Hippocampal growth and function are reduced in the newborn following fetal growth restriction

The rate of human brain growth is greatest in mid-to-late fetal gestation, corresponding to peak neuronal dendritogenesis. In pregnancies complicated by fetal growth restriction (FGR) caused by placental dysfunction, brain development is adversely impacted, with evidence of reduced total and hippocampal brain volume in childhood and cognitive deficits. The cellular basis for hippocampal maldevelopment and dysfunction in FGR is unknown. In this study we employed complementary preclinical and clinical investigations of hippocampal developmental trajectory in growth restricted neonates to address this knowledge gap. In the preclinical study (FGR n=18, control n=19), FGR was induced in fetal sheep via surgical induction of placental insufficiency at 89 days gestational age (dGA, term is 148dGA), and after near-term birth (136dGA), postnatal memory function was measured over four weeks. Neuronal dendritogenesis (dendrite length, branching, complexity) was assessed using Golgi-Cox staining of individual hippocampal Cornu Ammonis (CA)1 neurons at two neonatal timepoints, newborn age at 24 hours after birth and 4-weeks of age, to compare the trajectory of hippocampal neuron development in FGR and control lambs. Results show that, in control lambs, total dendrite length and branching of CA1 hippocampal neurons significantly increased between newborn age and 4-weeks. In FGR lamb brains, neither dendrite length or branching increased over this period, and dendrite deficits were worse in FGR lambs at 4-weeks, corresponding to reduced hippocampal area. In 4-week-old lambs, we observed a significant correlation between total dendrite length of CA1 neurons and memory function. Hippocampal growth trajectory and function deficits were corroborated in small for gestational age (SGA) infants born very preterm. Magnetic resonance imaging (MRI) was performed in very preterm infants in early life, and repeated at term equivalent age, showing that the trajectory of anterior hippocampal growth was significantly reduced in SGA infants (n=20) compared to appropriate for gestational age (AGA; n=139) infants. Within the SGA infant cohort, reduced anterior hippocampal volume was significantly associated with lower Bayley Cognitive Composite scores at 18 months corrected age, controlling for gestational age at birth and infant sex. Together, these findings demonstrate that the trajectory of hippocampal growth is significantly impaired in SGA/FGR infants, caused by disturbed neuronal dendritogenesis that is programmed by an adverse fetal environment and persists, or worsens, after birth. Results in the clinical cohort provide the critical link between programming of reduced dendritogenesis, hippocampal volume deficit and cognitive dysfunction in SGA infants.