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

Abstract

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 profound implications for corticostriatal signaling in the basal ganglia. SIGNIFICANCE STATEMENTCorticostriatal connections play an important role in regulating goal-directed and habitual behavior, and neuromodulators such as cortical dopamine play an important role in behavioral flexibility. Dopamine receptor expressing D1R+ and D2R+ projection neurons in the cortex mediate the effects of cortical dopamine, but whether these neurons are anatomically organized in a manner that would explain how these neurons mediate these complex effects, is not clear. Our results show a distinct topographical organization of D1R+ and D2R+ PFC pyramidal neurons that project to distinct striatal and midbrain subregions. These results suggest that effects of cortical dopamine are mediated by anatomically localized distinct receptor- and target-defined subcircuits.