BackgroundMaternal prenatal depression is a significant public health issue associated with mental disorders of offspring. This study aimed to determine if maternal prenatal depressive symptoms are associated with changes in neonatal behaviors and brain function at the resting state. MethodsA total of 204 pregnant women were recruited during the third trimester and were evaluated by Edinburgh Postpartum Depression Scale (EPDS). The mother-infant pairs were divided into the depressed group (n = 75) and control group (n = 129) based on the EPDS, using a cut-off value of 10. Cortisol levels in the cord blood and maternal blood collected on admission for delivery were measured. On day three of life, all study newborns were evaluated by the Neonatal Behavior Assessment Scale (NBAS) and 165 infants were evaluated by resting-state functional near-infrared spectroscopy (rs-fNIRS). To minimize the influences of potential bias on the rs-fNIRS results, we used a binary logistic regression model to carry out propensity score matching between the depressed group and the control group. Rs-fNIRS data from 21 pairs of propensity score-matched newborns were used for analysis. The associations between maternal EPDS scores, neonatal NBAS scores, and cortisol levels were analyzed using linear regressions and the mediation analysis models. ResultsCompared to the control group, the newborns in the depressed group had lower scores in the social-interaction and autonomic system dimensions of NBAS (P < 0.01). Maternal and umbilical cord plasma cortisol levels in the depressed group were higher (P < 0.01) than in the control group. However, only umbilical cord plasma cortisol played a negative mediating role in the relationship between maternal EPDS and NBAS in the social-interaction and autonomic system (β med = −0.054 [−0.115,−0.018] and −0.052 [−0.105,−0.019]. Proportional mediation was 13.57 % and 12.33 for social-interaction and autonomic systems, respectively. The newborns in the depressed group showed decreases in the strength of rs-fNIRS functional connections, primarily the connectivity of the left frontal-parietal and temporal-parietal regions. However, infants in the depressed and control groups showed no differences in topological characteristics of the brain network, including standardized clustering coefficient, characteristic path length, small-world property, global efficiency, and local efficiency (P > 0.05). The social-interaction Z-scores had positive correlations with functional connectivity strength of left prefrontal cortex-left parietal lobe (r = 0.57, p < 0.01),prefrontal cortex-left parietal lobe - left temporal lobe (r = 0.593, p < 0.01) and left parietal lobe - left temporal lobe (r = 0.498, p < 0.01). Autonomic system Z-scores were also significantly positive correlation with prefrontal cortex-left parietal lobe (r = 0.509, p < 0.01),prefrontal cortex-left parietal lobe - left temporal lobe (r = 0.464, p < 0.01), left parietal lobe - left temporal lobe (r = 0.381, p < 0.05), and right temporal lobe and left temporal lobe (r = 0.310, p < 0.05). ConclusionThis study shows that maternal prenatal depression may affect the development of neonatal social-interaction and autonomic system and the strength of neonatal brain functional connectivity. The fetal cortisol may play a role in behavioral development in infants exposed to maternal prenatal depression. Our findings highlight the importance of prenatal screening for maternal depression and early postnatal behavioral evaluation that provide the opportunity for early diagnosis and intervention to improve neurodevelopmental outcomes.