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

Abstract

Early life stress is associated with the development of psychiatric disorders. Because the locus coeruleus-norepinephrine (LC-NE) system is a major stress-response system that is implicated in psychopathology, developmental differences in the response of this system to stress may contribute to increased vulnerability. Here LC single unit and network activity were compared between adult and adolescent rats during resident-intruder stress. In some rats, LC and medial prefrontal cortex (mPFC) coherence was quantified. The initial stress tonically activated LC neurons and induced theta oscillations, while simultaneously decreasing LC auditory-evoked responses in both age groups. Stress increased LC-mPFC coherence within the theta range. With repeated exposures, adolescent LC neuronal and network activity remained elevated even in the absence of the stressor and were unresponsive to stressor presentation. In contrast, LC neurons of adult rats exposed to repeated social stress were relatively inhibited in the absence of the stressor and mounted robust responses upon stressor presentation. LC sensory-evoked responses were selectively blunted in adolescent rats exposed to repeated social stress. Finally, repeated stress decreased LC-mPFC coherence in the high frequency range (beta and gamma) while maintaining strong coherence in the theta range, selectively in adolescents. Together, these results suggest that adaptive mechanisms that promote stress recovery and maintain basal activity of the brain norepinephrine system in the absence of stress are not fully developed or are vulnerable stress-induced impairments in adolescence. The resulting sustained activation of the LC-NE system after repeated social stress may adversely impact cognition and future social behavior of adolescents.

Stress Facilitates the Development of Cognitive Dysfunction After Chronic Ethanol Exposure

“…Using c‐Fos immunohistochemistry, we saw reductions in PL activity in CIE‐exposed animals, combined with additional reductions in IL of CIE/FSS animals. Stress and EtOH‐exposed groups, and to a lesser degree EtOH alone, showed disruptions of neural signaling in the LC, an important ascending neuromodulatory input to mPFC that is known to regulate behavioral flexibility (McGaughy et al., ; Zitnik et al., ). The disruption in function across neural circuits after CIE/FSS may contribute to the rapid development of cognitive deficits.…”

Methylphenidate has nonlinear dose effects on cued response inhibition in adults but not adolescents

“…NE transporter levels in prefrontal cortex are higher in adolescence compared to early adulthood, suggesting reduced baseline NE function during adolescence (Bradshaw et al, 2016). Additionally, neurons in the adolescent locus coeruleus, the primary site of norepinephrine synthesis, respond differently to social stressors than in adults (Bingham et al, 2011; Zitnik et al, 2015). …”

The brain norepinephrine system, stress and cardiovascular vulnerability

“…The parallel activation of the HPA and LC-NE system would coordinate endocrine and cognitive limbs of the stress response (Valentino and Van Bockstaele, 2008). Electrophysiological recordings in anesthetized and unanesthetized rats have demonstrated that acute stress (including hypotensive stress, see below) and exposure to CRF shifts LC discharge towards a high tonic state that would favor heightened arousal, disengagement from ongoing behavior, labile attention and cognitive flexibility (Curtis et al, 2012; Valentino and Foote, 1987; Valentino and Foote, 1988; Valentino and Wehby, 1988; Zitnik et al, 2015). Consistent with this, CRF microinfused directly into the LC increases cognitive flexibility in an attentional set-shifting task (Snyder et al, 2012).…”