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Mice lacking integrin β3 expression exhibit altered response to chronic stress.

Varney S, Polston KF, Jessen T, Carneiro AM - Neurobiol Stress (2015)

Bottom Line: We found that genetic abrogation of integrin β3 expression elicits an exaggerated vulnerability to chronic unpredictable stress in the open field test.Semi-quantitative Western blot studies revealed that the synaptic expression, but not total tissue expression, of multiple signaling proteins is correlated with integrin αv levels in the midbrain.Moreover, loss of integrin β3 expression modifies this correlation network.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232-6600, USA.

ABSTRACT

Recent studies indicate multiple roles for integrin αvβ3 in adult neurons, including response to pharmacological agents such as cocaine and selective serotonin reuptake inhibitors. In this study, we examined the role of the integrin β3 gene (Itgb3) in the response to environmental stimuli by subjecting Itgb3 (+/+) and Itgb3 (-/-) mice to unpredictable chronic mild stressors. We found that genetic abrogation of integrin β3 expression elicits an exaggerated vulnerability to chronic unpredictable stress in the open field test. In this test, chronic stress elicited significant decreases in stereotypic behavior and horizontal locomotor activity, including increases in anxiety behaviors. Mild chronic stress led to reductions in dopamine turnover in midbrains of Itgb3 (+/+), but not Itgb3 (-/-) mice, suggesting a disruption of stress-dependent regulation of DA homeostasis. Chronic stress elicited altered synaptic expression of syntaxin and synaptophysin in midbrains of Itgb3 (-/-) mice, when compared to Itgb3 (+/+). Semi-quantitative Western blot studies revealed that the synaptic expression, but not total tissue expression, of multiple signaling proteins is correlated with integrin αv levels in the midbrain. Moreover, loss of integrin β3 expression modifies this correlation network. Together, these findings demonstrate that Itgb3 (-/-) mice display a pattern of changes indicating disrupted regulation of midbrain synaptic systems involved in conferring resilience to mild stressors.

No MeSH data available.


Related in: MedlinePlus

Exposure to unpredictable chronic mild stress reveals altered behavioral responses in Itgb3-/- mice. a, Shredding of a cotton nestlet was measured in mice exposed to UCMS and controls. The amount shredded is shown as percentage of total nestlet weight. Number of animals: Week 1: Itgb3+/+Control N = 15; Itgb3+/+UCMS N = 12; Itgb3-/-Control N = 11; Itgb3-/-UCMS N = 13. Week 8: Itgb3+/+Control N = 10; Itgb3+/+UCMS N = 10; Itgb3-/-Control N = 7; Itgb3-/-UCMS N = 8. b–f, Mice were exposed to the open field without habituation and activity measured for the first 10 min b, Open field total ambulatory distance. c–d, Stereotypic counts (c) and time spent on grooming and other stereotypic behaviors (d) were altered by UCMS. e–f, Thigmotaxis analysis of % of time spent in the center of the open field (e) and number of times the mouse explored the center of the filed (f). b–f Number of animals: Itgb3+/+Control N = 22; Itgb3+/+UCMS N = 20; Itgb3-/-Control N = 13; Itgb3-/-UCMS N = 12. *P < 0.05, **P < 0.01, and ***P < 0.001 for control vs. UCMS post-tests, and #P < 0.05 for genotype comparisons within treatment group. All post-tests P values are Bonferonni corrected.
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Figure 1: Exposure to unpredictable chronic mild stress reveals altered behavioral responses in Itgb3-/- mice. a, Shredding of a cotton nestlet was measured in mice exposed to UCMS and controls. The amount shredded is shown as percentage of total nestlet weight. Number of animals: Week 1: Itgb3+/+Control N = 15; Itgb3+/+UCMS N = 12; Itgb3-/-Control N = 11; Itgb3-/-UCMS N = 13. Week 8: Itgb3+/+Control N = 10; Itgb3+/+UCMS N = 10; Itgb3-/-Control N = 7; Itgb3-/-UCMS N = 8. b–f, Mice were exposed to the open field without habituation and activity measured for the first 10 min b, Open field total ambulatory distance. c–d, Stereotypic counts (c) and time spent on grooming and other stereotypic behaviors (d) were altered by UCMS. e–f, Thigmotaxis analysis of % of time spent in the center of the open field (e) and number of times the mouse explored the center of the filed (f). b–f Number of animals: Itgb3+/+Control N = 22; Itgb3+/+UCMS N = 20; Itgb3-/-Control N = 13; Itgb3-/-UCMS N = 12. *P < 0.05, **P < 0.01, and ***P < 0.001 for control vs. UCMS post-tests, and #P < 0.05 for genotype comparisons within treatment group. All post-tests P values are Bonferonni corrected.

