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

Abstract

Cognitive impairments associated with dysfunction of the medial prefrontal cortex (mPFC) are prominent in stress-related psychiatric disorders. We have shown that enhancing noradrenergic tone acutely in the rat mPFC facilitated extra-dimensional (ED) set-shifting on the attentional set-shifting test (AST), whereas chronic unpredictable stress (CUS) impaired ED. In this study, we tested the hypothesis that the acute facilitatory effect of norepinephrine (NE) in mPFC becomes detrimental when activated repeatedly during CUS. Using microdialysis, we showed that the release of NE evoked in mPFC by acute stress was unchanged at the end of CUS treatment. Thus, to then determine if repeated elicitation of this NE activity in mPFC during CUS may have contributed to the ED deficit, we infused a cocktail of a 1 -, b 1 -, and b 2 -adrenergic receptor antagonists into the mPFC prior to each CUS session, then tested animals drug free on the AST. Antagonist treatment prevented the CUS-induced ED deficit, suggesting that NE signaling during CUS compromised mPFC function. We confirmed that this was not attributable to sensitization of adrenergic receptor function following chronic antagonist treatment, by administering an additional microinjection into the mPFC immediately prior to ED testing. Acute antagonist treatment did not reverse the beneficial effects of chronic drug treatment during CUS, nor have any effect on baseline ED performance in chronic vehicle controls. Thus, we conclude that blockade of noradrenergic receptors in mPFC protected against the detrimental cognitive effects of CUS, and that repeated elicitation of noradrenergic facilitatory activity is one mechanism by which chronic stress may promote mPFC cognitive dysfunction.

Repeated Social Stress Increases Reward Salience and Impairs Encoding of Prediction by Rat Locus Coeruleus Neurons

“…social stress did not impair performance in any component of the task and, unexpectedly, enhanced IDS and REV performance. Notably, excessive activation of the LC-NE system has been implicated in stress-induced cognitive impairments (Birnbaum et al, 1999;Jett and Morilak, 2013). However, this does not occur in rats with repeated social stress history (Chaijale et al, 2013 and the present study).…”

“…Thus, acute tail pinch, chronic restraint, and chronic unpredictable stress impair attention set-shifting or strategy-shifting performance (Bondi et al, 2008;Butts et al, 2013;Jett and Morilak, 2013;Liston et al, 2006). However, this effect does not generalize across all stress conditions.…”

A Role for Microglia in Repeated Stress-Induced Functional Changes in the Medial Prefrontal Cortex in Rodents

“…Several groups including ours have shown a role for dopamine and noradrenaline in the mPFC [9][10][11][12] and inflammation-related molecules, such as IL-1β [11,13,14] and prostaglandin (PG) E 2 [9], in behavioral changes induced by repeated stress. It has been suggested that repeated stress activates microglia as a cellular source of inflammation-related molecules [9,11].…”

“…Thus, systemic administration with propranolol, a blocker for β-adrenergic receptors, reduces elevated anxiety induced by repeated social defeat stress, as measured by the light-dark box test [11]. Furthermore, local injection of a cocktail of α1, β1 and β2 adrenergic antagonists to the rat mPFC blocked chronic stress-induced decline in the performance of attentional set shifting, an mPFC-dependent cognitive task [12]. Therefore, noradrenaline and dopamine in the mPFC appear to play opposite roles in regulating stress susceptibility, though it is important to analyze and compare roles for these monoamines in the same behavioral platform in the future.…”

“…Besides a role for dopamine, recent studies have also shown a role for noradrenaline in behavioral changes induced by repeated stress [11,12]. Thus, systemic administration with propranolol, a blocker for β-adrenergic receptors, reduces elevated anxiety induced by repeated social defeat stress, as measured by the light-dark box test [11].…”