PT  - JOURNAL ARTICLE
AU  - Maria Chernysheva
AU  - Yaroslav Sych
AU  - Aleksejs Fomins
AU  - José Luis Alatorre Warren
AU  - Christopher Lewis
AU  - Laia Serratosa Capdevila
AU  - Roman Boehringer
AU  - Elizabeth A. Amadei
AU  - Benjamin F. Grewe
AU  - Eoin C. O’Connor
AU  - Benjamin J. Hall
AU  - Fritjof Helmchen
TI  - Striatum-projecting prefrontal cortex neurons support working memory maintenance
AID  - 10.1101/2021.12.03.471159
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.12.03.471159
4099  - http://biorxiv.org/content/early/2021/12/03/2021.12.03.471159.short
4100  - http://biorxiv.org/content/early/2021/12/03/2021.12.03.471159.full
AB  - The medial prefrontal cortex (mPFC) and the dorsomedial striatum (dmStr) are linked to working memory (WM) but how striatum-projecting mPFC neurons contribute to WM encoding, maintenance, or retrieval remains unclear. Here, we probed mPFC→dmStr pathway function in freely-moving mice during a T-maze alternation test of spatial WM. Fiber photometry of GCaMP6m-labeled mPFC→dmStr projection neurons revealed strongest activity during the delay period that requires WM maintenance. Demonstrating causality, optogenetic inhibition of mPFC→dmStr neurons only during the delay period impaired performance. Conversely, enhancing mPFC→dmStr pathway activity—via pharmacological suppression of HCN1 or by optogenetic activation during the delay— alleviated WM impairment induced by NMDA receptor blockade. Consistently, cellular-resolution miniscope imaging resolved preferred activation of >50% mPFC→dmStr neurons during WM maintenance. This subpopulation was distinct from neurons showing preference for encoding and retrieval. In all periods, including the delay, neuronal sequences were evident. Striatum-projecting mPFC neurons thus critically contribute to spatial WM maintenance.Competing Interest StatementThe authors have declared no competing interest.