Social Stress Engages Neurochemically-Distinct Afferents to the Rat Locus Coeruleus Depending on Coping Strategy

Abstract

Stress increases vulnerability to psychiatric disorders, partly by affecting brain monoamine systems, such as the locus coeruleus (LC)-norepinephrine system. During stress, LC activity is co-regulated by corticotropin-releasing factor (CRF) and endogenous opioids. This study identified neural circuitry that regulates LC activity of intruder rats during the resident-intruder model of social stress. LC afferents were retrogradely labeled with Fluorogold (FG) and rats were subjected to one or five daily exposures to an aggressive resident. Sections through the nucleus paragigantocellularis (PGi) and central amygdalar nucleus (CNA), major sources of enkephalin (ENK) and CRF LC afferents respectively, were immunocytochemically processed to detect c-fos, FG and CRF or ENK. In response to a single exposure, intruder rats assumed defeat with a relatively short latency (SL). LC neurons, PGI-ENK LC afferents and CNA-CRF LC afferents were activated in these rats as indicated by increased c-fos expression. With repeated stress rats exhibited either a SL or long latency (LL) to defeat and these strategies were associated with distinct patterns of neuronal activation. In SL rats, LC neurons were activated, as were CNA-CRF LC afferents but not PGI-ENK LC afferents. LL rats had an opposite pattern, maintaining activation of PGi-ENK LC afferents but not CNA-CRF LC afferents or LC neurons. Together, these results indicate that the establishment of different coping strategies to social stress is associated with changes in the circuitry that regulates activity of the brain norepinephrine system. This may underlie differential vulnerability to the consequences of social stress that characterize these different coping strategies.

Significance Statement: Social stress has been linked to psychiatric disorders, in part through activation of the locus coeruleus (LC)-norepinephrine system. This study identified circuits that are engaged during acute and repeated social stress to regulate this system. It was found that the establishment of different coping strategies with repeated social stress was associated with distinctions in stress-activated circuitry. In rats that resisted defeat, inhibitory enkephalin afferents to the LC were engaged, whereas in rats that are biased towards subordination, excitatory corticotropin-releasing factor inputs to the LC were engaged. The engagement of different circuits with opposing actions may underlie distinctions in the consequences of social stress in subjects with different coping strategies.