Archival ReportThalamic Control of Cognition and Social Behavior Via Regulation of Gamma-Aminobutyric Acidergic Signaling and Excitation/Inhibition Balance in the Medial Prefrontal Cortex
Section snippets
Methods and Materials
Detailed methods are described in the Supplement. Briefly, young adult male Sprague Dawley rats were injected with adeno-associated vectors into the MD (anterior–posterior: −3.3; medial–lateral: 0.7; dorsal–ventral: −5.3) or MD and mPFC (anterior–posterior: 3.2; medial–lateral: 0.5; dorsal–ventral: 2.5). With the exception of those for electrophysiological recordings, all animals were sacrificed for histological confirmation of viral expression. For quantification of the parvalbumin (PV)-hM3Dq
Expression of Inhibitory Gi-Coupled Designer Receptor Exclusively Activated by a Designer Drug Decreases MD Neuronal Activity
To decrease the activity of MD neurons, rats received a bilateral MD injection (Figure 1A), resulting in expression of the inhibitory hM4Di designer receptor exclusively activated by a designer drug (DREADD) receptor fluorescently tagged with mCherry (AAV8-CAMKIIα-hM4D(Gi)-mCherry [MD-hM4Di]; Figure 1B) or a control virus (AAV8-CaMKIIα-eYFP [yellow fluorescent protein] [MD-YFP]). To confirm the functionality of the hM4Di receptors, we used whole-cell patch-clamp recordings. The membrane
Discussion
Using pharmacogenetic inhibition of MD afferents, we decreased MD axonal release in the mPFC and observed significant reductions in inhibitory currents, decreased eIPSC amplitude, and an increased E/I ratio. This corresponded with significant behavioral impairments in WM, set shifting, and social interaction. Furthermore, pharmacological and pharmacogenetic approaches selected to increase GABAergic signaling were sufficient to alleviate physiological and behavioral deficits, highlighting a
Acknowledgments and Disclosures
This work was supported by the Dean’s Fellowship for Themed or Collaborative Research of the Graduate School of Biomedical Sciences and Professional Studies of the Drexel University College of Medicine (to BRF), the National Institutes of Health/National Institute of Mental Health (Grant No. F31MH111361 to BRF and Grant Nos. R01MH085666 and R21MH111609 to W-JG), the Helen S. Vernik Schizophrenia Pilot Research Project from the Department of Psychiatry, Drexel University College of Medicine (to
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