Sex-related differences and associated transcriptional signatures in the brain ventricular system and cerebrospinal fluid development in full-term neonates.

Background: The cerebrospinal fluid (CSF) is known to serve as a unique environment for neurodevelopment, with specific proteins secreted by epithelial cells of the choroid plexus (CP) playing crucial roles in cortical development and cell differentiation. Sex-related differences in the brain in early life have been widely identified, but few studies have investigated the neonatal CSF system and associated transcriptional signatures.

Methods: This study included 75 full-term neonates [44 males and 31 females; gestational age (GA) = 37-42 weeks] without significant MRI abnormalities from the dHCP (developing Human Connectome Project) database. Deep-learning automated segmentation was used to measure various metrics of the brain ventricular system and CSF. Sex-related differences and relationships with postnatal age were analyzed by linear regression. Correlations between the CP and CSF space metrics were also examined. LASSO regression was further applied to identify the key genes contributing to the sex-related CSF system differences by using regional gene expression data from the Allen Human Brain Atlas.

Results: Right lateral ventricles [2.42 ± 0.98 vs. 2.04 ± 0.45 cm3 (mean ± standard deviation), p = 0.036] and right CP (0.16 ± 0.07 vs. 0.13 ± 0.04 cm3, p = 0.024) were larger in males, with a stronger volume correlation (male/female correlation coefficients r: 0.798 vs. 0.649, p < 1 × 10^- 4). No difference was found in total CSF volume, while peripheral CSF (male/female β: 1.218 vs. 1.064) and CP (male/female β: 0.008 vs. 0.005) exhibited relatively faster growth in males. Additionally, the volumes of the lateral ventricular system, third ventricle, peripheral CSF, and total CSF were significantly correlated with their corresponding CP volume (r: 0.362 to 0.799, p < 0.05). DERL2 (Degradation in Endoplasmic Reticulum Protein 2) (r = 0.1319) and MRPL48 (Mitochondrial Large Ribosomal Subunit Protein) (r=-0.0370) were identified as potential key genes associated with sex-related differences in CSF system.

Conclusion: Male neonates present larger volumes and faster growth of the right lateral ventricle, likely linked to corresponding CP volume and growth pattern. The downregulation of DERL2 and upregulation of MRPL48 may contribute to these sex-related variations in the CSF system, suggesting a molecular basis for sex-specific brain development.