced velocity and distance traveled) in adult females, indicating that in utero exposure and postnatal care exert distinct effects.
  • Male Anxiety: Male offspring raised by C-CORT-treated dams (regardless of their prenatal exposure) exhibited increased anxiety-like behavior, highlighting sex-specific effects of the postnatal maternal environment.

Significance and Claims
The authors conclude that both fetal programming and the postnatal maternal environment contribute to sex-specific neurobiological, endocrine, and behavioral outcomes in offspring. The study provides evidence that prenatal exposure to excessive maternal corticosterone leads to long-lasting changes in the dam's physiology and behavior, which in turn shape the offspring's development. Specifically, the paper claims that certain sex-specific effects of prenatal C-CORT exposure on adult offspring—particularly those related to depression-like behavior, basal stress hormones, and hippocampal CRFR1 expression—are moderated by maternal care. Conversely, other effects, such as reduced locomotor activity, appear to be driven by direct fetal programming. The findings reinforce the necessity of considering the postnatal caregiving environment when evaluating the long-term consequences of prenatal stress.