Early Adolescence as a Critical Window During Which Social Stress Distinctly Alters Behavior and Brain Norepinephrine Activity

Abstract

Many neural programs that shape behavior become established during adolescence. Adverse events at this age can have enduring consequences for both adolescent and adult mental health. Here we show that repeated social stress at different stages of adolescent development differentially affects rat behavior and neuronal activity. Early-adolescent (PND 28, EA), mid-adolescent (PND 42, MA), and adult (PND 63) rats were subjected to resident-intruder social stress (7 days) and behavior was examined 24-72 h later. In EA rats selectively, resident-intruder stress increased proactive responses in the defensive burying and forced swim tests. In adult rats, resident-intruder stress decreased burying behavior regardless of whether the animal was stressed as an adult or during early adolescence. Because the locus coeruleus (LC)-norepinephrine system has been implicated in proactive defense behaviors, LC neuronal activity was quantified in separate cohorts. Stressed EA rats had elevated spontaneous LC discharge rates and diminished responses to sensory stimuli compared to controls. Microinjection of a CRF antagonist into the LC selectively inhibited neurons of stressed EA rats, suggesting that EA social stress induces tonic CRF release onto LC neurons, shifting the mode of discharge to an activated state that promotes active defensive behaviors. In all adult groups, resident-intruder stress resulted in an increased phasic response to sensory stimuli with no change in spontaneous rates. Mid-adolescence was a transition period during which social stress did not affect behavior or LC activity. The results suggest that social stress interacts with the brain norepinephrine system to regulate defensive strategies in an age-dependent manner.

Adolescent Social Stress Produces an Enduring Activation of the Rat Locus Coeruleus and Alters its Coherence with the Prefrontal Cortex

“…The present results imply that in adolescents exposed to repeated social stress the brain noradrenergic system will maintain a high tonic state that is associated with hyperarousal and labile attention. Consistent with this, defensive burying behavior is enhanced in adolescent rats exposed to repeated resident-intruder stress (Bingham et al, 2011). The duration the LC hyperactivity remains to be determined.…”

“…Rather, repeated social stress created a condition of LC hyperactivity in the absence of stress in adolescents. These findings are similar to those reported in anesthetized rats in which LC activity was recorded 24 h after the final exposure to the stressor, although in that study LC hyperactivity was observed in juvenile, but not in mid-adolescent rats (Bingham et al, 2011). However, the present study differed from the latter in that recordings were done in the unanesthetized state and during, rather than after, the resident-intruder stress.…”

“…Given the functions of the LC-NE system, the consequences of tonic hyperactivation would include sleep disturbances, inability to concentrate, behavioral hyperactivity, and anxiety. Previous studies from our laboratory suggest that this elevated basal discharge is associated with increased defensive behaviors (Bingham et al, 2011). Diminished LC sensory responses could additionally impair sensory processing and performance in attention-related tasks.…”

“…Specifically, there is evidence for enhanced opioid drive to the LC in adult male rats (Chaijale et al, 2013). In contrast, LC neurons of early adolescent rats recorded in the anesthetized state 24 h after the last resident-intruder stress were tonically activated, suggesting age-related differences in stress adaptation (Bingham et al, 2011).…”

“…The duration the LC hyperactivity remains to be determined. LC recordings from adult rats that were exposed to repeated residentintruder stress during adolescence suggest that this effect does not endure into adulthood although those recordings were performed in the anesthetized state (Bingham et al, 2011).…”