Biology subjects

Howe, M. W.

Publications and source records attributed to Howe, M. W..

3 recordsLinked to original sources

bioRxiv2026

An anatomical hotspot for striatal dopamine-acetylcholine interactions during reward and movement

Dopamine (DA) and acetylcholine (ACh) are key neuromodulators that regulate striatal circuits underlying movement and reinforcement learning. Evidence suggests that DA and ACh systems interact, but where and how interactions are expressed across striatal regions in behaviorally relevant release dynamics remains unknown. We applied micro-fiber arrays to simultaneously measure striatum-wide DA and ACh in behaving mice, revealing an anatomical organization in which DA-ACh anti-correlations were concentrated in a hotspot in the anterior dorsolateral striatum (aDLS). Anti-correlations resulted from temporally coincident pairs of spontaneous and event-locked transient peak and dip events occurring in a DA[->]ACh sequence. The aDLS localized hotspot was consistently expressed within distinct signals associated with unpredicted rewards, learned and extinguished Pavlovian cues, and locomotion initiation and invigoration phases, for which we revealed novel, opposing DA-ACh dynamics. Optogenetic activation of DA neurons selectively suppressed spontaneous ACh release within the aDLS hotspot, and ex vivo recordings revealed enhanced D2-mediated ACh inhibition in aDLS relative to ventral regions, suggesting a mechanistic basis for this spatial specificity. These findings demonstrate that DA-ACh interactions during behavior are spatially organized, rather than uniformly conserved, and shape behaviorally relevant dynamics to regulate region-specific functions in learning and movement control.

neuroscience↗

bioRxiv2024

Spatially organized striatum-wide acetylcholine dynamics for the learning and extinction of Pavlovian cues and actions

Striatal acetylcholine (ACh) signaling has been proposed to counteract reinforcement signals to promote extinction and behavioral flexibility. ACh dips to cues and rewards may open a temporal window for associative plasticity to occur, while elevations may promote extinction. Changes in multi-phasic striatal ACh signals have been widely reported during learning, but how and where signals are distributed to enable region-specific plasticity for the learning and degradation of cue-reward associations is poorly understood. We used array fiber photometry in mice to investigate how ACh release across the striatum evolves during learning and extinction of Pavlovian associations. We report a topographic organization of opposing changes in ACh release to cues, rewards, and consummatory actions across distinct striatum regions. We localized reward prediction error encoding in particular phases of the ACh dynamics to a specific region of the anterior dorsal striatum (aDS). Positive prediction errors in the aDS were expressed in ACh dips, and negative prediction errors in long latency ACh elevations. Silencing aDS ACh release impaired behavioral extinction, suggesting a role for ACh elevations in down-regulating cue-reward associations. Dopamine release in aDS dipped for cues during extinction, but glutamate input onto cholinergic interneurons did not change, suggesting an intrastriatal mechanism for the emergence of ACh elevations. Our large scale measurements indicate how and where ACh dynamics can shape region-specific plasticity to gate learning and promote extinction of Pavlovian associations.

neuroscience↗

bioRxiv2023

Targeted micro-fiber arrays for measuring and manipulating localized multi-scale neural dynamics over large, deep brain volumes during behavior

Neural population dynamics relevant for behavior vary over multiple spatial and temporal scales across 3-dimensional volumes. Current optical approaches lack the spatial coverage and resolution necessary to measure and manipulate naturally occurring patterns of large-scale, distributed dynamics within and across deep brain regions such as the striatum. We designed a new micro-fiber array and imaging approach capable of chronically measuring and optogenetically manipulating local dynamics across over 100 targeted locations simultaneously in head-fixed and freely moving mice. We developed a semi-automated micro-CT based strategy to precisely localize positions of each optical fiber. This highly-customizable approach enables investigation of multi-scale spatial and temporal patterns of cell-type and neurotransmitter specific signals over arbitrary 3-D volumes at a spatial resolution and coverage previously inaccessible. We applied this method to resolve rapid dopamine release dynamics across the striatum volume which revealed distinct, modality specific spatiotemporal patterns in response to salient sensory stimuli extending over millimeters of tissue. Targeted optogenetics through our fiber arrays enabled flexible control of neural signaling on multiple spatial scales, better matching endogenous signaling patterns, and spatial localization of behavioral function across large circuits.

neuroscience↗