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

Abstract

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-␤-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 corticotropinreleasing 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.

Too Much of a Good Thing: Blocking Noradrenergic Facilitation in Medial Prefrontal Cortex Prevents the Detrimental Effects of Chronic Stress on Cognition

“…Although the prelimbic region of the mPFC does not innervate the paraventricular nucleus of the hypothalamus (PVN) directly, there is evidence that attenuating stress-evoked NE release in the mPFC can reduce acute activation of the PVN (Radley et al, 2008). Thus, adrenergic receptor blockade in the mPFC may decrease the repeated stress-induced activation of the HPA axis, thereby reducing circulating levels of corticosterone during CUS and protecting the mPFC indirectly.…”

Current perspectives of the roles of the central norepinephrine system in anxiety and depression

“…[34,[90][91][92][93] Given that a failure in the central NE regulation of HPA activity and the subsequent inability to regulate the stress response can contribute to the pathogenesis of mood and anxiety symptoms, the neuroplastic changes after antidepressant treatments suggest that NE and/or 5-HT can have a direct role in regulating BDNF expression, and a disruption of NE and/or 5-HT functions in the brain can contribute to the cellular mechanisms underlying anxiety and depression. [34,[91][92][93][94][95][96][97] Furthermore, nonpharmacological approaches (e.g., exercise, diet control, and life-style changes) also increase BDNF and neurogenesis. [78,[98][99][100] These approaches may constitute an indirect way to modulate NE functions, which, in turn, regulate BDNF and neurogenesis-dependent mechanisms to normalize the state of anxious depression.…”

Role of Prefrontal Cortex Dopamine and Noradrenaline Circuitry in Addiction

“…Although moderate stress can have a positive value on cognition, strong or repeated stress will either be deleterious for cognitive functions or may be a determining factor in vulnerability to mental illness and drug addiction, likely through an alteration of catecholamine transmission in the PFC (Holmes andWelman 2009, George andGoldstein and Volkow, 2011). Indeed, it has recently been reported (Radley et al, 2008) that selectively ablating noradrenergic input into the rat medial PFC attenuates the effects of stress in the paraventricular hypothalamic nucleus, as well as the HPA axis secretory responses, while stress-induced Fos expression in dorsal medial PFC was enhanced and was negatively correlated with stress-induced paraventricular hypothalamic nucleus activation. These observations identify the locus coeruleus as an upstream component of a circuitry providing for dorsal medial PFC modulation of emotional stress-induced HPA activation.…”