Mark Howe

Striatal acetylcholine (ACh) signaling is thought to counteract reinforcement signals, promoting extinction and behavioral flexibility. Changes in striatal ACh signals have been reported during learning, but how ACh signals for learning and extinction are spatially organized to enable region-specific plasticity is unclear. We used array photometry in mice to reveal a topography of opposing changes in ACh release across distinct striatal regions. Reward prediction error encoding was localized to specific phases of ACh dynamics in anterior dorsal striatum (aDS): positive and negative prediction errors were expressed in dips and elevations respectively. Silencing ACh release in aDS impaired extinction, suggesting a role for ACh elevations in down-regulating cue-reward associations. Dopamine release in aDS dipped for cues during extinction, inverse to ACh, while glutamate input onto cholinergic interneurons was unchanged. These findings pinpoint where and suggest an intrastriatal mechanism for how ACh dynamics shape region-specific plasticity to gate learning and promote extinction.

Howe's Lab developed a new micro-fiber array approach capable of chronically measuring and optogenetically manipulating local dynamics across over 100 targeted locations simultaneously in head-fixed and freely moving mice, enabling investigation of cell-type and neurotransmitter-specific signals over arbitrary 3-D volumes. This protocol includes the immunohistology steps used to confirm viral expression, and/or stain for neurons after micro-CT scanning and contrast agent soaking procedure.