Aberrantly integrated adult-born immature neurons disrupt brain-wide networks during spatial memory processing

Memory deficits observed in various neurological and psychiatric disorders may, in part, arise from dysregulated adult-born immature neurons (ABNs) in the dentate gyrus (DG). However, the mechanisms by which these aberrant neurons contribute to brain-wide network dysfunction and memory impairment remain poorly understood. Using a well-established mouse model with aberrantly integrated ABNs and associated memory deficits, we employed resting-state functional magnetic resonance imaging (rs-fMRI) and found that a few hundred dysregulated ABNs (<0.1% of total DG granule neurons) were sufficient to disrupt functional connectivity between the DG and the insular cortex, two regions lacking direct anatomical connections. Further investigation using rabies-based retrograde tracing and fiber photometry recording revealed that dysregulated ABNs impaired calcium dynamics, inter-regional synchrony, and temporal coordination across both local hippocampal circuits and distal regions, including the mediodorsal thalamus and insular cortex, during a spatial memory task. Together, these findings reveal how a small population of aberrantly integrated ABNs can disrupt brain-wide network dynamics and ultimately impair spatial memory processing.