Unique Effects of Social Defeat Stress in Adolescent Male Mice on the Netrin-1/DCC Pathway, Prefrontal Cortex Dopamine and Cognition

Abstract

For some individuals, social stress is a risk factor for psychiatric disorders characterized by adolescent onset, prefrontal cortex (PFC) dysfunction and cognitive impairments. Social stress may be particularly harmful during adolescence when dopamine (DA) axons are still growing to the PFC, rendering them sensitive to environmental influences. The guidance cue Netrin-1 and its receptor, DCC, coordinate to control mesocorticolimbic DA axon targeting and growth during this age. Here, we adapted the accelerated social defeat (AcSD) paradigm to expose male mice to social stress in either adolescence or adulthood and categorized them as “resilient” or “susceptible” based on social avoidance behavior. We examined whether stress would alter the expression of DCC and Netrin-1 in mesolimbic DA regions and would have enduring consequences on PFC DA connectivity and cognition. While in adolescence the majority of mice are resilient but exhibit risk-taking behavior, AcSD in adulthood leads to a majority of susceptible mice without altering anxiety-like traits. In adolescent, but not adult mice, AcSD dysregulates DCC and Netrin-1 expression in mesolimbic DA regions. These molecular changes in adolescent mice are accompanied by changes in PFC DA connectivity. Following AcSD in adulthood, cognitive function remains unaffected, but all mice exposed to AcSD in adolescence show deficits in inhibitory control when they reach adulthood. These findings indicate that exposure to AcSD in adolescence versus adulthood has substantially different effects on brain and behavior and that stress-induced social avoidance in adolescence does not predict vulnerability to deficits in cognitive performance.

Mesocorticolimbic Dopamine Pathways Across Adolescence: Diversity in Development

“…Experience-induced regulation of Netrin-1 and/or DCC expression robustly shapes the adolescent brain. Social defeat stress in adolescence, but not in adulthood, downregulates Dcc expression in the VTA of male mice, disrupts PFC DA innervation, and leads to cognitive control deficits in adulthood (Vassilev et al, 2021 ). Mild traumatic brain injury in mid-adolescent male mice reduces Netrin-1 expression in the NAc and alters mesocorticolimbic DA organization (Kaukas et al, 2020 ).…”

The impact of psychosocial defeat stress on the bed nucleus of the stria terminalis transcriptome in adult male mice

“…Secondly, we have not queried the potential influence of age on resilience, susceptibility and the role of the BNST in this context. Our defeat stress paradigm was carried out in adults; several studies have demonstrated that it can also be applied during adolescence, when the brain is still developing and highly sensitive to the effects of stress (Iñiguez et al, 2016; Shimizu et al, 2020; Vassilev et al, 2021). Lastly, the rodent BNST is composed of approximately 20 different subregions with a highly diverse population of cell types with subregional specificity (Ortiz‐Juza et al, 2021; Turesson et al, 2013).…”

Identification of candidate biomarkers and pathways associated with type 1 diabetes mellitus using bioinformatics analysis

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