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

Gaburro S, Stiedl O, Giusti P, Sartori SB, Landgraf R, Singewald N - Int. J. Neuropsychopharmacol. (2011)

Bottom Line: 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.These findings indicate that assessment of autonomic response in addition to freezing might be a useful indicator of the efficacy of novel anxiolytic treatments.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Toxicology, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck, University of Innsbruck, Austria.

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.

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ROC curves of heart rate (HR) variability during the different fear-conditioning paradigms for discriminating mice with high anxiety behaviour (HAB) from those with normal anxiety-like behaviour (NAB). –○–, HR variability analysis (HRV1) during the first conditioned fear experiment; – –▿– –, HR variability analysis (HRV2) during home-cage conditioned fear; and – –□– –, HR variability analysis (HRV3) for the NK1 receptor antagonist fear-conditioning treatment.
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fig007: ROC curves of heart rate (HR) variability during the different fear-conditioning paradigms for discriminating mice with high anxiety behaviour (HAB) from those with normal anxiety-like behaviour (NAB). –○–, HR variability analysis (HRV1) during the first conditioned fear experiment; – –▿– –, HR variability analysis (HRV2) during home-cage conditioned fear; and – –□– –, HR variability analysis (HRV3) for the NK1 receptor antagonist fear-conditioning treatment.

Mentions: Analysis of the AUC assessed the diagnostic accuracy distinguishing between normal and high anxiety trait in the three sets of fear-conditioning experiments (Fig. 7). The AUCs for HR variability in the three sets of fear-conditioning experiments were 1.00, 1.00 and 0.964±0.033. The Z scores did not reveal any statistical difference between the AUC of the three experiments. The optimal cut-off of HR variability levels determined from the ROC curves were as follows: 0.587 ms for the first conditioned fear experiment, 0.723 ms for the home-cage fear conditioning and 0.633 ms for the experiment with NK1 receptor antagonist treatment. The sensitivity and specificity for the cut-off values of >0.587 ms and >0.723 ms demonstrated 100% specificity and sensitivity, whereas the cut-off value of >0.633 ms demonstrated a sensitivity and specificity of 92.9%.


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

Gaburro S, Stiedl O, Giusti P, Sartori SB, Landgraf R, Singewald N - Int. J. Neuropsychopharmacol. (2011)

ROC curves of heart rate (HR) variability during the different fear-conditioning paradigms for discriminating mice with high anxiety behaviour (HAB) from those with normal anxiety-like behaviour (NAB). –○–, HR variability analysis (HRV1) during the first conditioned fear experiment; – –▿– –, HR variability analysis (HRV2) during home-cage conditioned fear; and – –□– –, HR variability analysis (HRV3) for the NK1 receptor antagonist fear-conditioning treatment.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3198175&req=5

fig007: ROC curves of heart rate (HR) variability during the different fear-conditioning paradigms for discriminating mice with high anxiety behaviour (HAB) from those with normal anxiety-like behaviour (NAB). –○–, HR variability analysis (HRV1) during the first conditioned fear experiment; – –▿– –, HR variability analysis (HRV2) during home-cage conditioned fear; and – –□– –, HR variability analysis (HRV3) for the NK1 receptor antagonist fear-conditioning treatment.
Mentions: Analysis of the AUC assessed the diagnostic accuracy distinguishing between normal and high anxiety trait in the three sets of fear-conditioning experiments (Fig. 7). The AUCs for HR variability in the three sets of fear-conditioning experiments were 1.00, 1.00 and 0.964±0.033. The Z scores did not reveal any statistical difference between the AUC of the three experiments. The optimal cut-off of HR variability levels determined from the ROC curves were as follows: 0.587 ms for the first conditioned fear experiment, 0.723 ms for the home-cage fear conditioning and 0.633 ms for the experiment with NK1 receptor antagonist treatment. The sensitivity and specificity for the cut-off values of >0.587 ms and >0.723 ms demonstrated 100% specificity and sensitivity, whereas the cut-off value of >0.633 ms demonstrated a sensitivity and specificity of 92.9%.

Bottom Line: 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.These findings indicate that assessment of autonomic response in addition to freezing might be a useful indicator of the efficacy of novel anxiolytic treatments.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Toxicology, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck, University of Innsbruck, Austria.

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.

Show MeSH
Related in: MedlinePlus