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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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RR vs. RMSSD correlation analysis of high anxiety behaviour (HAB) and normal anxiety-like behaviour (NAB) mice across the different fear-conditioning experiments. (a) The correlation analysis shows that RR intervals are negatively correlated with root mean square of successive RR interval difference (RMSSD) values. Moreover, the lines show a different steepness of slope of the linear HR/RMSSD correlation function that is further shifted to reduced increase of heart rate (HR) variability with decreasing HR (increasing RR interval) upon treatment with the NK1 antagonist L-822429. (b) The zoom depicts the range of maximum HR/minimum HR variability in NAB mice and untreated vs. L-822429-treated HAB mice. The dashed line in panel (a) denotes the RR/RMSSD correlation in C57BL/6N mice for comparison (data as reported by Tovote et al. 2004).
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fig006: RR vs. RMSSD correlation analysis of high anxiety behaviour (HAB) and normal anxiety-like behaviour (NAB) mice across the different fear-conditioning experiments. (a) The correlation analysis shows that RR intervals are negatively correlated with root mean square of successive RR interval difference (RMSSD) values. Moreover, the lines show a different steepness of slope of the linear HR/RMSSD correlation function that is further shifted to reduced increase of heart rate (HR) variability with decreasing HR (increasing RR interval) upon treatment with the NK1 antagonist L-822429. (b) The zoom depicts the range of maximum HR/minimum HR variability in NAB mice and untreated vs. L-822429-treated HAB mice. The dashed line in panel (a) denotes the RR/RMSSD correlation in C57BL/6N mice for comparison (data as reported by Tovote et al. 2004).

Mentions: The relationship between HR (RR interval) and its variability (HR variability, quantified by the RMSSD measure) was compared in HAB and NAB mice (Fig. 6). The linear relationship between HR vs. RMSSD was determined in HAB and NAB mice along the whole dynamical range of HR encountered during baseline measurements and after HR adjustments in response to CS. The results indicated that HR variability is inversely related to absolute HR. Significant correlations between HR and HR variability were determined in NAB mice (F1,406=416.86, p<0.001) and HAB mice without treatment (F1,228=56.44, p<0.001) and after chronic NK1 receptor antagonist treatment (F1,91=8.75, p<0.01). The linear relationship approached minimum RMSSD values at maximum HR (generally ~800 bpm; RR interval ~75 ms). However, maximum HR values approached 850 bpm (RR interval ~70 ms) in HAB mice. Chronic treatment with the NK1 antagonist L-822429 reduced the slope of the RR/RMMSD relationship below the slope observed in NAB mice, i.e. resulted in a higher regularity of HR dynamics, and appeared to have limited maximum HR to values below 800 bpm.


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)

RR vs. RMSSD correlation analysis of high anxiety behaviour (HAB) and normal anxiety-like behaviour (NAB) mice across the different fear-conditioning experiments. (a) The correlation analysis shows that RR intervals are negatively correlated with root mean square of successive RR interval difference (RMSSD) values. Moreover, the lines show a different steepness of slope of the linear HR/RMSSD correlation function that is further shifted to reduced increase of heart rate (HR) variability with decreasing HR (increasing RR interval) upon treatment with the NK1 antagonist L-822429. (b) The zoom depicts the range of maximum HR/minimum HR variability in NAB mice and untreated vs. L-822429-treated HAB mice. The dashed line in panel (a) denotes the RR/RMSSD correlation in C57BL/6N mice for comparison (data as reported by Tovote et al. 2004).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig006: RR vs. RMSSD correlation analysis of high anxiety behaviour (HAB) and normal anxiety-like behaviour (NAB) mice across the different fear-conditioning experiments. (a) The correlation analysis shows that RR intervals are negatively correlated with root mean square of successive RR interval difference (RMSSD) values. Moreover, the lines show a different steepness of slope of the linear HR/RMSSD correlation function that is further shifted to reduced increase of heart rate (HR) variability with decreasing HR (increasing RR interval) upon treatment with the NK1 antagonist L-822429. (b) The zoom depicts the range of maximum HR/minimum HR variability in NAB mice and untreated vs. L-822429-treated HAB mice. The dashed line in panel (a) denotes the RR/RMSSD correlation in C57BL/6N mice for comparison (data as reported by Tovote et al. 2004).
Mentions: The relationship between HR (RR interval) and its variability (HR variability, quantified by the RMSSD measure) was compared in HAB and NAB mice (Fig. 6). The linear relationship between HR vs. RMSSD was determined in HAB and NAB mice along the whole dynamical range of HR encountered during baseline measurements and after HR adjustments in response to CS. The results indicated that HR variability is inversely related to absolute HR. Significant correlations between HR and HR variability were determined in NAB mice (F1,406=416.86, p<0.001) and HAB mice without treatment (F1,228=56.44, p<0.001) and after chronic NK1 receptor antagonist treatment (F1,91=8.75, p<0.01). The linear relationship approached minimum RMSSD values at maximum HR (generally ~800 bpm; RR interval ~75 ms). However, maximum HR values approached 850 bpm (RR interval ~70 ms) in HAB mice. Chronic treatment with the NK1 antagonist L-822429 reduced the slope of the RR/RMMSD relationship below the slope observed in NAB mice, i.e. resulted in a higher regularity of HR dynamics, and appeared to have limited maximum HR to values below 800 bpm.

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