Severe intrauterine ischemia is detrimental to developing fetuses, especially to their brains. However, the influence of mild intrauterine hypoperfusion (MIUH) on the developing brain is not well understood; because optimal animal models are still lacking. Recently, we developed a novel rat model of MIUH, which results in fetal growth restriction (FGR) and low-birth-weight (LBW). The objective of the present study was to evaluate the influences of MIUH on neurological and behavioral development and to discuss putative mechanisms.

We induced MIUH via arterial stenosis with metal microcoils wrapped around the bilateral uterine and ovarian arteries in pregnant rats on embryonic day 17 (E17), which is considered to be equivalent to embryonic weeks 20-25 in humans. Microcoil stenosis decreased blood flow to the fetuses and placentas to 84% and 72% of the pre-stenosis level, respectively. Fetuses were delivered via spontaneous labor and LBW (≤5.5g) pups were used. Pups underwent behavioral tests for executive functions. Low molecular compounds in brain slices were evaluated by MALDI-mass spectrometry imaging. Metabolites in the brains were quantified via metabolomics analysis.

Significant LBW occurred in most offspring. LBW males and females were hyperactive at 3 weeks of age, and only males were hyperactive at 5 weeks of age evaluated with open-field test. Control males and females showed interest in unfamiliar rats evaluated with 3-chamber sociability test at 6 weeks of age, but LBW males and females did not show interest. Gray and white matter areas in LBW rats were mildly decreased without obvious focal tissue damage at 15 days of age, but not at 8 weeks of age. MALDI-mass spectrometry imaging showed accumulation of GABA in the anterior part of hypothalamus in control animals, but such accumulation was not found in LBW hyperactive animals. Metabolomics analysis showed mild decrease of GABA in hypothalamus of LBW rats compared with controls; the decrease was statistically significant in females but not in males.

The present study demonstrates that even MIUH can cause LBW and alter neurological development and executive function as well. Our MIUH model reproduces the clinical signs and symptoms of children born with FGR and LBW. Decreased levels of GABA in the hypothalamus may be one of the mechanisms why LBW children develop neurodevelopmental disorders.