Adolescent Stress Reprograms the Medial Amygdala and Sex Differences in Reward

Overview

Drug overdose is currently the number one cause of death in the United States. Adolescence is a time of crucial development because structural and molecular changes occur within the brain. During this time, hormones designate sexually dimorphic behaviors and influence the development of Mesocorticolimbic Dopamine Circuitry. Adolescent Social Isolation (SI) stress is used to catalyze addiction-related behaviors in mice. Two cohorts of mice--the control living in a group-housed (GH) setting and the other group undergoing SI during adolescence before returning to the GH setting--were put in three experiments: marble burying, elevated plus maze, and cocaine CPP. Results show SI males began to behave like females, and SI females began to behave like males. For the cocaine CPP, the control females formed a stronger preference to cocaine, and in the SI cohort the exact opposite phenomenon occurred. Sexually dimorphic behavior of males and females flipped, and adolescent SI caused circuitry changes important for reward, and thus addiction. The important changes occurred in medial amygdala (meAMY) projections to the mesolimbic reward circuitry. Using immunohistochemistry imaging, we saw that there were more cells projecting from the meAMY into the reward circuitry in GH males than in GH females. However, after SI, male projections came down to female levels. Thus, adolescent SI alters sex-specific circuitry, especially in the meAMY. In order to confirm this phenomena, we used an inhibitory retrograde tracing DREADD virus to turn off projections in GH males of a separate cohort. SI males and the inhibitory DREADD GH males exhibited the same behavior. In the original cohort, the differences in circuitry reflect the sex specififc behavioral responses to cocaine. Through RNA sequencing of meAMY tissue, we observed transcriptional changes after SI. Reflecting the change in behavior, gene global transcriptome structure flipped in SI mice. SI males gained structure in gene modules (the number of active modules decreasing from 10 to 6) while SI females lost all structure in gene modules (number of modules increasing from 8 to 91). Using pattern and co-expression analysis of the RNA sequencing, results suggest Crystallin mu (Crym) is a key driver in sexually dimorphic behaviors due to its effect on thyroid hormone signaling.

Competition history

• AJAS 2020 Category not listed

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