Research Article

A mouse model of high trait anxiety shows reduced heart rate variability that can be reversed by anxiolytic drug treatment

Stefano Gaburro^a1a2, Oliver Stiedl^a3, Pietro Giusti^a2, Simone B. Sartori^a1, Rainer Landgraf^a4 and Nicolas Singewald^a1 c1

^a1 Department of Pharmacology and Toxicology, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck, University of Innsbruck, Austria

^a2 Department of Pharmacology and Anesthesiology, University of Padova, Italy

^a3 Center for Neurogenomics and Cognitive Research and Neuroscience Campus Amsterdam, VU University Amsterdam, The Netherlands

^a4 Max Planck Institute of Psychiatry, Munich, Germany

Abstract

Increasing evidence suggests that specific physiological measures may serve as biomarkers for successful treatment to alleviate symptoms of pathological anxiety. Studies of autonomic function investigating parameters such as heart rate (HR), HR variability and blood pressure (BP) indicated that HR variability is consistently reduced in anxious patients, whereas HR and BP data show inconsistent results. Therefore, HR and HR variability were measured under various emotionally challenging conditions in a mouse model of high innate anxiety (high anxiety behaviour; HAB) vs. control normal anxiety-like behaviour (NAB) mice. Baseline HR, HR variability and activity did not differ between mouse lines. However, after cued Pavlovian fear conditioning, both elevated tachycardia and increased fear responses were observed in HAB mice compared to NAB mice upon re-exposure to the conditioning stimulus serving as the emotional stressor. When retention of conditioned fear was tested in the home cage, HAB mice again displayed higher fear responses than NAB mice, while the HR responses were similar. Conversely, in both experimental settings HAB mice consistently exhibited reduced HR variability. Repeated administration of the anxiolytic NK1 receptor antagonist L-822429 lowered the conditioned fear response and shifted HR dynamics in HAB mice to a more regular pattern, similar to that in NAB mice. Additional receiver-operating characteristic (ROC) analysis demonstrated the high specificity and sensitivity of HR variability to distinguish between normal and high anxiety trait. These findings indicate that assessment of autonomic response in addition to freezing might be a useful indicator of the efficacy of novel anxiolytic treatments.

(Received June 12 2010)

(Reviewed August 31 2010)

(Revised December 07 2010)

(Accepted January 06 2011)

(Online publication February 15 2011)

Key Words:

• Anxiety;
• autonomic system;
• biomarker;
• fear conditioning

Correspondence:

^c1 Address for correspondence: Professor N. Singewald, Department of Pharmacology and Toxicology, Institute of Pharmacy, Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Peter-Mayer-Str. 1, A-6020 Innsbruck, Austria. Tel.: +43-512-507-5608 Fax: +43-512-507-2931 Email: nicolas.singewald@uibk.ac.at