Corticotropic-releasing hormone and serotonin interact in the human brainstem: behavioral implications

The objective of this human post mortem study was to determine whether neurons which synthesize corticotropic-releasing hormone and serotonin form circuits implicated in the pathophysiology of major depression and suicide. For the first time, a sensitive, dual immunocytochemical procedure was used to identify circuits formed by corticotropic-releasing hormone-synthesizing and serotonergic cell groups. Corticotropic-releasing hormone-immunoreactive varicose fibers and puncta with morphological characteristics of terminals were labeled in the midline raphe, periventricular gray and pontine parabrachial complex, on single-labeled tissues processed immunocytochemically with a rabbit antibody to rat/human corticotropic-releasing hormone. Presumptive synaptic interactions with monoaminergic neurons were demonstrated with dual labeling techniques. Corticotropic-releasing hormone-immunoreactive terminals apposed neuronal somata and primary dendrites of serotonergic neurons in the pontine raphe. Serotonergic neurons were immunolabeled with a mouse antibody to phenylalanine hydroxylase, an enzyme with substantial sequence homology to tryptophan hydroxylase. Interactions in the lateral parabrachial nucleus were suggested by precise overlap of corticotropic-releasing hormone and serotonergic terminal fields. Corticotropic-releasing hormone projections were confirmed to noradrenergic neurons containing neuromelanin in the locus ceruleus. Maps of corticotropic-releasing hormone fiber trajectories suggest that these pathways may derive from the forebrain and, locally, from the human homologue of Barrington's nucleus--a neurochemically specialized division of the laterodorsal tegmental complex. Chemosensory functions were predicted by novel evidence for corticotropic-releasing hormone- and monoaminergic neurovascular and subependymal fiber plexuses. In conclusion, corticotropic-releasing hormone may influence the activity of two major monoaminergic cell systems implicated in the stress-diathesis model of mental illness, through neural and humoral mechanisms.