Developmental changes in hippocampal neurite colocalize with the expression of genes involved in modulating low-theta oscillations

The hippocampus is a critical brain structure that supports the encoding and retrieval of episodic memories, yet the intricate development of its microstructure in humans remains unknown. Understanding this microstructural maturation and how it relates with the maturation of hippocampal function may provide critical insight into the basic mechanisms underlying memory and their disruption in disease. To address this gap, we non-invasively estimated the density and branching complexity of neurite (dendrites, axons, glial processes) using diffusion-weighted MRI in 364 participants aged 8–21. We found that these microstructural measures differ between subfields and along the longitudinal axis of the hippocampus. Notably, we observed spatially heterogeneous increases in the branching complexity of neurite until approximately 15 years of age, with prominence in CA1, stratum radiatum/lacunosum/moleculare, subiculum, and the anterior hippocampus. Furthermore, our imaging transcriptomics analysis shed light on the molecular underpinnings of these developmental dynamics. Regions exhibiting substantial age-related increases in neurite orientation dispersion also tend to express genes associated with the modulation of low-theta oscillations during memory encoding. These results suggest that the protracted maturation of hippocampal microstructure may be linked to the development of low-theta oscillation modulations during encoding.