Increased anxiety in corticotropin-releasing factor type 2 receptor-null mice requires recent acute stress exposure and is associated with dysregulated serotonergic activity in limbic brain areas

Orna Issler,Pauline M Jamieson,Henry J Olverman,Paul At Kelly,Adi Neufeld-Cohen,Evan D Paul,Yael Kuperman,Christopher A Lowry,Roderick N Carter,Alon Chen,Jonathan R Seckl

doi:10.1186/2045-5380-4-1

Abstract

BackgroundCorticotropin-releasing factor type 2 receptors (CRFR2) are suggested to facilitate successful recovery from stress to maintain mental health. They are abundant in the midbrain raphe nuclei, where they regulate serotonergic neuronal activity and have been demonstrated to mediate behavioural consequences of stress. Here, we describe behavioural and serotonergic responses consistent with maladaptive recovery from stressful challenge in CRFR2-null mice.ResultsCRFR2-null mice showed similar anxiety levels to control mice before and immediately after acute restraint stress, and also after cessation of chronic stress. However, they showed increased anxiety by 24 hours after restraint, whether or not they had been chronically stressed.Serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) contents were quantified and the level of 5-HIAA in the caudal dorsal raphe nucleus (DRN) was increased under basal conditions in CRFR2-null mice, indicating increased 5-HT turnover. Twenty-four hours following restraint, 5-HIAA was decreased only in CRFR2-null mice, suggesting that they had not fully recovered from the challenge. In efferent limbic structures, CRFR2-null mice showed lower levels of basal 5-HT in the lateral septum and subiculum, and again showed a differential response to restraint stress from controls.Local cerebral glucose utilization (LCMRglu) revealed decreased neuronal activity in the DRN of CRFR2-null mice under basal conditions. Following 5-HT receptor agonist challenge, LCMRglu responses indicated that 5-HT1A receptor responses in the DRN were attenuated in CRFR2-null mice. However, postsynaptic 5-HT receptor responses in forebrain regions were intact.ConclusionsThese results suggest that CRFR2 are required for proper functionality of 5-HT1A receptors in the raphe nuclei, and are key to successful recovery from stress. This disrupted serotonergic function in CRFR2-null mice likely contributes to their stress-sensitive phenotype. The 5-HT content in lateral septum and subiculum was notably altered. These areas are important for anxiety, and are also implicated in reward and the pathophysiology of addiction. The role of CRFR2 in stress-related psychopathologies deserves further consideration.

Highlights

Corticotropin-releasing factor type 2 receptors (CRFR2) are suggested to facilitate successful recovery from stress to maintain mental health
CRFR2-null mice show increased anxiety 24 to 48 h after acute restraint stress (ARS) Under basal conditions, where mice were not exposed to stress, CRFR2null mice and littermate controls showed no differences in anxiety-related behaviour in two well-validated behavioural tests, the Light/dark transfer test (LDT) (Figure 2) and the OF test (Figure 3), compared with littermate controls
Because this finding contrasted with previous reports [50,51], we hypothesized that stressful challenge was required to reveal the role of CRFR2 in anxiety

Summary

Introduction

Corticotropin-releasing factor type 2 receptors (CRFR2) are suggested to facilitate successful recovery from stress to maintain mental health. They are abundant in the midbrain raphe nuclei, where they regulate serotonergic neuronal activity and have been demonstrated to mediate behavioural consequences of stress. Serotonin (5-HT) is a key neurotransmitter in the control of mood It is the major target of current antidepressant medications, and often of treatments for anxiety disorders [1,2]. Corticotropin-releasing factor (CRF) is a key mediator of the stress response [5,6,7], and anxiety and affective disorders have been associated with CRF hyperactivity [8]. Electrophysiological studies show that exogenous CRF administered to the raphe modulates serotonergic neuronal firing activity [14,15,16], and CRF receptor-mediated effects on stress-related behaviours may be mediated via 5-HT in vivo [17,18,19,20]

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