Deconstructing the Role of Nucleus Accumbens Medium Spiny Neuron Subtypes in Depression-like Behavior

Abstract

The prevalence of depression worldwide and the ineffectiveness of many of the current treatments warrants significant study into genesis of depression. The Nucleus Accumbens (NAc), an integrator of emotional information and a key regulator of depression symptomology, displays profound electrophysiological, signaling, and molecular changes following repeated stress. The NAc consists primarily of two projection neuron subtypes, medium spiny neurons (MSNs), which are differentiated by dopamine receptor expression, either dopamine 1 receptors (D1) or dopamine 2 receptors. These MSN subtypes often display opposing outcomes to a variety of behaviors. Whole-cell patch clamp recordings following 10 days of chronic (C) social defeat stress (SDS), a well-validated stress model, reveal D2-MSNs from susceptible mice display enhanced excitatory synaptic transmission, while D1-MSNs display reduced excitatory transmission and increased excitability in susceptible mice. To attempt to restore normal excitatory input, we used optogenetic stimulation and found repeated high frequency (?50Hz) stimulation of D1-MSNs promotes resilience to CSDS, while D1-MSN chemogenetic inhibition promotes susceptibility. Similar stimulation parameters for D2-MSN stimulation promotes susceptibility to subthreshold (S)SDS. Using quantitative RT-PCR, we discovered repeated stimulation reduced the expression of the transcription factor Egr3. Cell-type specific RiboTag analysis revealed Egr3 expression was significantly enhanced in susceptible mice, suggesting a role for Egr3 in susceptibility. NAc D1-MSN specific, microRNA knockdown of Egr3 promoted resilience to CSDS, while D1-MSN Egr3 overexpression produced susceptibility to subthreshold stress. We further discovered D1-MSN dendritic arbor was significantly reduced by CSDS. These changes, along with changes in excitatory synaptic transmission and excitability were blocked by Egr3 knockdown. The negative cytoskeletal regulator and Egr3 target RhoA displayed increased expression in D1-MSNs of susceptible mice and increased Egr3 binding to its promoter, suggesting a potential role in dendritic atrophy. RhoA inhibition via the drug Rhosin prevented susceptibility to CSDS and blocked both intrinsic excitability changes and excitatory transmission deficits in D1-MSNs, but failed to restore dendritic arbor. However, enhancements in D1-MSN spine density were observed. Together, findings in this dissertation demonstrate novel roles for NAc MSN subtypes in depression and elucidate D1-MSN-specific molecular, electrophysiological, and morphological mechanistic underpinnings of stress-induced susceptibility.