Dopamine signaling in the dorsomedial striatum promotes compulsive behavior

Abstract

Compulsive behavior is a defining feature of disorders such as substance use disorders. Current evidence suggests that corticostriatal circuits control the expression of established compulsions, but little is known about the mechanisms regulating the development of compulsions. We hypothesized that dopamine, a critical modulator of striatal synaptic plasticity, could control alterations in corticostriatal circuits leading to the development of compulsions (defined here as continued reward seeking in the face of punishment). We used dual-site fiber photometry to measure dopamine axon activity in the dorsomedial striatum (DMS) and the dorsolateral striatum (DLS) as compulsions emerged. Individual variability in the speed with which compulsions emerged was predicted by DMS dopamine axon activity. Amplifying this dopamine signal accelerated animals' transitions to compulsion, whereas inhibition delayed it. In contrast, amplifying DLS dopamine signaling had no effect on the emergence of compulsions. These results establish DMS dopamine signaling as a key controller of the development of compulsive reward seeking.

Striatonigrostriatal circuit architecture for disinhibition of dopamine signaling

“…Finally, it is possible that the balance between inhibition and disinhibition of DA neurons is altered by training, either by synaptic plasticity or by the recruitment of additional circuits during learning. We and others have observed that the in vivo patterns of DA axon activity and DA release in the DMS and the DLS change with training ( Hamid et al, 2021 ; Seiler et al, 2022 ; Willuhn et al, 2012 ). The reasons for training-induced changes in DA signaling are not yet clear, but with the approaches developed here and with additional innovations to adapt them for in vivo investigations, we can begin to rigorously address this hypothesis and advance our mechanistic understanding of the complex process of habit formation.…”

“…Finally, it is possible that the balance between inhibition and disinhibition of DA neurons is altered by training, either by synaptic plasticity or by the recruitment of additional circuits during learning. We and others have observed that the in vivo patterns of DA axon activity and DA release in the DMS and the DLS change with training (Hamid et al, 2021;Seiler et al, 2022;Willuhn et al, 2012) Article ll OPEN ACCESS and advance our mechanistic understanding of the complex process of habit formation.…”

“…Although DA axonal fields in striatum are broad ( Matsuda et al, 2009 ), there is topography within the nigrostriatal system that can allow for separate control of DA release in the DMS and the DLS ( Farassat et al, 2019 ; Ikemoto, 2007 ; Joel and Weiner, 2000 ; Lerner et al, 2015 ). Indeed, DA neurons projecting to the DMS and those projecting to the DLS display distinct in vivo activity patterns ( Brown et al, 2011 ; Hamid et al, 2021 ; Lerner et al, 2015 ; Seiler et al, 2022 ; Tsutsui-Kimura et al, 2020 ).…”

Striatal dopamine signals are region specific and temporally stable across action-sequence habit formation

“…Conclusions were advanced on the grounds of anatomical studies and sparse functional evidence: one study tracked regionally shifting striatal dopamine signaling across development of a presumed habit reinforced by cocaine, 31 whereas another study reported no such shift using a natural reinforcer. 39 Thus, the central questions that remain are how region-specific and regionally shifting dopamine signals regulate habit formation.…”

Chronically elevated corticosterone impairs dopaminergic transmission in the dorsomedial striatum by sex-divergent mechanisms

“…Dopaminergic transmission in the striatum regulates reward processing (8). Specifically, dopamine in the nucleus accumbens core (NAcc) is critical for effortful responding for rewards, while dopamine in the dorsomedial striatum (DMS) is crucial for action-outcome learning and behavioral flexibility (9)(10)(11)(12). Dopaminergic transmission within the striatum occurs in two modes: tonic and phasic (13,14).…”