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The Journal of Neuroscience, August 13, 2008, 28(33):8169-8177; doi:10.1523/JNEUROSCI.0004-08.2008

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Behavioral/Systems/Cognitive
Failure to Mount Adaptive Responses to Stress Results in Dysregulation and Cell Death in the Midbrain Raphe

Jonathan G. McEuen,¹ Sheryl G. Beck,² and Tracy L. Bale¹

¹Department of Animal Biology, University of Pennsylvania, and ²Department of Anesthesiology, Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, Pennsylvania 19104

Correspondence should be addressed to Dr. Tracy L. Bale, 201E Vet, 6046, University of Pennsylvania, 3800 Spruce Street, Philadelphia, PA 19104-6046. Email: tbale{at}vet.upenn.edu

Stress is a common trigger in affective disorder onset, yet the mechanism and predisposing factors of vulnerability remain unknown. Effective disease prevention requires a critical balance of responses within the serotonergic raphe nucleus, including a coordination of corticotropin-releasing factor (CRF) actions at both of its receptors, CRF receptor-1 and CRF receptor-2. Mice deficient in CRF receptor-2 (R2KO) were used as a model of maladaptive stress responsivity to examine the physiological and molecular markers of stress dysregulation within the raphe in the absence of this receptor. After chronic stress, R2KO mice failed to display the robust stress-mediated adaptations characteristic of control mice, including elevations in tryptophan hydroxylase-2 and CRF receptor-1 expression and concordant increases in behavioral arousal. As a further indication of failed homeostatic mechanisms, R2KO mice displayed indices of cell death in the raphe after stress exposure, with elevations in proapoptotic factors but a failure to mount adaptive increases in antiapoptotic factors found in control mice. In vitro electrophysiological characterization of the specific influence of CRF on the raphe revealed both basal differences and a failure to respond to CRF administration in R2KO mice. These results support a requirement for homeostatic maintenance in response to stress in the raphe, where dysregulation may be a critical predictor of affective disorder onset.

Key words: serotonin; CRF; depression; anxiety; homeostasis; cell death

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Received June 13, 2007; revised June 23, 2008; accepted June 23, 2008.

Correspondence should be addressed to Dr. Tracy L. Bale, 201E Vet, 6046, University of Pennsylvania, 3800 Spruce Street, Philadelphia, PA 19104-6046. Email: tbale{at}vet.upenn.edu

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