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

R. van der Merwe,S. S. Pawelko,N. G. Hollon,M. Fox,J. R. Scott,M. Ghanem,J. A. Nadel,E. S. Ramsson,R. McLaughlin,C. D. Howard

doi:10.1038/s41598-021-99350-5

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.

Highlights

Habits are inflexible behaviors that develop after extensive repetition, and overreliance on habits is a hallmark of many pathological states
We injected Sepw1-NP67 mice with an AAV encoding either the Cre-dependent light-gated cation channel ChR2 or YFP in the dorsal striatum, which resulted in enriched ChR2 expression in striatal patches (Fig. 1d)
As no implantation site-dependent differences were observed in performance during operant training, responding following devaluation, or in omission, fiber optic placement groups were collapsed into a general “ChR2” group for comparison with YFP controls

Summary

Introduction

Habits are inflexible behaviors that develop after extensive repetition, and overreliance on habits is a hallmark of many pathological states. Habits have been studied by measuring perseverance of instrumental behaviors following reduction in reward value, or by measuring flexibility when action-outcome contingencies are manipulated[3,4]. Using these approaches, distinct neural circuits underlying goal-directed and habitual responding have been identified. Striatal patches have been recently shown to be necessary for normal habit formation: specific lesions of patch neurons diminish habitual responding following reward d evaluation[24] or following changes in action-outcome contingencies[25]

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