Corticotropin-releasing factor neurones of the central nucleus of the amygdala mediate locus coeruleus activation by cardiovascular stress

Hypotensive stress engages corticotropin-releasing factor (CRF) release within the rat locus coeruleus (LC), which activates LC neurones, initiating norepinephrine release in forebrain and activation of forebrain electroencephalographic activity. This study identified CRF afferents to the LC that are engaged during hypotensive stress. One of two potential CRF afferents, the central nucleus of the amygdala (CNA) or bed nucleus of the stria terminalis (BNST), was electrolytically lesioned and LC activation during hypotensive stress was quantified. Neither lesion altered LC spontaneous discharge rate or activation by intra-LC administered CRF. By contrast, LC activation by hypotensive stress was greatly attenuated in CNA-lesioned, but not BNST-lesioned, rats. Hypotensive stress-induced changes in transcriptional activation were immunohistochemically identified in CRF neurones that were retrogradely labelled from the LC region. c-fos immunoreactivity was prevalent in the paraventricular nucleus of the hypothalamus (PVN), CNA and BNST. However, only the PVN contained a substantial number of neurones that were doubly immunolabelled for CRF and c-fos, and few of these were retrogradely labelled from the LC. By contrast, immunoreactivity for the phosporylated form of cyclic AMP response-element binding protein (PCREB) was prevalent in CRF neurones in the CNA and BNST. Moreover, approximately one-third of the PCREB-expressing CRF neurones in the CNA were retrogradely labelled from the LC. These electrophysiological and anatomical findings implicate the CNA as a primary source of CRF that activates the LC during hypotensive stress. Additionally, CREB phosphorylation, rather than c-fos induction, is associated with hypotensive activation of CRF-CNA neurones that project to the LC.