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

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.


Animal behavior analysis in the open field 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 open field test, the total distance traveled (cm) (A), cumulative duration in the center (s) (B), center entry frequency (C), duration spent mobile (s) (D), maximum velocity (cm/s) (E) or mean velocity (cm/s) (F) were recorded over 5 min. n = 26 for the control group; n = 27 for the hM3D-Gq group. NS, not significant.
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Figure 3: Animal behavior analysis in the open field 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 open field test, the total distance traveled (cm) (A), cumulative duration in the center (s) (B), center entry frequency (C), duration spent mobile (s) (D), maximum velocity (cm/s) (E) or mean velocity (cm/s) (F) were recorded over 5 min. n = 26 for the control group; n = 27 for the hM3D-Gq group. NS, not significant.

Mentions: To determine the potential influence of PV-positive interneurons in the DG on locomotor activity, PV-Cre mice were injected with either DIO-mCherry control vector or DIO-hM3D-Gq-mCherry lentivirus. The overall motor function of injected mice was examined via the open field test. After the activation of PV-positive interneurons by intraperitoneal injection of CNO, the open field test showed no significant differences in the total distance traveled, cumulative duration in the center, center entry frequency, duration spent immobile, mean velocity or maximum velocity between two groups of animals (p>0.05 for all indexes; Fig. 3A-F), indicating that selective activation of PV-positive interneurons in the mouse DG does not affect the locomotor activity of mice.


DREADD in Parvalbumin Interneurons of the Dentate Gyrus Modulates Anxiety, Social Interaction and Memory Extinction
Animal behavior analysis in the open field 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 open field test, the total distance traveled (cm) (A), cumulative duration in the center (s) (B), center entry frequency (C), duration spent mobile (s) (D), maximum velocity (cm/s) (E) or mean velocity (cm/s) (F) were recorded over 5 min. n = 26 for the control group; n = 27 for the hM3D-Gq group. NS, not significant.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4997952&req=5

Figure 3: Animal behavior analysis in the open field 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 open field test, the total distance traveled (cm) (A), cumulative duration in the center (s) (B), center entry frequency (C), duration spent mobile (s) (D), maximum velocity (cm/s) (E) or mean velocity (cm/s) (F) were recorded over 5 min. n = 26 for the control group; n = 27 for the hM3D-Gq group. NS, not significant.
Mentions: To determine the potential influence of PV-positive interneurons in the DG on locomotor activity, PV-Cre mice were injected with either DIO-mCherry control vector or DIO-hM3D-Gq-mCherry lentivirus. The overall motor function of injected mice was examined via the open field test. After the activation of PV-positive interneurons by intraperitoneal injection of CNO, the open field test showed no significant differences in the total distance traveled, cumulative duration in the center, center entry frequency, duration spent immobile, mean velocity or maximum velocity between two groups of animals (p>0.05 for all indexes; Fig. 3A-F), indicating that selective activation of PV-positive interneurons in the mouse DG does not affect the locomotor activity of mice.

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.