Anatomic basis for differential regulation of the rostrolateral peri-locuscoeruleus region by limbic afferents

Background: Neurochemical and electrophysiological studies indicate that th e locus coeruleus (LC)-norepinephrine system is activated by physiological and external stressors. This activation is mediated in part by corticotropi n-releasing factor (CRF), the hypothalamic neurohormone that initiates the endocrine response to stress. lire have previously shown that the central n ucleus of the amygdala (CNA) provides CRF afferents to noradrenergic proces ses in the peri-LC area that may serve to integrate emotional and cognitive responses to stress. The bed nucleus of the stria terminalis (BNST) shaves many anatomical and neurochemical characteristics with the CNA, including a high density of CRF-immunoreactive cells and fibers; however, recent stud ies have suggested that the CNA and the BNST may differentially regulate re sponses to conditioned and unconditioned fear, respectively, suggesting div ergent neuroanatomical circuits underlying these processes. Methods: In the present study, neuroanatomical substrates subserving regula tion of the LC by the BNST were examined Anterograde tract-tracing was comb ined with immunoelectron microscopy to test the hypotheses that BNST effere nts target noradrenergic neurons of the LC and that these efferents exhibit immunolabeling for CRF, Results: Ultrastructural analysis of sections that were dually labeled for the anterograde tracer biotinylated dextran amine (BDA) injected into the B NST and tyrosine hydroxylase (TH)-immunoreactivity demonstrated that BDA-la beled axon terminals formed synaptic specializations (primarily inhibitory) with TH-labeled dendrites and dendrites that lacked TH immunoreactivity, I n contrast to CNA efferents that exhibited substantial immunolabeling far C RF, far fewer BDA-labeled terminals from the BNST in the rostrolateral peri -LC contained CRF. Conclusions: The present results indicate that the BNST may provide distinc t neurochemical regulation of the peri-LC as compared to other limbic affer ents such as the CNA, These data are interesting in light of behavioral stu dies showing that the CNA and BNST may be differentially involved in fear v ersus anxiety, respectively. Biol Psychiatry 1999;46:1352-1363 (C) 1999 Soc iety of Biological Psychiatry.