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

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.

Amelioration of oxidative stress-induced phenotype loss of parvalbumin interneurons might contribute to the beneficial effects of environmental enrichment in a rat model of post-traumatic stress disorder

“…Moreover, PV-positive GABAergic interneurons are closely linked to fear memory [27], which is also supported by our previous study [13].…”

Chronic activation of the relaxin‐3 receptor on GABA neurons in rat ventral hippocampus promotes anxiety and social avoidance

“…Similarly, hippocampal PV GABAergic interneurons have been implicated in anxiety and social behaviors (Çalışkan et al, ; Sun et al, ; Wöhr et al, ). Activation of these neurons in the vHip of mice induced anxiolytic effects in the EPM and impaired social behavior (Zou et al, ), while PV KO mice have been shown to display significant deficits in social interaction and serve as a model for autism spectrum disorders (Wöhr et al, ). Moreover, a rat model of PTSD displayed anxiety‐like behavior in the EPM and LOF, accompanied by significant decreases in glutamic acid decarboxylase (GAD)‐67, a marker of GABAergic neurons, and PV immunoreactivity (Sun et al, ).…”

“…At a neurochemical level, anxiety is correlated with dysfunctions in hippocampal inhibitory interneuron network activity (Engin & Treit, ; Kalueff, ). For instance, selective stimulation of parvalbumin (PV)‐expressing GABAergic interneurons in the DG, using designer receptors exclusively activated by designer drugs (DREADDs), reduced anxiety and promoted social interaction behavior (Zou et al, ). Meanwhile, recent studies of somatostatin (SST)‐expressing GABAergic neurons in the DG have reported their involvement in memory formation during aversive stimuli (Stefanelli et al, ).…”

Rats bred for high anxiety exhibit distinct fear‐related coping behavior, hippocampal physiology, and synaptic plasticity‐related gene expression

“…The hippocampus plays key roles in regulating emotional behavior and stress reactivity via its abundant neural connections with limbic structures that convey emotionally salient information from the environment. It has been shown to contribute to the regulation of anxiety‐like behavior (Bannerman et al, ; Bertoglio et al, ; Engin & Treit, ; Gray & McNaughton, ; McNaughton & Gray, ; Moser & Moser, ) as well as aggression (Ely, Greene, & Henry, ; Kolb & Nonneman, ), sociability (Felix‐Ortiz & Tye, ; Hitti & Siegelbaum, ; Maaswinkel, Baars, Gispen, & Spruijt, ; Maaswinkel, Gispen, & Spruijt, ; Stevenson & Caldwell, ; Zou et al, ), and reactive coping in the Forced Swim Test (FST; West, ). Our prior work with the selectively bred HR/LR rats has demonstrated marked differences across all of these behavioral domains, with LR rats (compared to HRs) generally displaying higher levels of anxiety‐like behavior (Clinton et al, , ; Perez et al, ; Stead et al, ; Turner et al, ), low aggression (Kerman et al, ), less interest in sex (Cummings, Clinton, Perry, Akil, & Becker, ) and social interaction (Cohen et al, ), as well as reactive coping (increased immobility) in the FST (Clinton, Watson, & Akil, ; Garcia‐Fuster et al, ; McCoy et al, ).…”