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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.


Fear conditioning 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. A sketch of experimental paradigm is shown (A). During the fear conditioning test, the percentage of freezing behavior in different trials, including (B) contextual fear conditioning-extinction learning, (C) cued fear conditioning-acclimation testing, and (D) cued fear conditioning-interval freezing, was calculated. n = 23 for the control group; n = 19 for the hM3D-Gq group. *p < 0.05.
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Figure 8: Fear conditioning 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. A sketch of experimental paradigm is shown (A). During the fear conditioning test, the percentage of freezing behavior in different trials, including (B) contextual fear conditioning-extinction learning, (C) cued fear conditioning-acclimation testing, and (D) cued fear conditioning-interval freezing, was calculated. n = 23 for the control group; n = 19 for the hM3D-Gq group. *p < 0.05.

Mentions: PV interneurons are required for synchronization of spiking activity in neuronal networks. Abnormal PV interneuron activity is known to affect fear memory [42, 43]. However, how local PV interneuron activity in the DG affect fear learning is not clear. Because we detected that activation of PV-positive interneurons in the DG leads to deficits in social interaction but not novelty recognition, we next investigated the fear memory in mice in the different experimental groups using a fear conditioning and extinction paradigm (Fig. 8A). No significant difference was detected in the contextual fear conditioning test during the first 6 days, suggesting that the hM3D-Gq mice had an intact memory. Interestingly, the hM3D-Gq mice show enhanced extinction formation on day 7 (Fig. 8B). No statistical difference in the cued fear test, a hippocampal-independent learning test, between the two groups (Fig. 8C, D) supports the enhancement in memory extinction is the DG-dependent.


DREADD in Parvalbumin Interneurons of the Dentate Gyrus Modulates Anxiety, Social Interaction and Memory Extinction
Fear conditioning 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. A sketch of experimental paradigm is shown (A). During the fear conditioning test, the percentage of freezing behavior in different trials, including (B) contextual fear conditioning-extinction learning, (C) cued fear conditioning-acclimation testing, and (D) cued fear conditioning-interval freezing, was calculated. n = 23 for the control group; n = 19 for the hM3D-Gq group. *p < 0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 8: Fear conditioning 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. A sketch of experimental paradigm is shown (A). During the fear conditioning test, the percentage of freezing behavior in different trials, including (B) contextual fear conditioning-extinction learning, (C) cued fear conditioning-acclimation testing, and (D) cued fear conditioning-interval freezing, was calculated. n = 23 for the control group; n = 19 for the hM3D-Gq group. *p < 0.05.
Mentions: PV interneurons are required for synchronization of spiking activity in neuronal networks. Abnormal PV interneuron activity is known to affect fear memory [42, 43]. However, how local PV interneuron activity in the DG affect fear learning is not clear. Because we detected that activation of PV-positive interneurons in the DG leads to deficits in social interaction but not novelty recognition, we next investigated the fear memory in mice in the different experimental groups using a fear conditioning and extinction paradigm (Fig. 8A). No significant difference was detected in the contextual fear conditioning test during the first 6 days, suggesting that the hM3D-Gq mice had an intact memory. Interestingly, the hM3D-Gq mice show enhanced extinction formation on day 7 (Fig. 8B). No statistical difference in the cued fear test, a hippocampal-independent learning test, between the two groups (Fig. 8C, D) supports the enhancement in memory extinction is the DG-dependent.

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.