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DREADD in Parvalbumin Interneurons of the Dentate Gyrus Modulates Anxiety, Social Interaction and Memory Extinction

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ABSTRACT

Parvalbumin (PV)-positive interneurons in the hippocampus play a critical role in animal memory, such as spatial working memory. However, how PV-positive interneurons in the subregions of the hippocampus affect animal behaviors remains poorly defined. Here, we achieved specific and reversible activation of PV-positive interneurons using designer receptors exclusively activated by designer drugs (DREADD) technology. Inducible DREADD expression was demonstrated in vitro in cultured neurons, in which co-transfection of the hM3D-Gq-mCherry vector with a Cre plasmid resulted in a cellular response to hM3Dq ligand clozapine-N-oxide (CNO) stimulation. In addition, the dentate gyrus (DG) of PV-Cre mice received bilateral injection of control lentivirus or lentivirus expressing double floxed hM3D-Gq-mCherry. Selective activation of PV-positive interneurons in the DG did not affect locomotor activity or depression-related behavior in mice. Interestingly, stimulation of PV-positive interneurons induced an anxiolytic effect. Activation of PV-positive interneurons appears to impair social interaction to novelty, but has no effect on social motivation. However, this defect is likely due to the anxiolytic effect as the exploratory behavior of mice expressing hM3D-Gq is significantly increased. Mice expressing hM3D-Gq did not affect novel object recognition. Activation of PV-positive interneurons in the DG maintains intact cued and contextual fear memory but facilitates fear extinction. Collectively, our results demonstrated that proper control of PV interneurons activity in the DG is critical for regulation of the anxiety, social interaction and fear extinction. These results improve our fundamental understanding of the physiological role of PV-positive interneurons in the hippocampus.

No MeSH data available.


Novel object recognition test. PV-Cre mice were injected with the lentiviral control vector or lentiviral DIO-hM3D-Gq-mCherry vector. Thirty minutes before behavioral testing, mice were given CNO (0.5 mg/kg body weight) by intraperitoneal injection. During the novel object recognition test, the duration of contact (sec) over 5 min was recorded. n = 23 for the control group; n = 22 for the hM3D-Gq group. (A) Short-term memory (1 h). Statistical analysis was conducted using two-way analysis of variance (ANOVA). Treatment F(1,86)=2.762, P=0.100; object F(1,86)=2.050, P=0.156). (B) Long-term memory (24 h). Treatment F(1,86)=0.099, P=0.754; object F(1,86)= 0.078, P=0.780.
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Figure 7: Novel object recognition test. PV-Cre mice were injected with the lentiviral control vector or lentiviral DIO-hM3D-Gq-mCherry vector. Thirty minutes before behavioral testing, mice were given CNO (0.5 mg/kg body weight) by intraperitoneal injection. During the novel object recognition test, the duration of contact (sec) over 5 min was recorded. n = 23 for the control group; n = 22 for the hM3D-Gq group. (A) Short-term memory (1 h). Statistical analysis was conducted using two-way analysis of variance (ANOVA). Treatment F(1,86)=2.762, P=0.100; object F(1,86)=2.050, P=0.156). (B) Long-term memory (24 h). Treatment F(1,86)=0.099, P=0.754; object F(1,86)= 0.078, P=0.780.

Mentions: As we detected a deficit in social recognition, we decided to test how activation of PV interneurons in the DG affect the ability to recognize novel objects. Alteration of PV-interneuron activity has been shown to affect recognition [40, 41]. To further evaluate the effects of PV-positive interneurons on short- and long-term recognition memory in mice, we applied the novel object recognition test. The novel object recognition test showed no significant differences in both the test session for short-term memory (1 h) (Fig. 7A) (treatment F(1,86)=2.762, P=0.100; object F(1,86)=2.050, P=0.156) and the test session for long-term memory (24 h) (Fig. 7B) (treatment F(1,86)=0.099, P=0.754; object F(1,86)= 0.078, P=0.780) between two groups of animals, indicating that selective activation of PV-positive interneurons in the mouse DG does not affect the object recognition activity of mice. Our data suggested that the deficits in the social recognition is not caused by the defect in recognition performance.


