Retrograde labeling illuminates distinct topographical organization of D1 and D2 receptor-positive neurons in the prefrontal cortex of mice

The cortex plays an important role in regulating motivation and cognition, and does so by regulating multiple subcortical brain circuits. Glutamatergic pyramidal neurons in the prefrontal cortex (PFC) are topographically organized in different subregions such as the prelimbic, infralimbic and orbitofrontal, and project to topographically-organized subcortical target regions. Dopamine D1 and D2 receptors are expressed on glutamatergic pyramidal neurons in the PFC. However, it is unclear whether D1 and D2 receptor-expressing pyramidal neurons in the PFC are also topographically organized. We used a retrograde adeno-associated virus (AAVRG)-based approach to illuminate the topographical organization of D1 and D2 receptor-expressing neurons, projecting to distinct striatal and midbrain subregions. Our experiments reveal that AAVRG injection in the nucleus accumbens (NAcc) or dorsal striatum (dSTR) of D1Cre mice labeled distinct neuronal subpopulations in medial orbitofrontal or prelimbic PFC, respectively. However, AAVRG injection in NAcc or dSTR of D2Cre mice labeled medial orbitofrontal, but not medial prelimbic PFC, respectively. Additionally, D2R+ but not D1R+ PFC neurons were labeled upon injection of AAVRG in substantia nigra pars compacta (SNpc). Thus, our data are the first to highlight a unique dopamine receptor-specific topographical pattern in the PFC, which could have rofound implications for corticostriatal signaling in the basal ganglia. SIGNIFICANCE STATEMENT Cortical dopamine is critical for motivation and cognition, and its dysfunction is implicated in multiple psychiatric disorders. Cortical dopamine mediates its effects through dopamine receptors expressed on neurons that connect to multiple brain regions. Our data highlight that dopamine receptor-expressing neurons in the cortex are more organized than previously thought. Dopamine receptor expressing cortical neurons are organized in distinct subcircuits that project to different target brain regions. Our findings will help us better understand the regional and global effects of cortical dopamine and its receptors, and how these discrete pathways regulate distinct dopamine-dependent functions such as reward, movement and cognition.