5 years ago

Synaptic Regulation of a Thalamocortical Circuit Controls Depression-Related Behavior

Synaptic Regulation of a Thalamocortical Circuit Controls Depression-Related Behavior
Benjamin J. Hall, Andreas Bruns, Oliver H. Miller, Imen Ben Ammar, Thomas Mueggler


The NMDA receptor (NMDAR) antagonist ketamine elicits a long-lasting antidepressant response in patients with treatment-resistant depression. Understanding how antagonism of NMDARs alters synapse and circuit function is pivotal to developing circuit-based therapies for depression. Using virally induced gene deletion, ex vivo optogenetic-assisted circuit analysis, and in vivo chemogenetics and fMRI, we assessed the role of NMDARs in the medial prefrontal cortex (mPFC) in controlling depression-related behavior in mice. We demonstrate that post-developmental genetic deletion of the NMDAR subunit GluN2B from pyramidal neurons in the mPFC enhances connectivity between the mPFC and limbic thalamus, but not the ventral hippocampus, and reduces depression-like behavior. Using intersectional chemogenetics, we show that activation of this thalamocortical circuit is sufficient to elicit a decrease in despair-like behavior. Our findings reveal that GluN2B exerts input-specific control of pyramidal neuron innervation and identify a medial dorsal thalamus (MDT)→mPFC circuit that controls depression-like behavior.

Publisher URL: http://www.cell.com/cell-reports/fulltext/S2211-1247(17)31071-9

DOI: 10.1016/j.celrep.2017.08.002

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