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The Journal of Neuroscience, May 28, 2008, 28(22):5806-5816; doi:10.1523/JNEUROSCI.0552-08.2008

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Behavioral/Systems/Cognitive
Noradrenergic Innervation of the Dorsal Medial Prefrontal Cortex Modulates Hypothalamo-Pituitary-Adrenal Responses to Acute Emotional Stress

Jason J. Radley, Brandon Williams, and Paul E. Sawchenko

Laboratory of Neuronal Structure and Function, The Salk Institute for Biological Studies, and Clayton Medical Research Foundation, La Jolla, California 92037

Correspondence should be addressed to either Jason J. Radley or Paul E. Sawchenko, 10010 North Torrey Pines Road, La Jolla, CA 92037. Email: radley{at}salk.edu or Email: sawchenko{at}salk.edu

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-β-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.

Key words: ACTH; CRF; dopamine-β-hydroxylase; Fos; HPA axis; hypothalamus; immunotoxin; locus ceruleus (coeruleus); norepinephrine; paraventricular nucleus; saporin

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Received Feb. 6, 2008; revised March 28, 2008; accepted April 18, 2008.

Correspondence should be addressed to either Jason J. Radley or Paul E. Sawchenko, 10010 North Torrey Pines Road, La Jolla, CA 92037. Email: radley{at}salk.edu or Email: sawchenko{at}salk.edu

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