Optogenetic stimulation of medial prefrontal cortex Drd1 neurons produces rapid and long-lasting antidepressant effects

Brendan D Hare,Ryota Shinohara,Ralph J Dileone,Rong Jian Liu,Santosh Pothula,Ronald S Duman

doi:10.1038/s41467-018-08168-9

Brendan D Hare, Ryota Shinohara + Show 4 more

Open Access

https://doi.org/10.1038/s41467-018-08168-9

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Journal: Nature Communications	Publication Date: Jan 15, 2019
Citations: 153	License type: open-access

Affiliation: Yale University

Abstract

Impaired function in the medial prefrontal cortex (mPFC) contributes to depression, and the therapeutic response produced by novel rapid-acting antidepressants such as ketamine are mediated by mPFC activity. The mPFC contains multiple types of pyramidal cells, but it is unclear whether a particular subtype mediates the rapid antidepressant actions of ketamine. Here we tested two major subtypes, Drd1 and Drd2 dopamine receptor expressing pyramidal neurons and found that activating Drd1 expressing pyramidal cells in the mPFC produces rapid and long-lasting antidepressant and anxiolytic responses. In contrast, photostimulation of Drd2 expressing pyramidal cells was ineffective across anxiety-like and depression-like measures. Disruption of Drd1 activity also blocked the rapid antidepressant effects of ketamine. Finally, we demonstrate that stimulation of mPFC Drd1 terminals in the BLA recapitulates the antidepressant effects of somatic stimulation. These findings aid in understanding the cellular target neurons in the mPFC and the downstream circuitry involved in rapid antidepressant responses.

Highlights

Impaired function in the medial prefrontal cortex contributes to depression, and the therapeutic response produced by novel rapid-acting antidepressants such as ketamine are mediated by mPFC activity
The results demonstrate that prior stimulation of Drd[1], but not Drd2-expressing pyramidal neurons, in the mPFC produces rapid and sustained antidepressant responses, and that activation of Drd[1] neurons is required for the antidepressant actions of ketamine
The results demonstrate that photostimulation of Drd1-expressing pyramidal cells in the mPFC produces rapid and long-lasting antidepressant actions similar to ketamine

Summary

Introduction

Impaired function in the medial prefrontal cortex (mPFC) contributes to depression, and the therapeutic response produced by novel rapid-acting antidepressants such as ketamine are mediated by mPFC activity. We tested two major subtypes, Drd[1] and Drd[2] dopamine receptor expressing pyramidal neurons and found that activating Drd[1] expressing pyramidal cells in the mPFC produces rapid and long-lasting antidepressant and anxiolytic responses. Repeated stress exposure attenuates dopamine D1 receptor (D1r) signaling and causes atrophy of Drd1-expressing neurons[15] These findings suggest that stress-sensitive circuits involving mPFC Drd1-expressing neurons may represent therapeutic targets of ketamine. We test this hypothesis by selectively manipulating Drd1/type B vs Drd2/type A cell activity using Creinducible transgenic lines to determine if one or both of these principal neuron subtypes mediate the rapid antidepressant actions of ketamine. The results demonstrate that prior stimulation of Drd[1], but not Drd2-expressing pyramidal neurons, in the mPFC produces rapid and sustained antidepressant responses, and that activation of Drd[1] neurons is required for the antidepressant actions of ketamine

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