Abstract
The medial prefrontal cortex (mPFC) is a critical component of a cortico-basal ganglia-thalamo-cortical loop regulating limbic and cognitive functions. Within this circuit, two distinct nucleus accumbens (NAc) output neuron types, dopamine D1 or D2 receptor-expressing neurons, dynamically control the flow of information through basal ganglia nuclei that eventually project back to the mPFC to complete the loop. Thus, chronic dysfunction of the NAc may result in mPFC transcriptomal changes, which in turn contribute to disease conditions associated with the mPFC and basal ganglia. Here, we used RNA sequencing to analyse differentially expressed genes (DEGs) in the mPFC following a reversible neurotransmission blocking technique in D1 or D2 receptor-expressing NAc neurons, respectively (D1-RNB, or D2-RNB). Gene Set Enrichment Analysis revealed that gene sets of layer 5b and 6 pyramidal neurons were enriched in DEGs of the mPFC downregulated in both NAc D1- and D2-RNB mice. In contrast, gene sets of layer 5a pyramidal neurons were enriched in upregulated DEGs of the mPFC in D1-RNB mice, and downregulated DEGs of the mPFC in D2-RNB mice. These findings reveal for the first time that NAc output pathways play an important role in controlling mPFC gene expression.
Highlights
The medial prefrontal cortex is a critical component of a cortico-basal ganglia-thalamo-cortical loop regulating limbic and cognitive functions
In the medial prefrontal cortex (mPFC) samples of D2-reversible neurotransmission blocking (RNB) mice compared with wild type (WT) controls, edgeR and voom identified differentially expressed genes (DEGs) were significantly overlapped for 175 up-regulated genes (Fig. 1; −logP = 753.31) and 92 down-regulated genes (Fig. 1; −logP = 427.43)
Given that gene set for S100a10-expressing layer 5a pyramidal neurons (Ctx.S100a10) was enriched in both genes up-regulated in the mPFC of D1-RNB mice and down-regulated in the mPFC of D2-RNB mice, we investigated whether opposing patterns of expression were occurring in the same genes
Summary
The medial prefrontal cortex (mPFC) is a critical component of a cortico-basal ganglia-thalamo-cortical loop regulating limbic and cognitive functions. In the parallel cortico-basal ganglia-thalamo-cortical sensorimotor loop, it has been shown that optogenetic activation of dorsal striatal D1- and D2-MSNs is able to enhance or suppress, respectively, the activity of primary motor cortex neurons[15,16] This connectivity between the NAc and the mPFC raises the possibility that chronic dysregulation of NAc activity could produce long-lasting alterations in mPFC gene regulation, contributing to the development of disorders associated with dysfunction of the mPFC-basal ganglia-thalamo-mPFC circuit. Transmission blocking of NAc D1- or D2-MSNs bidirectionally altered gene expression in genes associated with Layer 5a pyramidal neurons, known to project to striatal regions[19,20], suggesting that chronic dysfunction of distinct NAc output pathways results in transcriptomal changes that may affect specific cortical pathways within the mPFC-basal ganglia-thalamo-mPFC circuit
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