PRENATAL STRESS REWIRES ADULT- AND DEVELOPMENTAL-BORN DENTATE GRANULE NEURONS CONNECTIVITY

Prenatal stress (PS) induces long-lasting alterations in brain function and connectivity, potentially contributing to cognitive and emotional disturbances later in life. In the dentate gyrus (DG) of the hippocampus, granule neurons generated during development or adulthood integrate into existing circuits and support hippocampal-dependent functions. While we previously showed that PS reduces dentate granule neuron (DGN) production from early life onward, whether PS differentially affects the integration and connectivity of DGNs generated across these two distinct time windows remains unknown. To address this question, dividing cells in the DG of one-day-old (P1) and two-month-old (P60) female and male mice were labeled using a GFP-expressing retrovirus to target developmental- and adult-born DGNs, respectively. Twelve weeks later, direct presynaptic inputs to these neurons were mapped using monosynaptic rabies virus tracing. Starter cells in the granule cell layer (GCL) were quantified, and afferent connectivity from hippocampal, cortical, and septal regions was assessed using a connectivity ratio. PS did not alter the number of starter cells or the total population of GFP+ neurons in either DGN population. However, in adult-born DGNs, PS-exposed male mice displayed increased connectivity from the lateral entorhinal cortex and diagonal band of Broca, along with reduced connectivity from the supramammillary nucleus. Ongoing analyses will determine whether similar alterations occur in developmental-born DGNs.
Overall, these findings strengthen the link between hippocampal connectivity disruptions and stress-related disorders, suggesting that prenatal stress not only reduces neurogenesis but also remodels synaptic integration within hippocampal circuits in a time window-dependent manner.