Corticotropin-releasing factor-dopamine interactions in male and female macaque: Beyond the classic VTA

Dopamine (DA) is involved in stress and stress-related illnesses, including many psychiatric disorders. Corticotropin-releasing factor (CRF) plays a role in stress responses and targets the ventral midbrain DA system, which is composed of DA and non-DA cells, and divided into specific subregions. Although CRF inputs to the midline A10 nuclei (classic VTA) are known, in monkeys, CRF-containing terminals are also highly enriched in the expanded A10 parabrachial pigmented nucleus (PBP) and in the A8 retrorubral field subregions. We characterized CRF-labeled synaptic terminals on DA (tyrosine hydroxylase, TH+) and non-DA (TH-) cell types in the PBP and A8 regions using immunoreactive electron microscopy (EM) in male and female macaques. CRF labeling was present mostly in axon terminals, which mainly contacted TH-negative dendrites in both subregions. Most CRF-positive terminals had symmetric profiles. In both PBP and A8, CRF symmetric (putative inhibitory) synapses onto TH-negative dendrites were significantly greater than asymmetric (putative excitatory) profiles. This overall pattern was similar in males and females, despite shifts in the size of these effects between regions depending on sex. Because stress and gonadal hormone shifts can influence CRF expression, we also did hormonal assays over a 6-month time period and found little variability in basal cortisol across similarly housed animals at the same age. Together our findings suggest that at baseline, CRF-positive synaptic terminals in the primate PBP and A8 are poised to regulate DA indirectly through synaptic contacts onto non-DA neurons. Using light and electron microscopy, we investigated CRF/Dopamine interactions in two subregions of the ventral midbrain associated with salience coding. CRF-positive synaptic terminals in the parabrachial pigmented nucleus (A10) and retrorubral field (A8) predominantly make symmetric synapses onto TH-negative profiles. We hypothesize that under stress, CRF may enhance inhibitory effects on TH-negative profiles (presumptive GABA interneurons), resulting in a disinhibition of DA neurons.image

Automated summary

Dopamine is involved in stress-related illnesses, and corticotropin-releasing factor plays a role in stress responses. This study examined the synaptic terminals between dopamine and non-dopamine cells and found that dopamine regulation may occur indirectly through contacts with non-dopamine neurons.