DREADD in Parvalbumin Interneurons of the Dentate Gyrus Modulates Anxiety, Social Interaction and Memory Extinction
Novel object recognition test. PV-Cre mice were injected with the lentiviral control vector or lentiviral DIO-hM3D-Gq-mCherry vector. Thirty minutes before behavioral testing, mice were given CNO (0.5 mg/kg body weight) by intraperitoneal injection. During the novel object recognition test, the duration of contact (sec) over 5 min was recorded. n = 23 for the control group; n = 22 for the hM3D-Gq group. (A) Short-term memory (1 h). Statistical analysis was conducted using two-way analysis of variance (ANOVA). Treatment F(1,86)=2.762, P=0.100; object F(1,86)=2.050, P=0.156). (B) Long-term memory (24 h). Treatment F(1,86)=0.099, P=0.754; object F(1,86)= 0.078, P=0.780.
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Figure 7: Novel object recognition test. PV-Cre mice were injected with the lentiviral control vector or lentiviral DIO-hM3D-Gq-mCherry vector. Thirty minutes before behavioral testing, mice were given CNO (0.5 mg/kg body weight) by intraperitoneal injection. During the novel object recognition test, the duration of contact (sec) over 5 min was recorded. n = 23 for the control group; n = 22 for the hM3D-Gq group. (A) Short-term memory (1 h). Statistical analysis was conducted using two-way analysis of variance (ANOVA). Treatment F(1,86)=2.762, P=0.100; object F(1,86)=2.050, P=0.156). (B) Long-term memory (24 h). Treatment F(1,86)=0.099, P=0.754; object F(1,86)= 0.078, P=0.780.
Mentions: As we detected a deficit in social recognition, we decided to test how activation of PV interneurons in the DG affect the ability to recognize novel objects. Alteration of PV-interneuron activity has been shown to affect recognition [40, 41]. To further evaluate the effects of PV-positive interneurons on short- and long-term recognition memory in mice, we applied the novel object recognition test. The novel object recognition test showed no significant differences in both the test session for short-term memory (1 h) (Fig. 7A) (treatment F(1,86)=2.762, P=0.100; object F(1,86)=2.050, P=0.156) and the test session for long-term memory (24 h) (Fig. 7B) (treatment F(1,86)=0.099, P=0.754; object F(1,86)= 0.078, P=0.780) between two groups of animals, indicating that selective activation of PV-positive interneurons in the mouse DG does not affect the object recognition activity of mice. Our data suggested that the deficits in the social recognition is not caused by the defect in recognition performance.

View Article: PubMed Central - PubMed

ABSTRACT

Parvalbumin (PV)-positive interneurons in the hippocampus play a critical role in animal memory, such as spatial working memory. However, how PV-positive interneurons in the subregions of the hippocampus affect animal behaviors remains poorly defined. Here, we achieved specific and reversible activation of PV-positive interneurons using designer receptors exclusively activated by designer drugs (DREADD) technology. Inducible DREADD expression was demonstrated in vitro in cultured neurons, in which co-transfection of the hM3D-Gq-mCherry vector with a Cre plasmid resulted in a cellular response to hM3Dq ligand clozapine-N-oxide (CNO) stimulation. In addition, the dentate gyrus (DG) of PV-Cre mice received bilateral injection of control lentivirus or lentivirus expressing double floxed hM3D-Gq-mCherry. Selective activation of PV-positive interneurons in the DG did not affect locomotor activity or depression-related behavior in mice. Interestingly, stimulation of PV-positive interneurons induced an anxiolytic effect. Activation of PV-positive interneurons appears to impair social interaction to novelty, but has no effect on social motivation. However, this defect is likely due to the anxiolytic effect as the exploratory behavior of mice expressing hM3D-Gq is significantly increased. Mice expressing hM3D-Gq did not affect novel object recognition. Activation of PV-positive interneurons in the DG maintains intact cued and contextual fear memory but facilitates fear extinction. Collectively, our results demonstrated that proper control of PV interneurons activity in the DG is critical for regulation of the anxiety, social interaction and fear extinction. These results improve our fundamental understanding of the physiological role of PV-positive interneurons in the hippocampus.

No MeSH data available.