Regulation of the dorsal raphe nucleus serotonin system by the stress related peptide corticotropin-releasing factor

Maria Waselus, Thomas Jefferson University


Dysfunctions of both the corticotropin-releasing factor (CRF) and dorsal raphe nucleus serotonergic (DRN-5-HT) systems are reported in stress-related psychiatric disorders such as depression. The mechanisms underlying the impact of stress and CRF on the DRN-5-HT system, however, are only beginning to emerge. These studies utilized neuroanatomical methods including immunohistochemistry, immunoelectron microscopy, retrograde neuronal tract tracing, along with behavioral analysis to elucidate substrates involved in CRF regulation of the DRN. The complex effects of CRF in the DRN were delineated by characterizing contacts between CRF axon terminals and 5-HT- or gamma-aminobutyric acid (GABA)-labeled processes. Although CRF terminals contacted 5-HT dendrites, CRF terminal interactions with GABAergic profiles were more frequent suggesting direct and indirect effects of CRF on 5-HT in the DRN. The identification of potential co-transmitters for CRF in the DRN indicated glutamate (indicated by vGlut1 or vGlut2) and CRF colocalize in some DRN axon terminals suggesting coordinate modulation of DRN neuronal activity. Forebrain regions innervated by the DRN respond differently to stress, and retrograde tracing studies provided evidence for divergent innervation of the lateral septum and striatum by topographically organized populations of DRN neurons. Further, CRF fibers differentially targeted DRN neurons projecting to these regions implicating CRF in the regulation of specific DRN-forebrain projections. Studies then shifted to examine CRF receptors in the DRN. Axon terminals, but more frequently dendrites, exhibited immunoreactivity for CRF type 2 receptor (CRF2) in the DRN and CRF2 dendrites often colocalized 5-HT. Studies also provided evidence for the differential localization of CRF receptors following stress, with CRF1 internalized and CRF 2 increase at the plasma membrane 24 hours following a single exposure to swim stress. Although a behavioral correlate for the shift in CRF receptor distribution was not readily apparent in this study, physiological evidence supporting the trafficking studies corroborates neuronal inhibition via CRF1 and excitation via CRF2 in the DRN. In summary, these findings have made substantial contributions to the understanding of the functional circuitry that mediate responses to stress and may potentially lead to the development of more effective pharmacological agents for the treatment of depression.

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Recommended Citation

Waselus, Maria, "Regulation of the dorsal raphe nucleus serotonin system by the stress related peptide corticotropin-releasing factor" (2008). ETD Collection for Thomas Jefferson University. AAI3551860.