Open Access Open Badges Research

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 Issler1, Roderick N Carter2, Evan D Paul3, Paul AT Kelly4, Henry J Olverman4, Adi Neufeld-Cohen1, Yael Kuperman1, Christopher A Lowry3, Jonathan R Seckl2, Alon Chen1 and Pauline M Jamieson2*

Author Affiliations

1 Department of Neurobiology, Weizmann Institute of Science, Rehovot 76100, Israel

2 Centre for Cardiovascular Science, Queens Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK

3 Department of Integrative Physiology and Center for Neuroscience, University of Colorado Boulder, Boulder, CO 80309, USA

4 Centre for Cognitive and Neural Systems, University of Edinburgh, 1 George Square, Edinburgh EH8 9JZ, UK

For all author emails, please log on.

Biology of Mood & Anxiety Disorders 2014, 4:1  doi:10.1186/2045-5380-4-1

Published: 21 January 2014



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. Here, we describe behavioural and serotonergic responses consistent with maladaptive recovery from stressful challenge in CRFR2-null mice.


CRFR2-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.


These 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.

5-HT1A receptor; Anxiety; Corticotropin-releasing factor type 2 receptor; Raphe nuclei; Serotonin; Stress