Mentions: To examine the role of integrin αvβ3 in the neurochemical and behavioral responses to chronic stress, we utilized a modified version of unpredictable chronic mild stress procedure (UCMS) (Nollet et al., 2013). After exposure to the UCMS, Itgb3+/+ mice exhibited increases in nestlet shredding, while Itgb3-/- mice exhibited no stress-dependent responses in this behavior (Fig. 1a. 2-way ANOVA Gene x time effect: F(3,78) 3.175, P = 0.028. Post-tests with Bonferroni's corrections: Itgb3+/+ Stress: Week 1 vs. Week 7 P = 0.0001). We then exposed mice to the open field to determine genotype- and stress-induced alterations in locomotor activity and anxiety behaviors. UCMS induced a significant reduction in ambulatory distance only in Itgb3-/- mice (Fig. 1b. Stress: F(1,68) = 7.80; P = 0.007. Itgb3-/-Control vs. Itgb3-/-UCMS, P = 0.015). We also observed reductions in stereotypy in response to UCMS only in Itgb3-/- mice, in both number of stereotypic counts (Fig. 1c. Interaction: F(1,68) = 4.911; p = 0.030. Itgb3/Control vs. Itgb3-/-UCMS, P = 0.001), or time spent engaging in stereotypic behaviors (Fig. 1d. Stress: F(1,68) = 2.88; P = 0.004. Itgb3-/-Control vs. Itgb3-/-UCMS, P = 0.008). Thigmotaxis analysis revealed a significant gene × stress interaction on the time spent in the center of the open field chamber (Fig. 1e. Interaction: F(1,67) = 4.900; P = 0.030) and in the number of entries in the center of the open field (Fig. 1f. Stress effect: F(1,68) = 5.15; P = 0.026. Itgb3-/-Control vs. Itgb3-/-UCMS, P = 0.032).


Mice lacking integrin β3 expression exhibit altered response to chronic stress.

Varney S, Polston KF, Jessen T, Carneiro AM - Neurobiol Stress (2015)

