Dopaminergic innervation at the central nucleus of the amygdala reveals distinct topographically and functionally segregated regions

The central nucleus of the amygdala (CeA) is involved in the expression of fear and anxiety disorders. Anatomically, it is divided in a medial, lateral (CeL), and capsular (CeC) divisions. The CeA is densely innervated by dopaminergic projections that originate in the ventral periaqueductal gray/dorsal raphe (vPAG/DR) and the ventral tegmental area/substantia nigra compacta (VTA/SNc). However, whether dopamine (DA) exerts a homogenous control over the CeA or differentially regulates the various CeA subdivisions is still unknown. Here, we performed a neuroanatomical and functional analysis of the mouse CeA and found that DAergic innervations from the PAG/DR and VTA/SNc constitute distinct, non-overlapping, pathways differing also in the relative expression of the dopamine transporter. By quantifying the distribution of DAergic fibers and the origin of DA inputs we identified two distinct regions in the CeL: a frontal region innervated by the VTA/SNc and vPAG/DR, a caudal region innervated only by the vPAG/DR and, three distinct regions in the CeC: fronto-dorsal innervated only by the VTA/SNc, fronto-ventral with sparse DAergic innervation, and a caudal region with low innervation from the vPAG/DR. In addition, we found that each region displays a unique pattern of c-Fos activation following the administration of cocaine, SKF 38393, quinpirole or haloperidol; demonstrating that all these regions are functionally distinct. In summary, we revealed unique properties of the DAergic pathways innervating the CeA, distinguishing six topographically segregated and functionally distinct regions. This unanticipated level of functional heterogeneity calls for more precise anatomical specificity in future functional studies of the CeA.