A preconceptional stress model identifies thalamostriatal substrates of intergenerational vulnerability

Antenatal depression affects up to 20% of pregnancies worldwide and is associated with increased neuropsychiatric vulnerability in offspring, yet the enduring behavioural, neuroanatomical, and molecular features associated with maternal mood disturbance remain incompletely characterized. To model depression that begins before conception, female mice were subjected to social-isolation rearing (SIR) from weaning through gestation and lactation, and behavioural, neuroanatomical, and molecular outcomes were assessed in adult offspring of both sexes. Offspring of SIR dams exhibited robust anxiety-like behaviours across multiple paradigms. High-resolution ex vivo structural magnetic resonance imaging revealed reduced relative volumes of the thalamus and striatum, together with relative expansion of gustatory/visceral and visual cortices. Multivariate analyses identified a pattern of thalamostriatal and other regional volume differences that covaried with behavioural impairment. Diffusion tensor imaging further identified region-specific elevations in fractional anisotropy, consistent with persistent differences in brain microstructure. Transcriptomic profiling of the thalamus revealed widespread, sex-dependent differences in gene expression, implicating pathways related to synaptic organization, protein synthesis, neuronal plasticity, and myelination. Exploratory DNA-methylation analyses identified nominal, sex-dependent pathway enrichments that did not survive false-discovery-rate correction. Together, these findings show that maternal stress beginning before pregnancy leaves a persistent imprint on offspring brain structure, microstructure, and epigenetic regulation, converging on the thalamus as a central hub of intergenerational vulnerability. This work establishes SIR as a translationally relevant model of depression that predates conception and provides integrated MRI- and molecular-level biomarkers for dissecting mechanisms and informing early preventive strategies.