Exposure to unpredictable chronic mild stress reveals altered behavioral responses in Itgb3-/- mice. a, Shredding of a cotton nestlet was measured in mice exposed to UCMS and controls. The amount shredded is shown as percentage of total nestlet weight. Number of animals: Week 1: Itgb3+/+Control N = 15; Itgb3+/+UCMS N = 12; Itgb3-/-Control N = 11; Itgb3-/-UCMS N = 13. Week 8: Itgb3+/+Control N = 10; Itgb3+/+UCMS N = 10; Itgb3-/-Control N = 7; Itgb3-/-UCMS N = 8. b–f, Mice were exposed to the open field without habituation and activity measured for the first 10 min b, Open field total ambulatory distance. c–d, Stereotypic counts (c) and time spent on grooming and other stereotypic behaviors (d) were altered by UCMS. e–f, Thigmotaxis analysis of % of time spent in the center of the open field (e) and number of times the mouse explored the center of the filed (f). b–f Number of animals: Itgb3+/+Control N = 22; Itgb3+/+UCMS N = 20; Itgb3-/-Control N = 13; Itgb3-/-UCMS N = 12. *P < 0.05, **P < 0.01, and ***P < 0.001 for control vs. UCMS post-tests, and #P < 0.05 for genotype comparisons within treatment group. All post-tests P values are Bonferonni corrected.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 1: Exposure to unpredictable chronic mild stress reveals altered behavioral responses in Itgb3-/- mice. a, Shredding of a cotton nestlet was measured in mice exposed to UCMS and controls. The amount shredded is shown as percentage of total nestlet weight. Number of animals: Week 1: Itgb3+/+Control N = 15; Itgb3+/+UCMS N = 12; Itgb3-/-Control N = 11; Itgb3-/-UCMS N = 13. Week 8: Itgb3+/+Control N = 10; Itgb3+/+UCMS N = 10; Itgb3-/-Control N = 7; Itgb3-/-UCMS N = 8. b–f, Mice were exposed to the open field without habituation and activity measured for the first 10 min b, Open field total ambulatory distance. c–d, Stereotypic counts (c) and time spent on grooming and other stereotypic behaviors (d) were altered by UCMS. e–f, Thigmotaxis analysis of % of time spent in the center of the open field (e) and number of times the mouse explored the center of the filed (f). b–f Number of animals: Itgb3+/+Control N = 22; Itgb3+/+UCMS N = 20; Itgb3-/-Control N = 13; Itgb3-/-UCMS N = 12. *P < 0.05, **P < 0.01, and ***P < 0.001 for control vs. UCMS post-tests, and #P < 0.05 for genotype comparisons within treatment group. All post-tests P values are Bonferonni corrected.
Mentions: To examine the role of integrin αvβ3 in the neurochemical and behavioral responses to chronic stress, we utilized a modified version of unpredictable chronic mild stress procedure (UCMS) (Nollet et al., 2013). After exposure to the UCMS, Itgb3+/+ mice exhibited increases in nestlet shredding, while Itgb3-/- mice exhibited no stress-dependent responses in this behavior (Fig. 1a. 2-way ANOVA Gene x time effect: F(3,78) 3.175, P = 0.028. Post-tests with Bonferroni's corrections: Itgb3+/+ Stress: Week 1 vs. Week 7 P = 0.0001). We then exposed mice to the open field to determine genotype- and stress-induced alterations in locomotor activity and anxiety behaviors. UCMS induced a significant reduction in ambulatory distance only in Itgb3-/- mice (Fig. 1b. Stress: F(1,68) = 7.80; P = 0.007. Itgb3-/-Control vs. Itgb3-/-UCMS, P = 0.015). We also observed reductions in stereotypy in response to UCMS only in Itgb3-/- mice, in both number of stereotypic counts (Fig. 1c. Interaction: F(1,68) = 4.911; p = 0.030. Itgb3/Control vs. Itgb3-/-UCMS, P = 0.001), or time spent engaging in stereotypic behaviors (Fig. 1d. Stress: F(1,68) = 2.88; P = 0.004. Itgb3-/-Control vs. Itgb3-/-UCMS, P = 0.008). Thigmotaxis analysis revealed a significant gene × stress interaction on the time spent in the center of the open field chamber (Fig. 1e. Interaction: F(1,67) = 4.900; P = 0.030) and in the number of entries in the center of the open field (Fig. 1f. Stress effect: F(1,68) = 5.15; P = 0.026. Itgb3-/-Control vs. Itgb3-/-UCMS, P = 0.032).

Bottom Line: We found that genetic abrogation of integrin β3 expression elicits an exaggerated vulnerability to chronic unpredictable stress in the open field test.Semi-quantitative Western blot studies revealed that the synaptic expression, but not total tissue expression, of multiple signaling proteins is correlated with integrin αv levels in the midbrain.Moreover, loss of integrin β3 expression modifies this correlation network.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232-6600, USA.

ABSTRACT

Recent studies indicate multiple roles for integrin αvβ3 in adult neurons, including response to pharmacological agents such as cocaine and selective serotonin reuptake inhibitors. In this study, we examined the role of the integrin β3 gene (Itgb3) in the response to environmental stimuli by subjecting Itgb3 (+/+) and Itgb3 (-/-) mice to unpredictable chronic mild stressors. We found that genetic abrogation of integrin β3 expression elicits an exaggerated vulnerability to chronic unpredictable stress in the open field test. In this test, chronic stress elicited significant decreases in stereotypic behavior and horizontal locomotor activity, including increases in anxiety behaviors. Mild chronic stress led to reductions in dopamine turnover in midbrains of Itgb3 (+/+), but not Itgb3 (-/-) mice, suggesting a disruption of stress-dependent regulation of DA homeostasis. Chronic stress elicited altered synaptic expression of syntaxin and synaptophysin in midbrains of Itgb3 (-/-) mice, when compared to Itgb3 (+/+). Semi-quantitative Western blot studies revealed that the synaptic expression, but not total tissue expression, of multiple signaling proteins is correlated with integrin αv levels in the midbrain. Moreover, loss of integrin β3 expression modifies this correlation network. Together, these findings demonstrate that Itgb3 (-/-) mice display a pattern of changes indicating disrupted regulation of midbrain synaptic systems involved in conferring resilience to mild stressors.

No MeSH data available.


Related in: MedlinePlus