Striatal indirect pathway controls the maintenance and retrieval but not encoding of spatial working memory via striatopallidal output projections

Spatial working memory (SWM) is fundamental to cognition by caching behaviorally relevant cues on a timescale of seconds and by tapping into several executive processes including encoding, maintenance and retrieval of information for adaptive behavioral response. The striatum plays a critical role in gating WM representations, but the specific contribution of the striatal indirect pathway to WM is undefined. Specifically, the specific temporal phases (the encoding, maintenance and retrieval) of spatial WM that are controlled by the striatal indirect pathway is not known mainly due to the lack of the methods to control SWM with required spatiotemporal resolution. In this study, we employed bidirectional optogenetic manipulation (Channel-rhodopsin or archaerhodopsin) of striatal indirect pathway coupled with a rodent delayed non-match-to-place (DNMTP) WM task to define the causal role of the striatal indirect pathway control of specific temporal phase of SWM. We demonstrated that optogenetic silencing of striatal indirect pathway in the dorsomedial striatum selectively at the sample phase did not affect SWM performance. By contrast, optogenetic silencing and activation of the striatal indirect pathway selectively at the delay or choice phases improved and inhibited, respectively, SWM performance. Furthermore, optogenetic activation of the striatal indirect pathway output projection terminals into the external globus pallidus (Gpe) during the delay period also improved SWM performance. Thus, the striatal indirect pathway in the dorsomedial striatum selectively control the maintenance and retrieval (but not encoding) of SWM via the striatopallidal output projection, suggesting a plausible mechanism for the striatum to achieve updating of SWM.