Activation of raphe efferents to the medial prefrontal cortex by corticotropin-releasing factor: correlation with anxiety-like behavior.
BACKGROUND
Parallel lines of research suggest that dysfunction affecting both corticotropin-releasing factor (CRF) and serotonin (5-HT) systems is involved in the pathophysiology of psychiatric illnesses such as anxiety and depression. The effect of CRF on behavior and on the accompanying change in activity of 5-HT neurons in the dorsal and median raphe nuclei (DR and MR) that project to the ventral medial prefrontal cortex (mPFC), a brain area implicated in mood and anxiety disorders, was studied.


METHODS
Male Sprague-Dawley rats with intra-mPFC deposits of fluorescent microspheres received injections of CRF (1 microg, intracerebroventricular [i.c.v.]) and were tested for CRF-enhanced startle, a behavioral assay believed to reflect stress- or anxiety-like states. C-Fos immunohistochemistry was used to measure CRF-induced activity in retrogradely labeled neurons in the DR and MR and correlate this level of activity with the level of CRF-enhanced startle.


RESULTS
The CRF-enhanced startle was accompanied by an increased c-Fos expression in retrogradely labeled cells in the raphe. In the DR and MR, there was a clear topography of activation, with a higher-percent activation in retrogradely labeled neurons in caudal sections. In the caudal DR, this effect was positively correlated with the level of CRF-enhanced startle. Co-expression of retrogradely labeled cells with tryptophan hydroxylase showed that the majority (> 90%) of raphe efferents to the mPFC were from serotonergic neurons.


CONCLUSIONS
These data indicate that CRF activates a subpopulation of cortical-projecting 5-HT raphe neurons and suggest that increased 5-HT release in the mPFC might be an important component driving some types of anxiety-like behaviors.
Meloni
Edward G
EG
Department of Psychiatry, Harvard Medical School and McLean Hospital, Belmont, Massachusetts 02478, USA. emeloni@mclean.harvard.edu
Reedy
Catherine L
CL
Cohen
Bruce M
BM
Carlezon
William A
WA
D000339:Affect / Q000502:physiology; D000818:Animals; D001008:Anxiety Disorders / Q000503:physiopathology*; D001143:Arousal / Q000502:physiology; D001931:Brain Mapping; D003346:Corticotropin-Releasing Hormone / Q000502:physiology*; D004525:Efferent Pathways / Q000503:physiopathology; D008297:Male; D009474:Neurons / Q000502:physiology; D017397:Prefrontal Cortex / Q000503:physiopathology*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D011903:Raphe Nuclei / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013216:Reflex, Startle / Q000502:physiology; D012701:Serotonin / Q000502:physiology
D016760:Proto-Oncogene Proteins c-fos; D012701:Serotonin; D003346:Corticotropin-Releasing Hormone