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Early life adversity in mice enhances structural reward circuit connectivity during development and leads to enduring adaptations into adulthood

Creative Commons 'BY-NC' version 4.0 license

Early life adversity (ELA) comprises a wide variety of negative experiences during early life and has been linked to cognitive impairments, reduced experiences of pleasure (anhedonia), and other long-term consequences implying that ELA impacts the reward circuitry. In these studies, we probed the effects of ELA on reward connectivity, structural integrity of the DR-VTA-NAcc projection, and reward behaviors in adulthood. Next we evaluated global and regional brain volume changes after ELA exposure in a sex specific manner, followed by investigation of developmental trajectories of reward regions, their connectivity, and reward behavior. We focused on reward regions, primarily dorsal raphe (DR), ventral tegmental area (VTA), and the nucleus accumbens (NAcc) and the connectivity between these regions. We hypothesized that the reward circuitry would be modified by ELA and emerges early in development and could be observed in adulthood. We used the limited bedding and nesting model to induce ELA in mice and measured reward-related behaviors in development and adulthood using the three-chamber social interaction and sucrose preference tests. High resolution ex vivo diffusion tensor imaging (DTI) was utilized for regional DTI metrics, network measures, and tractography to assess circuit organization. We also used T2-weighted imaging (T2WI) in order to evaluate brain volumes. We found brain-wide changes in brain volume and diffusion metrics in adulthood. We identified increased connectivity of the VTA-NAcc circuit in both development and adulthood. The increased connectivity was associated with augmented maturation and complexity of the reward circuits of ELA males at PND 30. Increased radial diffusivity within the NAcc and increased axial diffusivity within the VTA segment of the DR-VTA-NAcc projections are consistent with modified projections in adulthood. Behaviorally, ELA elicited an increase in sociability at PND 30 that was decreased in adults. Our findings suggest ELA enhances structural reward circuit connectivity during development and leads to enduring circuit adaptations into adulthood. These studies aid the characterization of critical reward circuits and their development following ELA, providing additional understanding of the mechanisms that contribute to negative outcomes later in life.

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