Circuit-dependent striatal PKA and ERK signaling underlies rapid behavioral shift in mating reaction of male mice

Significance Selection of actions that allow the seeking of rewards and avoidance of uncomfortable environments is a fundamental animal behavior. Here, we report an in vivo method, in which the activities of PKA and ERK were optically recorded by microendoscopy of Förster resonance energy transfer responses of biosensors in distinct D1 and D2 dopamine receptor-expressing neurons of the dorsal striatum. The PKA and ERK were coordinately but reciprocally regulated not only by rewarding and aversive stimuli but also between the two parallel projection neurons. Importantly, the cell type-specific regulation of PKA and ERK was causally linked to active and indifferent mating reactions of male mice. The dynamic modulation of PKA and ERK in the striatum underlies the selection of alternative actions. The selection of reward-seeking and aversive behaviors is controlled by two distinct D1 and D2 receptor-expressing striatal medium spiny neurons, namely the direct pathway MSNs (dMSNs) and the indirect pathway MSNs (iMSNs), but the dynamic modulation of signaling cascades of dMSNs and iMSNs in behaving animals remains largely elusive. We developed an in vivo methodology to monitor Förster resonance energy transfer (FRET) of the activities of PKA and ERK in either dMSNs or iMSNs by microendoscopy in freely moving mice. PKA and ERK were coordinately but oppositely regulated between dMSNs and iMSNs by rewarding cocaine administration and aversive electric shocks. Notably, the activities of PKA and ERK rapidly shifted when male mice became active or indifferent toward female mice during mating behavior. Importantly, manipulation of PKA cascades by the Designer Receptor recapitulated active and indifferent mating behaviors, indicating a causal linkage of a dynamic activity shift of PKA and ERK between dMSNs and iMSNs in action selection.