Structural Magnetic Resonance Imaging and Genome-Wide Transcriptional Profiling Reveal Intergenerational Vulnerability in a Mouse Model of Preconceptional Stress

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Abstract
Antenatal depression, affecting 10–20% of pregnancies worldwide, represents a major public health concern due to its association with maternal suicide, obstetric complications, and long-term neurodevelopmental and psychiatric vulnerability in offspring. Despite its prevalence and impact, the neurobiological mechanisms by which maternal mood disturbance shapes offspring brain development remain poorly understood. To address this, we employed a social-isolation rearing (SIR) paradigm in female C57BL/6N mice spanning preconception, gestation, and lactation. Adult offspring were evaluated using established assays of anxiety-like behavior, high-resolution ex vivo structural magnetic resonance imaging, and thalamic bulk RNA sequencing. Offspring of SIR dams exhibited consistent anxiety phenotypes across multiple behavioral tests. Neuroimaging revealed thalamic and striatal hypotrophy together with expansion of gustatory/visceral and visual cortices. Multivariate partial least-squares modelling identified thalamostriatal reductions as the principal latent factor associated with behavioral variance, whereas cortical hypertrophy covaried with exploratory drive. Transcriptomic analysis demonstrated extensive, sex-divergent reprogramming: males showed enrichment of pathways regulating protein synthesis and synaptic organization, while females exhibited alterations related to neuronal plasticity and myelin development. These findings establish preconceptional SIR as a translational model of maternal depression, identify the thalamus as a key locus of intergenerational vulnerability, and provide integrated imaging and molecular markers that may inform mechanistic studies and preventive interventions for offspring exposed to maternal mood disorders.

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