Maltreatment in adolescence poses a major public health crisis as a primary factor for the development of adult psychiatric disorders. The anterior insula (AI) has been implicated as a hub in adult psychiatric disorders but the gene expression profile of AI in psychiatric disease in either humans or animal models is unknown. RNA sequencing of AI in adult male mice exposed to maltreatment in adolescence revealed altered expression of multiple ribosomal proteins and genes related to neurodegeneration. AI-specific neuronal rescue of a top RNA binding protein target, Hnrnpa2b1, in adulthood after adolescent maltreatment, significantly restored normative social behavior in defeated male mice. Together these preclinical findings reveal a regionally specific molecular pathway in male mice that should be further investigated as a possible target to reduce fear-based symptoms of adolescent maltreatment.

Physical abuse in childhood and adolescence results in long lasting effects on mental and physical health in adulthood. The prefrontal cortex of adults exposed to abuse in childhood shows both functional and structural abnormalities in comparison to healthy controls. However, the changes in prefrontal innervation of specific downstream targets as a result of early life abuse are unclear. Here we used a novel abbreviated early adolescent chronic social defeat stress paradigm (5 day eaCSDS) to assess changes to prefrontal innervation in adult male and female C57BL/6 J mice. We injected control and defeated mice with virally encoded GFP in the prelimbic region of prefrontal cortex (PL) and examined axon density in basolateral amygdala (BLA), nucleus accumbens (NAc) and ventral tegmental area (VTA). We find that both male and female mice show robust but seemingly opposing changes in social interaction after 5 day eaCSDS. We found significantly decreased PL innervation of BLA and increased fragmentation of PL axons in BLA. Males, but not females, also show increased fragmentation of PL axons in NAc. Interestingly, PL innervation of BLA significantly correlates with adult social behavior in males and females. Our findings suggest that PL innervation of downstream targets is dramatically affected by early life social defeat in both a regional and sex-specific manner. This differential change in innervation across regions and sexes may underlie the social behavioral deficits seen after early life social defeat.

Physical abuse and trauma in childhood is reported in as many as 1 in 7 children and is a major risk factor for the development of psychiatric diseases, such as Post-Traumatic Stress Disorder (PTSD), in adolescence and adulthood. Hallmark behavioral symptoms of PTSD include avoidance of cues and contexts associated with trauma. The ability to model long-lasting changes in the brain due to early life trauma is critical to determine potential circuit and molecular targets for the modulation of resultant symptoms. This manuscript describes a protocol for modeling early life physical and psychological trauma in early adolescent male mice that produces socially avoidant behavior.

The ability to correctly associate cues and contexts with threat is critical for survival, and the inability to do so can result in threat-related disorders such as posttraumatic stress disorder. The prefrontal cortex (PFC) and hippocampus are well known to play critical roles in cued and contextual threat memory processing. However, the circuits that mediate prefrontal-hippocampal modulation of context discrimination during cued threat processing are less understood. Here, we demonstrate the role of a previously unexplored projection from the ventromedial region of PFC (vmPFC) to the lateral entorhinal cortex (LEC) in modulating the gain of behavior in response to contextual information during threat retrieval and encoding. We used optogenetics followed by in vivo calcium imaging in male C57/B6J mice to manipulate and monitor vmPFC-LEC activity in response to threat-associated cues in different contexts. We then investigated the inputs to, and outputs from, vmPFC-LEC cells using Rabies tracing and channelrhodopsin-assisted electrophysiology.

Early-life stress (ELS) leaves signatures upon the brain that persist throughout the lifespan and increase the risk of psychiatric illnesses including mood and anxiety disorders. In humans, myriad forms of ELS—including childhood abuse, bullying, poverty, and trauma— are increasingly prevalent. Understanding the signs of ELS, including those associated with psychiatric illness, will enable improved treatment and prevention. Here, we developed a novel procedure to model human ELS in mice and identify translationally-relevant biomarkers of mood and anxiety disorders. We exposed male mice (C57BL/6J) to an early-life (juvenile) chronic social defeat stress (jCSDS) and examined social interaction and responsivity to reward during adulthood. As expected, jCSDS-exposed mice showed a socially avoidant phenotype in open-field social interaction tests. However, sucrose preference tests failed to demonstrate ELS induced reductions in choice for the sweetened solution, suggesting no effect on reward function. To explore whether other tasks might be more sensitive to changes in motivation, we tested the mice in the Probabilistic Reward Task (PRT), a procedure often used in humans to study reward learning deficits associated with depressive illness. In a touchscreen PRT variant that was reverse translated to maximize alignment with the version used in human subjects, mice exposed to jCSDS displayed significant reductions in the tendency to develop response biases for the more richly-rewarded stimulus, a hallmark sign of anhedonia when observed in humans. Our findings suggest that translationally-relevant procedures that utilize the same endpoints across species may enable the development of improved model systems that more accurately predict outcomes in humans.