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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 showed increased fear expression, pronounced tachycardia, and reduced heart rate (HR) variability in retention of cued-conditioned fear tested using air stream as unconditioned stimulus. (a) Upon conditioned stimulus (CS) presentation, fear expression as indicated by the percentage of freezing was elevated in both lines but significantly more in HAB (□) than in normal anxiety-like behaviour (NAB) (▪) mice. (b) Both, NAB and HAB mice displayed a reduction in locomotor activity upon CS exposure. The decrease in locomotor activity was more pronounced in HAB mice than in NAB mice. (c) CS induced a tachycardic response in both lines with an exacerbated increase of HR in beats per min (bpm) in HAB mice. (d) In contrast, CS presentation reduced HR variability (root mean square of successive RR interval differences; RMSSD) in both lines. Data are means±s.e.m. (n=8/line). ** p<0.01, *** p<0.001 HAB vs. NAB; # p<0.05, ### p<0.001 CS vs. pre-CS values.
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fig003: High anxiety behaviour (HAB) mice showed increased fear expression, pronounced tachycardia, and reduced heart rate (HR) variability in retention of cued-conditioned fear tested using air stream as unconditioned stimulus. (a) Upon conditioned stimulus (CS) presentation, fear expression as indicated by the percentage of freezing was elevated in both lines but significantly more in HAB (□) than in normal anxiety-like behaviour (NAB) (▪) mice. (b) Both, NAB and HAB mice displayed a reduction in locomotor activity upon CS exposure. The decrease in locomotor activity was more pronounced in HAB mice than in NAB mice. (c) CS induced a tachycardic response in both lines with an exacerbated increase of HR in beats per min (bpm) in HAB mice. (d) In contrast, CS presentation reduced HR variability (root mean square of successive RR interval differences; RMSSD) in both lines. Data are means±s.e.m. (n=8/line). ** p<0.01, *** p<0.001 HAB vs. NAB; # p<0.05, ### p<0.001 CS vs. pre-CS values.

Mentions: During the fear retention test, there was a significant line×CS interaction for freezing behaviour (F1,28=111.97, p<0.001; Fig. 3 a) Post-hoc tests showed that the fear response was higher in HAB than in NAB mice during CS exposure (Fig. 3 a). In both lines, freezing was higher during the CS phase than during pre-CS phase (Fig. 3 a). Furthermore, a significant line×CS interaction was found for locomotor activity (F1,60=5.54, p<0.001; Fig. 3 b). Post-hoc test revealed reduced locomotor activity of HAB mice upon CS exposure compared to NAB mice (Fig. 3 b). A significant line×CS interaction was found for HR (F1,60=59.50, p<0.001; Fig. 3 c). Post-hoc tests revealed higher tachycardic responses in HAB mice than in NAB mice (Fig. 3 c). Indeed, upon CS exposure HAB mice reached maximum physiological HR levels of up to 820 bpm that are higher than those previously reported for other mouse lines (Stiedl et al. 1999). Furthermore, there was a significant line×CS interaction for HR variability (F1,60=4.78, p<0.05; Fig. 3 d). Post-hoc tests yielded a reduced HR variability (RMSSD) in HAB mice compared to NAB mice (Fig. 3 d). Finally, Pearson coefficient demonstrated a highly significant negative correlation (Supplementary Fig. S2) between freezing responses and locomotor activity during the retention test indicating that telemetrically determined locomotor activity can also serve as an index of fear response.


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 showed increased fear expression, pronounced tachycardia, and reduced heart rate (HR) variability in retention of cued-conditioned fear tested using air stream as unconditioned stimulus. (a) Upon conditioned stimulus (CS) presentation, fear expression as indicated by the percentage of freezing was elevated in both lines but significantly more in HAB (□) than in normal anxiety-like behaviour (NAB) (▪) mice. (b) Both, NAB and HAB mice displayed a reduction in locomotor activity upon CS exposure. The decrease in locomotor activity was more pronounced in HAB mice than in NAB mice. (c) CS induced a tachycardic response in both lines with an exacerbated increase of HR in beats per min (bpm) in HAB mice. (d) In contrast, CS presentation reduced HR variability (root mean square of successive RR interval differences; RMSSD) in both lines. Data are means±s.e.m. (n=8/line). ** p<0.01, *** p<0.001 HAB vs. NAB; # p<0.05, ### p<0.001 CS vs. pre-CS values.
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fig003: High anxiety behaviour (HAB) mice showed increased fear expression, pronounced tachycardia, and reduced heart rate (HR) variability in retention of cued-conditioned fear tested using air stream as unconditioned stimulus. (a) Upon conditioned stimulus (CS) presentation, fear expression as indicated by the percentage of freezing was elevated in both lines but significantly more in HAB (□) than in normal anxiety-like behaviour (NAB) (▪) mice. (b) Both, NAB and HAB mice displayed a reduction in locomotor activity upon CS exposure. The decrease in locomotor activity was more pronounced in HAB mice than in NAB mice. (c) CS induced a tachycardic response in both lines with an exacerbated increase of HR in beats per min (bpm) in HAB mice. (d) In contrast, CS presentation reduced HR variability (root mean square of successive RR interval differences; RMSSD) in both lines. Data are means±s.e.m. (n=8/line). ** p<0.01, *** p<0.001 HAB vs. NAB; # p<0.05, ### p<0.001 CS vs. pre-CS values.
Mentions: During the fear retention test, there was a significant line×CS interaction for freezing behaviour (F1,28=111.97, p<0.001; Fig. 3 a) Post-hoc tests showed that the fear response was higher in HAB than in NAB mice during CS exposure (Fig. 3 a). In both lines, freezing was higher during the CS phase than during pre-CS phase (Fig. 3 a). Furthermore, a significant line×CS interaction was found for locomotor activity (F1,60=5.54, p<0.001; Fig. 3 b). Post-hoc test revealed reduced locomotor activity of HAB mice upon CS exposure compared to NAB mice (Fig. 3 b). A significant line×CS interaction was found for HR (F1,60=59.50, p<0.001; Fig. 3 c). Post-hoc tests revealed higher tachycardic responses in HAB mice than in NAB mice (Fig. 3 c). Indeed, upon CS exposure HAB mice reached maximum physiological HR levels of up to 820 bpm that are higher than those previously reported for other mouse lines (Stiedl et al. 1999). Furthermore, there was a significant line×CS interaction for HR variability (F1,60=4.78, p<0.05; Fig. 3 d). Post-hoc tests yielded a reduced HR variability (RMSSD) in HAB mice compared to NAB mice (Fig. 3 d). Finally, Pearson coefficient demonstrated a highly significant negative correlation (Supplementary Fig. S2) between freezing responses and locomotor activity during the retention test indicating that telemetrically determined locomotor activity can also serve as an index of fear response.

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