Cell-type-specific asynchronous modulation of PKA by dopamine in learning

Abstract

Summary Reinforcement learning models postulate that dopamine (DA) releasing neurons (DANs) encode information about action and action outcome and provide a teaching signal to striatal spiny projection neurons (SPNs) in the form of DA release 1 . DA is thought to guide learning via dynamic and differential modulation of protein kinase A (PKA) in each class of SPN 2 . However, the real-time relationship between DA and SPN PKA remains untested in behaving animals. Here, we monitor the activity of DANs, extracellular DA levels, and net PKA activity in SPNs in the nucleus accumbens in mice during learning. We find positive and negative modulation of DA that evolves across training and is both necessary and sufficient to explain concurrent fluctuations in SPN PKA activity. The modulations of PKA in SPNs that express type-1 and type-2 DA receptors are dichotomous such that they are selectively sensitive to increases and decreases in DA, respectively, which occur at different phases of learning. Thus, PKA-dependent pathways in each class of SPNs are asynchronously engaged by positive or negative DA signals during learning.

Dopamine differentially modulates the size of projection neuron ensembles in the intact and dopamine-depleted striatum

“…Instead, the observed ensemble changes support the view that, despite differences in the apparent affinity of D 1 and D 2 receptors for DA, basal DA levels promote the recruitment of dSPNs and limit that of iSPNs. The latter is consistent with the recent observation that protein kinase A is strongly activated in iSPNs in response to phasic dips in extracellular DA ( Lee et al, 2021 ). Thus, periods of diminished DA signaling (i.e.…”

“…Given the marked effects of D 1/2 R antagonists on SPN ensemble size, we next investigated whether increasing DA signaling would exert the opposite effect. We hypothesized that dSPN ensembles would grow in size with rising DA, whereas iSPNs would be insensitive ( Iino et al, 2020 ; Lee et al, 2021 ). To test this, we imaged striatal activity upon concomitant pharmacological stimulation of D 1 and D 2 receptors (n = 20 FOVs in 14 mice) while mice locomoted on motorized treadmills to mitigate effects on spontaneous behavior ( Figure 4—figure supplement 1A–C ).…”

“…We therefore investigated how movement-related SPN ensembles are affected by manipulations that preferentially elevate endogenous DA levels in striatum. We first considered the effects of natural rewards, which are well established to elevate extracellular DA throughout striatum ( Figure 4D ), and which were recently shown to elevate protein kinase A activity in dSPNs for 10 s of seconds ( Lee et al, 2021 ). To do so, we imaged striatal activity in a cohort of water-restricted mice locomoting on a motorized treadmill before and after delivering water rewards.…”

“…Given that a single pulse of DA alters the excitability of SPNs for several minutes ( Lahiri and Bevan, 2020 ), additional modulation by rising DA may be occluded in vivo. Alternatively, the relatively low affinity of D 1 receptors for DA compared to D 2 receptors raises the possibility that dSPNs may only be sensitive to rising DA levels, while iSPNs may selectively respond to drops in extracellular DA ( Beaulieu and Gainetdinov, 2011 ; Iino et al, 2020 ; Lee et al, 2021 ). Third, although in vivo studies comparing SPN discharge before and after DA neuron lesions in animal models of Parkinson’s disease support the view that DA differentially modulates firing rates in dSPNs and iSPNs ( Mallet et al, 2006 ; Ryan et al, 2018 ), they do not directly speak to DA’s actions under physiological conditions, as chronic loss of DA evokes widespread homeostatic adaptations in striatal circuits ( Zhai et al, 2019 ).…”

Attenuated dopamine signaling after aversive learning is restored by ketamine to rescue escape actions

“…Importantly, after LH, the responses of VTA DA neurons to both inescapable and escapable shocks are significantly changed. Since DA release has been shown to be highly correlated with somatic DA neuronal activity (de Jong et al, 2019;Lee et al, 2020;Patriarchi et al, 2018), we predict that downstream DA release in the NAc and amygdala are also modulated after LH and ketamine treatment.…”