A sex difference in mouse dopaminergic projections from the midbrain to basolateral amygdala.

BACKGROUND: Dopaminergic circuits play important roles in the motivational control of behavior and dysfunction in dopaminergic circuits have been implicated in several psychiatric disorders, such as schizophrenia and depression. While these disorders exhibit different incidence rates in men and women, the potential sex differences in the underlying neural circuits are not well-understood. Previous anatomical tracing studies in mammalian species have revealed a prominent circuit projection connecting the dopaminergic midbrain ventral tegmental area (VTA) to the basolateral amygdala (BLA), which is involved in emotional processing and associative learning. However, whether there is any sex difference in this anatomical circuit remains unknown. METHODS: To study the potential sex differences in the VTA-to-BLA dopaminergic circuit, we injected two viral vectors encoding fluorescent reporters of axons and synaptic boutons (AAV-FLEX-tdTomato and AAV-FLEX-SynaptophysinGFP, respectively) into the VTA of a mouse transgenic driver line (tyrosine hydroxylase promoter-driven Cre, or TH-Cre), which restricts the reporter expression to dopaminergic neurons. We then used confocal fluorescent microscopy to image the distribution and density of dopaminergic axons and synaptic boutons in serial sections of both male and female mouse brain. RESULTS: We found that the overall labeling intensity of VTA-to-BLA dopaminergic projections is intermediate among forebrain dopaminergic pathways, significantly higher than the projections to the prefrontal cortex, but lower than the projections to the nucleus accumbens. Within the amygdala areas, dopaminergic axons are concentrated in BLA. Although the size of BLA and the density of dopaminergic axons within BLA are similar between male and female mice, the density of dopaminergic synaptic boutons in BLA is significantly higher in male brain than female brain. CONCLUSIONS: Our results demonstrate an anatomical sex difference in mouse dopaminergic innervations from the VTA to BLA. This finding may provide a structural foundation to study neural circuit mechanisms underlying sex differences in motivational and emotional behaviors and related psychiatric dysfunctions.

Comparative anatomical analysis of dopamine systems in Mus musculus and Peromyscus californicus.

Dopamine plays important roles in motivational and social behaviors in mammals, and it has been implicated in several human neurological and psychiatric disorders. Rodents are used extensively as experimental models to study dopamine function in health and disease. However, interspecies differences of dopamine systems remain incompletely characterized. Here, we assessed whether the commonly referenced anatomical organization of dopamine systems in Mus musculus differs from another rodent species, Peromyscus californicus, which exhibits unique social behaviors such as biparental care. We applied tyrosine hydroxylase immunofluorescence labeling and high-throughput microscopy to establish whole-brain maps of dopamine systems in P. californicus. By comparing these maps to those from M. musculus, we identified unexpected anatomical similarity and difference between these two species. A sex difference in dopamine neurons at the anteroventral periventricular nucleus of hypothalamus, which has been implicated in regulating the maternal behaviors of the uniparental M. musculus, is similarly present in the biparental P. californicus. In contrast, major interspecies differences from M. musculus are found in the ventral midbrain and striatum of P. californicus, including the expansion of midbrain dopamine neurons into the ventral substantia nigra and the presence of an internal capsule-like white matter tract that demarcates a dorsomedial area from the rest of the striatum. These features identified in P. californicus resemble the anatomical organization of the primate brain more closely compared to those in M. musculus. Our findings suggest that P. californicus is a unique model organism for studying the evolution of dopamine systems in mammals and the disorders of dopamine systems.