Synaptic Regulation of a Thalamocortical Circuit Controls Depression-Related Behavior

Abstract

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.

Bidirectional Optogenetically-Induced Plasticity of Evoked Responses in the Rat Medial Prefrontal Cortex Can Impair or Enhance Cognitive Set-Shifting

“…CUS decreased local field potentials evoked in the mPFC by stimulation of the thalamic afferent, but not the ventral hippocampus (Jett et al, 2017). Likewise, the NMDA receptor subunit GluN2B specifically regulates synaptic input from the MDT, through which activation can attenuate depressive-like behaviors, suggesting pathwayspecific molecular differences as well (Miller et al, 2017). Further evidence that chronic stress can disrupt specific prefrontal circuits mediating higher order executive processes was reported in a recent study showing that chronic stress produced a functional disconnect in a prefrontal-striatal pathway that specifically targets striosomes, resulting in disruption of cost-benefit conflict decision making (Friedman et al, 2017).…”

Molecular and Circuit Architecture of Social Hierarchy

“…Because rank-1 males showed increased activity in MDT, we hypothesized that MDT may inhibit the cACC. Indeed, reports using viral tracing (Delevich et al, 2015; Lu et al, 2017), optogenetic assisted circuit mapping (Delevich et al, 2015; Ferguson and Gao, 2018; Miller et al, 2017), and neurophysiological studies of decision making (Schmitt et al, 2017) suggest that MDT projections can drive feedforward inhibition of the PFC through connections with PV interneurons (Delevich et al, 2015). We confirmed this connectivity and assessed its relevance to neuronal activity associated with hierarchy with the following experiments.…”

“…Converging evidence from different studies shows that MDT activates inhibitory interneurons of the frontal cortex (Ferguson and Gao, 2018; Miller et al, 2017), including the ACC (Delevich et al, 2015), and that functional roles of this circuity include the control of reward-seeking strategies (Kvitsiani et al, 2013; Sparta et al, 2014) and fear expression (Courtin et al, 2013). Intriguingly, increased firing of ACC PV cells encodes longer wait times during a foraging task (Kvitsiani et al, 2013) and reduces fearful behavior in a fear conditioning task (Courtin et al, 2013).…”

A multivariate neuroimaging biomarker of individual outcome to transcranial magnetic stimulation in depression

“…While signal power influences the signal to noise ratio and may influence the capacity of MRI to detect correlated activity, the amplitude of synchronized neural oscillatory activity relative to neural "noise" is one factor that may influence the capacity of networks to communicate effectively (Deco & Kringelbach, 2016). This could involve neurotransmitter abnormalities (Feyissa, Chandran, Stockmeier, & Karolewicz, 2009;Gsell et al, 2006), excitatory drive (Miller, Bruns, Ben Ammar, Mueggler, & Hall, 2017), or loss of synchrony within local neuronal ensembles (Zalesky, Fornito, Egan, et al, 2012). Understanding the mechanistic causes of aberrant BOLD signal power in MDD may ultimately assist in elucidating the pathophysiological basis of network and behavioral dysfunction in depression.…”

“…Understanding the mechanistic causes of aberrant BOLD signal power in MDD may ultimately assist in elucidating the pathophysiological basis of network and behavioral dysfunction in depression. This could involve neurotransmitter abnormalities (Feyissa, Chandran, Stockmeier, & Karolewicz, 2009;Gsell et al, 2006), excitatory drive (Miller, Bruns, Ben Ammar, Mueggler, & Hall, 2017), or loss of synchrony within local neuronal ensembles (Zalesky, Fornito, Egan, et al, 2012).…”