Noradrenergic innervation of the dorsal medial prefrontal cortex modulates hypothalamo-pituitary-adrenal responses to acute emotional stress.
The medial prefrontal cortex (mPFC) has been proposed to play a role in the inhibition of hypothalamo-pituitary-adrenal (HPA) responses to emotional stress via influences on neuroendocrine effector mechanisms housed in the paraventricular hypothalamic nucleus (PVH). Previous work also suggests an involvement of the locus ceruleus (LC) in behavioral and neuroendocrine responses to a variety of acute stressors. The LC issues a widespread set of noradrenergic projections, and its innervation of the prefrontal cortex plays an important role in the modulation of working memory and attention. Because these operations are likely to be critical for stimulus selection, evaluation, and comparison with past experience in mounting adaptive responses to emotional stress, it follows that the LC-to-mPFC pathway might also be involved in regulating HPA activity under such conditions. Therefore, in the present study, we assessed the effects of selectively ablating noradrenergic inputs into the mPFC, using the axonally transported catecholamine immunotoxin, saporin-conjugated antiserum to dopamine-beta-hydroxylase, on acute restraint stress-induced activation of HPA output. Immunotoxin injections in the dorsal mPFC (centered in the prelimbic cortex) attenuated increments in restraint-induced Fos and corticotropin-releasing factor mRNA expression in the neurosecretory region of PVH, as well as HPA secretory responses. Stress-induced Fos expression in dorsal mPFC was enhanced after noradrenergic deafferentation and was negatively correlated with stress-induced PVH activation, independent of lesion status. These findings identify the LC as an upstream component of a circuitry providing for dorsal mPFC modulation of emotional stress-induced HPA activation.
Laboratory of Neuronal Structure and Function, The Salk Institute for Biological Studies, Clayton Medical Research Foundation, La Jolla, California 92037, USA. radley@salk.edu
Jason J
JJ
Radley
Brandon
B
Williams
Paul E
PE
Sawchenko
D000324:Adrenocorticotropic Hormone / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects; D003345:Corticosterone / Q000097:blood; D003346:Corticotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism; D003714:Denervation / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000378:metabolism*; D000922:Immunotoxins / Q000009:adverse effects; D008125:Locus Coeruleus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism*; D016761:Oncogene Proteins v-fos / Q000378:metabolism; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000378:metabolism*; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013315:Stress, Psychological / Q000097:blood / Q000139:chemically induced / Q000473:pathology*
D000922:Immunotoxins; D009419:Nerve Tissue Proteins; D016761:Oncogene Proteins v-fos; D012333:RNA, Messenger; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone; D003345:Corticosterone; D009638:Norepinephrine