Social Reward Learning Deficits and Concordant Brain Alterations in Rats Overexpressing Disrupted-in-Schizophrenia 1 (DISC1)

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Abstract
Social deficits are a hallmark of schizophrenia, often characterized by impairments in processing and integrating socially transmitted information. However, translational models that accurately capture these deficits remain scarce. The Disrupted-in-Schizophrenia 1 gene ( DISC1 ), a key susceptibility factor implicated in the etiology of psychiatric disorders, has been shown to cause DISC1 protein aggregation and dysfunctional signaling when modestly overexpressed, ultimately resulting in aberrant dopamine homeostasis. In this study, we employed a transgenic rat model overexpressing human DISC1 (tgDISC1 rats) to investigate social reward learning and microstructural integrity in the brain. Using a modified Social Transmission of Food Preference (STFP) task, we report that male tgDISC1 rats failed to update reward preferences based on social information, despite intact nonsocial reward learning—suggesting a specific deficit in social reward learning. Diffusion tensor imaging (DTI) in a behaviorally naive cohort revealed reduced fractional anisotropy (FA) in key subcortical regions, including the nucleus accumbens, amygdala, and substantia nigra, as well as areas mediating cortical-subcortical communication as the thalamus. Structural alterations in corresponding neuroanatomical areas have also been described in DTI of schizophrenia patients. Our findings link aberrant DISC1 signaling with impaired connectivity in parts of the mesolimbic system, critical for integrating social information into decision-making. This model recapitulates both behavioral and structural endophenotypes of schizophrenia and suggests that social impairments may stem from a fine-grained circuit-selective dysfunction rather than a generalized reward processing deficit. The tgDISC1 rat thus offers a translational platform for probing the neural substrates of social dysfunction in psychiatric disorders.
Funding Information
  • Deutsche Forschungsgemeinschaft (KO 1679 / 14-1, KA 2675/5-3)

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