Dopamine D2 receptors modulate the cholinergic pause and inhibitory learning

Abstract

Cholinergic interneurons (CINs) in the striatum respond to salient stimuli with a multiphasic response, including a pause, in neuronal activity. Slice physiology experiments have shown the importance of dopamine D2 receptors (D2Rs) in regulating CIN pausing yet the behavioral significance of the CIN pause and its regulation by dopamine in vivo is still unclear. Here, we show that D2R upregulation in CINs of the nucleus accumbens (NAc) lengthens the pause in CIN activity ex vivo and enlarges a stimulus-evoked decrease in acetylcholine (ACh) levels during behavior. This enhanced dip in ACh levels is associated with a selective deficit in the learning to inhibit responding in a Go/No-Go task. Our data demonstrate, therefore, the importance of CIN D2Rs in modulating the CIN response induced by salient stimuli and point to a role of this response in inhibitory learning. This work has important implications for brain disorders with altered striatal dopamine and ACh function, including schizophrenia and attention-deficit hyperactivity disorder (ADHD).

Dopamine D2Rs Coordinate Cue-Evoked Changes in Striatal Acetylcholine Levels

“…This finding is consistent with recent inhibition studies in which CIN inhibition in the NAc during Pavlovian to Instrumental Transfer (PIT) enhanced the ability of the pavlovian cue to invigorate behavior (Collins et al, 2019). Note, however, that mice with selective Drd2 ablation do not show a deficit in PIT suggesting a more subtle deficit affecting latencies rather than the level of responding (Gallo et al, 2021).…”

“…This suggests that even with a shortened dip mice still can learn cue-reward associations. Similarly, we recently described that enhancing the dip lengths by selective overexpression of D2Rs in CINs of the NAc (D2R-OENAcChAT mice) did not affect Pavlovian learning but was associated with a deficit in Go/No-Go learning (Gallo et al, 2021).…”

“…Consistent with this, more recent slice physiology studies in rodents have shown that pauses in CIN activity can be induced by local application of DA or DA terminal stimulation, which both are eliminated by pharmacological blockade of D2Rs (Augustin et al, 2018;Chuhma et al, 2014;Straub et al, 2014;Wieland et al, 2014). Additionally, optogenetic stimulation of NAc DA terminals results in a pause in CIN firing and this pause is prolonged when D2Rs are selectively overexpressed in CINs (Gallo et al, 2021). Lastly, pauses generated by DA or local stimulation of the striatum are eliminated in a selective CIN D2 knockout mouse (Augustin et al, 2018;Kharkwal et al, 2016).…”

“…Cannula-implanted mice began behavioral training 4 weeks after surgery. At the end of experiments, animals were perfused, and brains were processed post-hoc to validate virus expression and optic fiber location as in (Gallo et al, 2021).…”

Behavioral and Neuroanatomical Consequences of Cell-Type Specific Loss of Dopamine D2 Receptors in the Mouse Cerebral Cortex

“…Additionally, loss of D2R in either cell population neither altered basal nor amphetamine-induced locomotor activity. Importantly, the GABA-D2R-cKO mice also likely exhibit loss of D2 receptors from cholinergic interneurons in the striatum and nucleus accumbens (Magno et al, 2017 ), and loss of those receptors may contribute to the observed phenotypes given the roles for D2R regulation of striatal cholinergic functions (Gallo et al, 2021 ; Simpson et al, 2021 ).…”