Topographic architecture of stress-related pathways targeting the noradrenergic locus coeruleus

Peripheral sympathetic nerves and brainstem noradrenergic neurons of the locus coeruleus (LC) respond in parallel to a variety of stress-related stimuli which results in norepinephrine release both peripherally and centrally. Elucidation of central pathways subserving modulation of LC neurons point to extranuclear noradrenergic dendrites of LC somata that extend into peri-coerulear areas as a major target of afferents that participate in behavioral and physiological responses to stress. Anterograde tract tracing combined with immunoelectron microscopic detection of the catecholamine synthesizing enzyme tyrosine hydroxylase (TH) has demonstrated that the nucleus of the solitary tract (NTS) and the ventrolateral aspect of the periaqueductal gray (PAG), regions that participate in coordinating autonomic and motor behavior in response to stress, preferentially target the rostral ventromedial aspect of the peri-LC. In contrast, limbic forebrain afferents including the central nucleus of the amygdala (CNA) and the bed nucleus of the stria terminalis (BNST), regions that coordinate emotional responses to external stressors, provide direct synaptic input to noradrenergic dendrites that extend into rostral dorsolateral peri-coerulear areas. Neurochemical identification of transmitter systems impinging on LC indicate that the CNA provides corticotropin-releasing factor (CRF), a peptide essential for integrated physiological responses to stress, to the dorsolateral LC. Endogenous opioid peptides that originate from medullary sources, however, target primarily the "core" of the LC. Our physiological data suggest that stress engages CRF and opioid afferents to the LC, which have opposing influences on this noradrenergic system. The balance between opioid and CRF influences acting in the LC may, in part, maintain the balance of active and passive coping behaviors in response to stress. Understanding the afferent and neurochemical organization of the LC may help elucidate adaptations in neural circuits associated with stress which impact on central noradrenergic function.