A preconceptional stress model identifies thalamostriatal substrates of intergenerational vulnerability

Abstract 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. T o 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.