The medial frontal cortex (mFC) and locus coeruleus (LC) are two brain areas that have been implicated in a range of cognitive phenomena, such as attention, memory, and decision making. Regulators of these brain regions at the molecular level are not well understood, but might help to elucidate underlying mechanisms of disorders that present with deficits in these cognitive domains. To probe this, we used chemogenetic stimulation of neurons in the LC with axonal projections to the prelimbic subregion (PrL) of the mFC, and subsequent bulk RNA-sequencing from the mouse PrL. We found that stimulation of this circuit caused an increase in transcription of a host of genes, including the Apoe gene. To investigate cell type-specific expression of Apoe in the PrL, we used a dual-virus approach to express either the excitatory DREADD receptor hM3Dq in LC neurons with projections to the PrL, or a control virus, and found that increases in Apoe expression in the PrL following depolarization of LC inputs is enriched in GABAergic neurons in a sex-dependent manner. The results of these experiments yield insights into how Apoe expression affects function in a cortical microcircuit that is important for attention, memory, and decision making, and point to interneuron-specific expression of Apoe as a potential biomarker for circuit function in disorders such as attention-deficit hyperactivity disorder (ADHD), schizophrenia, and Alzheimer's disease (AD).Significance Statement Identifying patterns of gene expression in specific brain circuits is an important first step toward developing treatments for cognitive and behavioral symptoms that rely on those circuits. In this paper, we describe a transcriptome-scale motif in one such circuit - neurons in the LC that project to the PrL. This circuit has been implicated in attention, memory, and decision making, and deficits in these cognitive domains are common across many neuropsychiatric disorders. We further explored one of the top differentially expressed genes, Apoe, to identify how it is expressed in distinct cell types following stimulation of this circuit, paving the way for spatially- and genetically-specific targeting of this gene in disorders that feature dysfunction in this circuit.
Read full abstract