Optogenetic stimulation of striatal patches modifies habit formation and inhibits dopamine release

Abstract

Habits are inflexible behaviors that develop after extensive repetition, and overreliance on habits is a hallmark of many pathological states. The striatum is involved in the transition from flexible to inflexible responding, and interspersed throughout the striatum are patches, or striosomes, which make up ~15% of the volume of the striatum relative to the surrounding matrix compartment. Previous studies have suggested that patches are necessary for normal habit formation, but it remains unknown exactly how patches contribute to habit formation and expression. Here, using optogenetics, we stimulated striatal patches in Sepw1-NP67 mice during variable interval training (VI60), which is used to establish habitual responding. We found that activation of patches at reward retrieval resulted in elevated responding during VI60 training by modifying the pattern of head entry and pressing. Further, this optogenetic manipulation reduced subsequent responding following reinforcer devaluation, suggesting modified habit formation. However, patch stimulation did not generally increase extinction rates during a subsequent extinction probe, but did result in a small ‘extinction burst’, further suggesting goal-directed behavior. On the other hand, this manipulation had no effect in omission trials, where mice had to withhold responses to obtain rewards. Finally, we utilized fast-scan cyclic voltammetry to investigate how patch activation modifies evoked striatal dopamine release and found that optogenetic activation of patch projections to the substantia nigra pars compacta (SNc) is sufficient to suppress dopamine release in the dorsal striatum. Overall, this work provides novel insight into the role of the patch compartment in habit formation, and provides a potential mechanism for how patches modify habitual behavior by exerting control over dopamine signaling.

Sst+ GPi output neurons provide direct feedback to key nodes of the basal ganglia and drive behavioral flexibility

“…Our findings challenge the notion that GPi-LHb neurons are a part of the "critic" circuitry of the basal ganglia, for example by encoding the action value and prediction errors. Instead, our data suggests that Sst+ GPi neurons influence the balance between the goal-directed versus habitual domain of the "actor" circuitry of the basal ganglia, for example by regulating dopamine release in the dorsal striatum and via striosome-dependent mechanisms 33,[36][37][38] .…”

Striosomes constrain locomotor vigor with respect to an innate valence differential

“…The lowering of BIL speed may also evince allocation of energy or attention. Striosome activity positively correlates with task-engagement and perseveration (Jenrette, Logue et al 2019, Friedman, Hueske et al 2020, Nadel, Pawelko et al 2020, Nadel, Pawelko et al 2021, implying support for habitual modes. Thus, by lowering BIL speed, striosomes may mediate a shift away from high-alert and toward habit.…”

Excessive self-grooming, gene dysregulation and imbalance between the striosome and matrix compartments in the striatum ofShank3mutant mice

“…Imbalances in striosome to matrix activity have been suggested in several movement disorders [Huntington’s disease, Parkinson’s disease, dyskinesia, dystonia, for a review see 49 ], psychostimulant-induced motor stereotypies 54 , and more recently in anxiety disorder 46 . Corticostriatal path targeting striosomes also control decision-making under cost-benefit conflict 55,56 and habit formation 57 . Our finding that four striosome markers had increased expression associated with excessive self-grooming in Shank3 Δ11/Δ11 mice prompted us to explore the compartmental architecture of the striatum in these mice.…”