Elsevier

Biological Psychiatry

Volume 83, Issue 8, 15 April 2018, Pages 657-669
Biological Psychiatry

Archival Report
Thalamic Control of Cognition and Social Behavior Via Regulation of Gamma-Aminobutyric Acidergic Signaling and Excitation/Inhibition Balance in the Medial Prefrontal Cortex

https://doi.org/10.1016/j.biopsych.2017.11.033Get rights and content

Abstract

Background

The mediodorsal thalamus plays a critical role in cognition through its extensive innervation of the medial prefrontal cortex (mPFC), but how the two structures cooperate at the single-cell level to generate associated cognitive functions and other mPFC-dependent behaviors remains elusive. Maintaining the proper balance between excitation and inhibition (E/I balance) is of principal importance for organizing cortical activity. Furthermore, the PFC E/I balance has been implicated in successful execution of multiple PFC-dependent behaviors in both animal research and the context of human psychiatric disorders.

Methods

Here, we used a pharmacogenetic strategy to decrease mediodorsal thalamic activity in adult male rats and evaluated the consequences for E/I balance in PFC pyramidal neurons as well as cognition, social interaction, and anxiety.

Results

We found that dampening mediodorsal thalamic activity caused significant reductions in gamma-aminobutyric acidergic signaling and increased E/I balance in the mPFC and was concomitant with abnormalities in these behaviors. Furthermore, by selectively activating parvalbumin interneurons in the mPFC with a novel pharmacogenetic approach, we restored gamma-aminobutyric acidergic signaling and E/I balance as well as ameliorated all behavioral impairments.

Conclusions

These findings underscore the importance of thalamocortical activation of mPFC gamma-aminobutyric acidergic interneurons in a broad range of mPFC-dependent behaviors. Furthermore, they highlight this circuitry as a platform for therapeutic investigation in psychiatric diseases that involve impairments in PFC-dependent behaviors.

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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