Emerging Role for Nucleus Accumbens Medium Spiny Neuron Subtypes in Depression

Abstract

The ventral striatum (nucleus accumbens) and its role in mood, reward, and motivation has been the focus of significant research. Despite this interest, little work has addressed cell type-specific distinctions in medium spiny neurons (MSNs), the main projection neurons in the nucleus accumbens and dorsal striatum, and their function in relation to stress and depression. Previous work has shown opposing roles for D₁ and D₂ receptor MSN subtypes in depression-like outcomes to stress, particularly in regard to repeated neuronal stimulation and excitatory transmission. Yet the mechanisms of action are still unknown. We discuss potential mechanisms by which MSN subtype function promotes dichotomous behavioral outcomes caused by differences in cellular plasticity, subcellular signaling pathways, and genetic expression. This review aims to address our current understanding about the role of nucleus accumbens MSN subtypes in stress-related depression behavior and speculates on how currently understood mechanisms contribute to factors that control the activity of MSNs.

Keywords: Deep brain stimulation; Excitatory synaptic transmission; Medium spiny neuron; Social defeat; Stress; Striatum.

Figure 1. Afferent and efferent connections of the Nucleus Accumbens

Upper left The Prelimibic cortex of the mPFC innervates the NAc Core (NAcC) and the infralimibic region of the mPFC innervates the NAc Shell (NAcS). Lower left Thalamic and basolateral amygdala (BLA) inputs do not display preferential innervation for NAc subregions. The dorsal hippocampus (dHipp) preferentially innervates the lateral NAcS. The arcuate nucleus (Arc) of the hypothalamus innervates shell regions of the NAc with melanocortin input. The lateral hypothalamus (LH) is innervated preferentially by D1-MSNs. Center NAc MSNs display a dorsolateral to ventromedial innervation and projection topology. NAcC D1-MSNs project to substantia nigra reticulata (SN) and D1-MSNs and D2-MSNs project to dorsolateral regions of the VP. NAcS D1-MSNs project to VTA and both subtypes in the NAcS project to ventromedial VP. Upper right Ventral hippocampus (vHipp) projects preferentially to ventromedial NAc and VTA provides diffuse terminals to all of the NAc. Lower right Lateral VP regions project to SN and medial VP projections project to VTA.

Figure 2. Electrophysiological properties correlate with stress-induced behavioral changes in MSN subtypes

(A) D2-MSN mEPSC frequency displays a strong negative correlation with time in interaction zone (Pearson r(12)= −0.750, p= 0.003, N= 13) and D1-MSNs show no correlation (Pearson r(12)= 0.180, p= 0.557, N= 13). (B) A moderate positive correlation between D1-MSN rheobase and time in interaction zone was observed (Pearson r(25)= 0.573, p= 0.002, N= 26) and D2-MSNs displayed no correlation (Pearson r(15)= −0.195, p= 0.470, N= 16). (C) In agreement with rheobase measures, correlations between the number of spikes in D1-MSNs (elicited by a 250pA, 500msec square pulse of current) and time in the interaction zone negatively correlated (Pearson r(10)= −0.668, p= 0.025, N= 11), a correlation not observed between D2-MSNs spiking and time in the interaction zone (Pearson r(10)= −0.049 p= 0.879, N= 11). Each point represents the average rheobase, mEPSC frequency, or number of spikes for each individual mouse. All mice in this study were 8–14 week old D1-GFP or D2-GFP male mice on a C57 wild-type background.