Midbrain dopaminergic inputs gate amygdala intercalated cell clusters by distinct and cooperative mechanisms

Abstract

Dopaminergic signaling plays an important role in associative learning including fear and extinction learning. Dopaminergic midbrain neurons encode prediction error-like signals when threats differ from expectations. Within the amygdala, GABAergic intercalated cell (ITC) clusters receive the densest dopaminergic projections, but their physiological consequences are incompletely understood. ITCs are important for fear extinction, a function thought to be supported by activation of ventromedial cluster ITCs that inhibit central amygdala fear output. In mice, we reveal two distinct mechanisms how mesencephalic dopaminergic afferents control ITCs. Firstly, they co-release GABA to mediate rapid, direct inhibition. Secondly, dopamine suppresses inhibitory interactions between distinct ITC clusters via presynaptic D1-receptors. Early extinction training augments both, GABA co-release onto dorso-medial ITCs and dopamine-mediated suppression of dorso- to ventromedial inhibition between ITC clusters. These findings provide novel insights into dopaminergic mechanisms shaping the activity balance between distinct ITC clusters that could support their opposing roles in fear behavior.

Dopaminergic circuits underlying associative aversive learning

“…The source of DA input to ITCs has largely remained elusive due to lack of molecular tools that can selectively target these neurons. However, recent studies suggest that DA input to ITCs originates from VTA/SN, similar to BLA (Ferrazzo et al, 2019;Aksoy-Aksel et al, 2021). D1, but not D2, receptors are abundantly expressed in the ITCs (Jacobsen et al, 2006).…”

“…However, different ITC clusters are connected and exert feedforward inhibition onto each other (Royer et al, 1999(Royer et al, , 2000Paré et al, 2003;Asede et al, 2015Asede et al, , 2021. Notably, a recent study demonstrated that lateral ITCs (l-ITCs) located in the external capsule send feedforward inhibition onto dm-ITCs and DA application reduces this inhibition onto dm-ITCs (Aksoy-Aksel et al, 2021). These findings suggest that DA likely inhibits l-ITCs, dampening the feedforward inhibition these neurons exert on BLA and dm-ITCs, and thus indirectly activates BLA 10.3389/fnbeh.2022.1041929 and dm-ITC neurons during aversive learning (Figure 1).…”