Working memory is the ability to keep information available for a short period of time in order to guide behavior. It is essential for flexible cognition, but the circuit mechanisms that allow prefrontal networks to maintain information across a delay remain incompletely understood. Together with Fritjof Helmchen’s group at the University of Zurich, we investigated how specific projection pathways from the medial prefrontal cortex contribute to working memory.
This study focused on a specific prefrontal output pathway: neurons in the medial prefrontal cortex that project to the dorsomedial striatum. The prefrontal cortex and striatum are both known to contribute to goal-directed behavior, but the precise role of this projection in different phases of working memory — encoding, maintenance and retrieval — had remained unclear.
Using optical recordings, optogenetic perturbations and pharmacological interventions in freely moving mice, the study showed that dorsomedial-striatum-projecting prefrontal neurons are specifically required during the maintenance phase of a spatial working-memory task. In a T-maze task, mice must remember information across a delay before choosing the appropriate arm. Activity in the prefrontal-to-striatal pathway was strongest during this delay period, when information had to be maintained internally rather than directly sensed from the environment.
The causal role of this pathway was demonstrated by perturbation experiments: inhibiting these neurons during the delay impaired working-memory performance, whereas enhancing pathway activity could alleviate working-memory deficits induced by NMDA receptor blockade. Cellular-resolution miniscope imaging further revealed that more than half of the recorded mPFC→dmStr neurons were active during working-memory maintenance, and that this population was distinct from neurons preferentially active during encoding or retrieval.
The broader message is that working memory is not supported by the prefrontal cortex as a uniform block. Instead, specific projection-defined subpopulations contribute to distinct computational phases of the task. In this case, prefrontal neurons projecting to the dorsomedial striatum appear to help keep information “online” during the delay, supporting the bridge between past sensory information and future action.
A useful way to summarize the result is: remembering something for a few seconds is not simply a matter of persistent activity in the prefrontal cortex; it depends on specific communication channels between prefrontal cortex and striatum.
This work refines our understanding of cortico-striatal circuits in cognition. It shows that pathways classically associated with action selection and behavioral control also contribute to the maintenance of internal information, linking working memory to the distributed dynamics of frontal–basal ganglia networks.
To know more:
- Wilhelm, M., Sych, Y., Fomins, A., Warren, J. L. A., Lewis, C., Capdevila, L. S., Boehringer, R., Amadei, E. A., Grewe, B., O’Connor, E. C., et al. (2023). Striatum-projecting prefrontal cortex neurons support working memory maintenance. Nature Communications, 14, 7016. https://doi.org/10.1038/s41467-023-42777-3.