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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.


Comparison of the immobile time between control mice and mice with hM3D-Gq-expressing PV-positive interneurons in the tail suspension 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 tail suspension test, the immotility time (sec) was recorded. n = 26 for each group. NS, not significant.
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Figure 5: Comparison of the immobile time between control mice and mice with hM3D-Gq-expressing PV-positive interneurons in the tail suspension 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 tail suspension test, the immotility time (sec) was recorded. n = 26 for each group. NS, not significant.

Mentions: The tail suspension test initially proposed by Steru et al. is a well-established behavioral test for determining the efficacy of anti-depressant drugs and is also used to determine the effects of genetic and neurobiological manipulations [33]. Using the tail suspension test, we examined depression-related behavior in mice and found that the depression-related behavior of mice was not affected by CNO-induced activation of PV-positive interneurons in the DG. The immobility time (lack of escape-related behavior) was not significantly altered for mice with activated PV-positive interneurons compared with that for control mice (Fig. 5). These data indicate that selective activation of PV-positive interneurons in the mouse DG does not affect the depression-related behaviors of mice.


DREADD in Parvalbumin Interneurons of the Dentate Gyrus Modulates Anxiety, Social Interaction and Memory Extinction
Comparison of the immobile time between control mice and mice with hM3D-Gq-expressing PV-positive interneurons in the tail suspension 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 tail suspension test, the immotility time (sec) was recorded. n = 26 for each group. NS, not significant.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 5: Comparison of the immobile time between control mice and mice with hM3D-Gq-expressing PV-positive interneurons in the tail suspension 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 tail suspension test, the immotility time (sec) was recorded. n = 26 for each group. NS, not significant.
Mentions: The tail suspension test initially proposed by Steru et al. is a well-established behavioral test for determining the efficacy of anti-depressant drugs and is also used to determine the effects of genetic and neurobiological manipulations [33]. Using the tail suspension test, we examined depression-related behavior in mice and found that the depression-related behavior of mice was not affected by CNO-induced activation of PV-positive interneurons in the DG. The immobility time (lack of escape-related behavior) was not significantly altered for mice with activated PV-positive interneurons compared with that for control mice (Fig. 5). These data indicate that selective activation of PV-positive interneurons in the mouse DG does not affect the depression-related behaviors 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.