Striatopallidal neurons control avoidance behavior in exploratory tasks

Abstract

The dorsal striatum has been linked to decision-making under conflict, but the mechanism by which striatal neurons contribute to approach-avoidance conflicts remains unclear. We hypothesized that striatopallidal dopamine D2 receptor (D2R)-expressing neurons promote avoidance, and tested this hypothesis in two exploratory approach-avoidance conflict paradigms in mice: the elevated zero maze and open field. Genetic elimination of D2Rs on striatopallidal neurons (iMSNs), but not other neural populations, increased avoidance of the open areas in both tasks, in a manner that was dissociable from global changes in movement. Population calcium activity of dorsomedial iMSNs was disrupted in mice lacking D2Rs on iMSNs, suggesting that disrupted output of iMSNs contributes to heightened avoidance behavior. Consistently, artificial disruption of iMSN output with optogenetic stimulation heightened avoidance of open areas of these tasks, while inhibition of iMSN output reduced avoidance. We conclude that dorsomedial striatal iMSNs control approach-avoidance conflicts in exploratory tasks, and highlight this neural population as a potential target for reducing avoidance in anxiety disorders.

Fig. 1

Removing D2Rs from iMSNs promoted avoidance in exploratory tasks. a Path plots for control and iMSN-Drd2KO mouse in the zero maze. b Time in open arms, c movements into the open arms, and d movements into the closed arms for iMSN-Drd2KO, CIN-Drd2KO, and DAT-Drd2KO mice. e Correlation between time in open arms and number of movements into the open for iMSN-Drd2KO mice. f–j Same presentation as (a–e), but for open field data. Circles reflect individual mice, lines are linear regressions. *s denote significance between control and iMSN-Drd2KO by Sidak’s post hoc test following 2-way ANOVA

Fig. 2

Population calcium signaling in iMSN-Control and iMSN-Drd2KO mice. a Schematic of photometry system. b Example traces from iMSN-Control, iMSN-Drd2KO, and iMSN-GFP mice. c Time spent in open arms and center for iMSN-Control and iMSN-Drd2KO mice. d–f Average photometry recordings around movements into the open arms for iMSN-Control, iMSN-Drd2KO, and iMSN-GFP mice. Periods for ANOVA analysis noted in vertical bars. g Average df/f for baseline, pre-movement, and movement periods. h–k Same as (d–g) but for all movements. l–s Same data presentation as (d–k) but for open field. *s denote significance between control and iMSN-Drd2KO by Sidak’s post hoc test following two-way ANOVA

Fig. 3

Optogenetic stimulation of iMSNs promoted avoidance of open areas. a Example movement traces on zero maze during optogenetic stimulation. b Time in open arms, c movements into the open arms, and d movements into the closed arms for control and iMSN-ChR2 mice. e Correlation between time in open arms and number of movements into the open during LED ON for iMSN-ChR2 mice. f–j Same data format as (a–e) but for open field. Black lines reflect paired comparison for individual mice, red lines are linear regressions. *s denote significance between control and iMSN-Drd2KO by Sidak’s post hoc test following two-way ANOVA

Fig. 4

Effect of brief optogenetic stimulation at transition zones on behavior in zero maze. a Schematic of stimulation while moving from the closed arm to the transition zone. b Probability of movements into the closed arm for stimulated and unstimulated trials. c Latency to leave the transition zone following stimulation. d Duration in the closed arms following stimulation. e–h Same data format as (a–d), but for stimulation while moving from open to transition. Black lines reflect paired comparison for individual mice. *’s indicate significance with paired 1-tailed t-tests

Fig. 5

KOR DREADD inhibition of iMSNs reduced avoidance behavior. a Path plots showing movement during vehicle and SalB treatment on zero-maze. b Time in open arms, c movements into open arms, d movements into the closed arms, e correlation between time in open arms and number of movements into the open. f–j Same data format as (a–e), but for open field. Black lines reflect paired comparison for individual mice, red lines are linear regressions. *’s indicate significance with paired 1-tailed t-tests