Target-dependent expression of the netrin-1 receptor, UNC5C, in projection neurons of the ventral tegmental area

We have shown previously that the netrin-1 receptor, unc-5 homologue C (UNC5C), is expressed by ventral tegmental area (VTA) dopamine (DA) neurons of rodents, but only from adolescence onwards (Manitt et al., 2010; Auger et al., 2013). The goal of this study was to characterize the expression of UNC5C by these neurons. Specifically, we assessed whether UNC5C expression is selective to DA neurons that project to the medial prefrontal cortex (mPFC), which undergo significant maturation during the adolescent period. To this end, we injected fluorescent retrograde tracer beads into the mPFC, nucleus accumbens (NAcc) core, or NAcc lateral shell of adult male wild-type C57Bl/6J mice and processed their brains for tyrosine hydroxylase (TH) and UNC5C immunofluorescence 2-3weeks later. VTA neurons with any combination of these immunolabels were visualized and counted using optical fractionator stereology. Our analysis revealed two main findings: (1) there are no differences in the proportions of UNC5C-positive DA neurons projecting to the mPFC, NAcc core, or NAcc lateral shell, and (2) the proportion of non-DA UNC5C-positive neurons targeting the mPFC is greater than the proportions of non-DA UNC5C-positive neurons targeting the NAcc core or lateral shell. These findings show that, contrary to our hypothesis, DA neurons projecting to the mPFC do not express UNC5C selectively. However, UNC5C expression by non-DA VTA neurons is predominantly found in those projecting to the mPFC and, as such, may play a role in their function.