Choice suppression is achieved through opponent but not independent function of the striatal indirect pathway in mice

Abstract

SignificanceThere is significant clinical value to understanding how we reject or suppress making a choice, and the dorsomedial striatum (DMS) is a critical arbiter of this process. While optogenetic stimulation of DMS indirect pathway spiny projection neurons (iSPNs) can inhibit movement, it is unclear how iSPNs contribute to suppression of choices. A simple 'no go' function has been proposed for iSPNs, suggesting their activity enables choice suppression, but we found that chemogenetic activation of iSPNs impaired suppression of low value choices. This effect was explained by an algorithmic model in which the relative output of direct pathway (dSPNs) and iSPNs determines choice. Our findings have important implications for designing interventions to improve maladaptive decision-making in psychiatric disorders and addiction. AbstractThe dorsomedial striatum (DMS) plays a key role in action selection, but little is known about how direct and indirect pathway spiny projection neurons (dSPNs and iSPNs) contribute to serial decision-making. A popular 'select/suppress' heuristic proposes that dSPNs encode selected actions while iSPNs encode the suppression of alternate actions. Here, we used pathway-specific chemogenetic manipulation during serial choice behavior to test predictions generated by the 'select/suppress' heuristic versus a network inspired OpAL (Opponent Actor Learning) model of basal ganglia function in which the relative balance of dSPN and iSPN output determines choice. In line with OpAL predictions, chemogenetic activation, not inhibition, of iSPNs disrupted learned suppression of nonrewarded choices. These results cannot be explained by the classic view that choice suppression is an extension of iSPN stopping or 'no go' function.Together, our computational and empirical data challenge the 'select/suppress' interpretation of striatal function in the context of choice behavior and highlight the ability of iSPNs to modulate choice exploration.

Opponent control of behavior by dorsomedial striatal pathways depends on task demands and internal state

“…Indeed, our results would not necessarily predict opposing correlates of movements in indirect and direct pathways of the DMS, but rather opposing correlates of a decision process 23,25,54 . The much larger effect of pathway-specific inhibition we observed during the accumulation of evidence task is consistent with a role for the DMS in decision-making and the dynamic comparison of the value of competing options [22][23][24][25][26][54][55][56][57][58] . Together, our work raises the importance of optogenetic inhibition in complex cognitive settings to probe models of striatal function.…”

A neural substrate of sex-dependent modulation of motivation by value

“…Our limited knowledge of the neural mechanisms mediating sex differences in decisionmaking is due to the focus of previous neuroscience studies on male subjects [8][9][10][11][12] . This previous work identified a distributed network of brain regions that contribute to value-based decisions, including the anterior cingulate cortex (ACC) as well as its major striatal target (the dorsomedial striatum, or DMS) [18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35] . These regions may be important not only for the value-dependent selection of actions, but also in regulating motivation to engage in reward-seeking behavior, which is also modulated by value (or expected reward) of the environment or chosen action 29,[36][37][38][39][40][41][42][43][44] .…”