Major depression is a debilitating psychiatric disease that may be precipitated by a dysregulation of stress neurocircuitry caused by chronic or severe stress exposure. Moreover, hyperresponsivity to stressors correlates with depressed mood and may contribute to the etiology of major depression. The serotonergic dorsal raphe nucleus (DRN) is an important site in the neurocircuitry underlying behavioral responses to stressors, and is tightly regulated, in part, by a combination of intrinsic cell properties, autoinhibition, and GABAergic synaptic transmission. The stress-related neurotransmitter corticotropin-releasing factor (CRF) modulates DRN neuronal excitability and subsequent 5-HT release in the forebrain. Wistar Kyoto (WKY) rats exhibit exaggerated behavioral responses to stressors, that is, stress hyperresponsivity, and are considered an animal model of depression. To better understand the neurobiological basis of the stress hyperresponsivity, we used a combination of mRNA analysis and whole-cell electrophysiological techniques to measure differences in intrinsic activity and receptor response, in 5-HT- and non-5-HT-containing neurons of the DRN in WKY rats compared with Sprague-Dawley controls. In the WKY rat, there was a decrease in the neuronal excitability of 5-HT neurons coupled with decreased TPH2 production. Additionally, we found that CRF did not increase GABAergic activity in 5-HT neurons as is normally seen in 5-HT neurons of Sprague-Dawley controls. The CRF modulation of 5-HT DRN neurotransmission at the single-cell level is selectively disrupted in the WKY animal model of depression and may be one of the cellular correlates underlying depression.
Bibliographical noteFunding Information:
We thank Dr Jean Rivier of the Clayton Foundation Laboratories for Peptide Biology at The Salk Institute for his generous donations of oCRF and Ucn II for use in these studies. We also thank Abigail Schindler for her useful suggestions on the manuscript. This work was supported by grants from a Young Investigator Award from the National Alliance for Research on Schizophrenia and Depression (NARSAD) and the National Institute of Mental Health (MH 63301 and DA 20126) to LGK and NIMH (MH 60773) and the Office of Naval Research (N00014-03-1-0311) grants issued to Dr Beck.
- corticotropin-releasing factor
- dorsal raphe
- stress hyperresponsive