title: A mouse model of high trait anxiety shows reduced heart rate variability that can be reversed by anxiolytic drug treatment.
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.
authors.affiliation: Department of Pharmacology and Toxicology, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck, University of Innsbruck, Austria.
authors.forename: Stefano
authors.initials: S
authors.lastname: Gaburro
authors.forename: Oliver
authors.initials: O
authors.lastname: Stiedl
authors.forename: Pietro
authors.initials: P
authors.lastname: Giusti
authors.forename: Simone B
authors.initials: SB
authors.lastname: Sartori
authors.forename: Rainer
authors.initials: R
authors.lastname: Landgraf
authors.forename: Nicolas
authors.initials: N
authors.lastname: Singewald
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001007:Anxiety / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology / Q000523:psychology; D001341:Autonomic Nervous System / Q000187:drug effects* / Q000503:physiopathology; D001522:Behavior, Animal / Q000187:drug effects*; D002940:Circadian Rhythm; D003213:Conditioning, Psychological / Q000187:drug effects; D003463:Cues; D004195:Disease Models, Animal; D015716:Electrocardiography, Ambulatory; D004597:Electroshock; D005239:Fear / Q000187:drug effects; D005260:Female; D006321:Heart / Q000294:innervation*; D006339:Heart Rate / Q000187:drug effects*; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D064729:Neurokinin-1 Receptor Antagonists; D009622:Noise; D010880:Piperidines / Q000494:pharmacology*; D012372:ROC Curve; D013610:Tachycardia / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology / Q000523:psychology; D013686:Telemetry; D013997:Time Factors; D014741:Video Recording
chemical_list: D014151:Anti-Anxiety Agents; C532739:N-((2-cyclopropoxy-5-(5-trifluomethyl)tetrazol-1-yl)benzyl)-2-phenylpiperidin-3-amine; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines