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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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High anxiety behaviour (HAB) mice exhibited reduced locomotor activity and heart rate (HR) variability to conditioned auditory fear in the home cage. (a) Presentation of conditioned stimulus (CS) induced a significant reduction in locomotor activity in HAB (□) and normal anxiety-like behaviour (NAB) (▪) mice. The reduction in activity levels was more pronounced in HAB mice compared to NAB mice. (b) The CS presentation induced an increase in HR rate in beats per min (bpm) along with a decline in (c) HR variability (root mean square of successive RR interval differences; RMSSD) in both lines. However, significantly lower HR variability (RMSSD) was detected in HAB mice than in NAB mice. Data are means±s.e.m. (n=8/line). *** p<0.001 HAB vs. NAB; ## p<0.01, ### p<0.001 CS vs. pre-CS values.
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fig004: High anxiety behaviour (HAB) mice exhibited reduced locomotor activity and heart rate (HR) variability to conditioned auditory fear in the home cage. (a) Presentation of conditioned stimulus (CS) induced a significant reduction in locomotor activity in HAB (□) and normal anxiety-like behaviour (NAB) (▪) mice. The reduction in activity levels was more pronounced in HAB mice compared to NAB mice. (b) The CS presentation induced an increase in HR rate in beats per min (bpm) along with a decline in (c) HR variability (root mean square of successive RR interval differences; RMSSD) in both lines. However, significantly lower HR variability (RMSSD) was detected in HAB mice than in NAB mice. Data are means±s.e.m. (n=8/line). *** p<0.001 HAB vs. NAB; ## p<0.01, ### p<0.001 CS vs. pre-CS values.

Mentions: Next, we investigated HR and HR variability responses to a fear retention test performed in the home cage. Locomotion, as indicated from the previous correlation analysis, was taken as an indirect measure of fear response because the lid of the cage prevented direct visual assessment of freezing. There was a significant line×CS interaction for locomotor activity (F1,60=8.31, p<0.01; Fig. 4 a). Post-hoc comparison indicated reduced locomotor activity upon CS presentation compared to baseline conditions. HAB mice displayed lower activity than NAB mice upon CS exposure (Fig. 4 a). There was no line×CS interaction for HR (F1,60=0.24, p>0.05; Fig. 4 b). A main significant CS effect was found indicating increased HR levels in both lines during CS presentation (F1,60=834.58, p<0.001; Fig. 4 b) compared to baseline values. There was a significant CS phase×line interaction for HR variability (RMSSD) (F1,60=5.20, p<0.05; Fig. 4 c). Compared to baseline values, post-hoc comparison showed reduced HR variability (RMSSD) in both lines during CS presentation. HR variability (RMSSD) was lower in HAB mice than in NAB mice during CS exposure.


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)

High anxiety behaviour (HAB) mice exhibited reduced locomotor activity and heart rate (HR) variability to conditioned auditory fear in the home cage. (a) Presentation of conditioned stimulus (CS) induced a significant reduction in locomotor activity in HAB (□) and normal anxiety-like behaviour (NAB) (▪) mice. The reduction in activity levels was more pronounced in HAB mice compared to NAB mice. (b) The CS presentation induced an increase in HR rate in beats per min (bpm) along with a decline in (c) HR variability (root mean square of successive RR interval differences; RMSSD) in both lines. However, significantly lower HR variability (RMSSD) was detected in HAB mice than in NAB mice. Data are means±s.e.m. (n=8/line). *** p<0.001 HAB vs. NAB; ## p<0.01, ### p<0.001 CS vs. pre-CS values.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig004: High anxiety behaviour (HAB) mice exhibited reduced locomotor activity and heart rate (HR) variability to conditioned auditory fear in the home cage. (a) Presentation of conditioned stimulus (CS) induced a significant reduction in locomotor activity in HAB (□) and normal anxiety-like behaviour (NAB) (▪) mice. The reduction in activity levels was more pronounced in HAB mice compared to NAB mice. (b) The CS presentation induced an increase in HR rate in beats per min (bpm) along with a decline in (c) HR variability (root mean square of successive RR interval differences; RMSSD) in both lines. However, significantly lower HR variability (RMSSD) was detected in HAB mice than in NAB mice. Data are means±s.e.m. (n=8/line). *** p<0.001 HAB vs. NAB; ## p<0.01, ### p<0.001 CS vs. pre-CS values.
Mentions: Next, we investigated HR and HR variability responses to a fear retention test performed in the home cage. Locomotion, as indicated from the previous correlation analysis, was taken as an indirect measure of fear response because the lid of the cage prevented direct visual assessment of freezing. There was a significant line×CS interaction for locomotor activity (F1,60=8.31, p<0.01; Fig. 4 a). Post-hoc comparison indicated reduced locomotor activity upon CS presentation compared to baseline conditions. HAB mice displayed lower activity than NAB mice upon CS exposure (Fig. 4 a). There was no line×CS interaction for HR (F1,60=0.24, p>0.05; Fig. 4 b). A main significant CS effect was found indicating increased HR levels in both lines during CS presentation (F1,60=834.58, p<0.001; Fig. 4 b) compared to baseline values. There was a significant CS phase×line interaction for HR variability (RMSSD) (F1,60=5.20, p<0.05; Fig. 4 c). Compared to baseline values, post-hoc comparison showed reduced HR variability (RMSSD) in both lines during CS presentation. HR variability (RMSSD) was lower in HAB mice than in NAB mice during CS exposure.

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