Everyday decisions depend on linking sensory stimuli with actions and outcomes. The striatum supports these sensorimotor associations through dopamine-dependent plasticity. Thus, the timing and magnitude of dopamine release is critical for learning. Recent work has characterized a local striatal microcircuit in which cholinergic interneurons (CINs) modulate dopamine release via acetylcholine activation of nicotinic receptors on dopamine axons. Here, we show that visual stimuli evoke dopamine responses in the dorsomedial striatum through this cholinergic-dependent mechanism. Using anatomical and functional methods to identify which pathways elicit these signals, we found that primary visual cortex and early sensory areas that project to the striatum exhibited only weak connectivity to CINs, despite robust connectivity to projection neurons, and were unable to drive dopamine release. In contrast, frontal cortical regions, including the prelimbic and anterior cingulate cortices, strongly recruited CINs and acetylcholine, producing robust dopamine release both and . These findings reveal a fundamental distinction between sensory and frontal cortical inputs to the striatum, demonstrating that only the latter provide effective access to cholinergic-dependent dopamine signaling. This work establishes a framework for understanding how cortical circuits shape striatal dopamine to support reinforcement learning.

The striatum is a major cortical input site of the basal ganglia and plays a critical role in the control of orofacial movements such as licking. However, how striatal activity relates to the spatial features of licking behavior remains unclear. In this study, we examined whether neural activity in the striatal matrix and striosomal compartments is associated with the spatial position of a licking target during an operant task. Head-fixed male mice performed a licking task in which the target positions were varied across three spatial dimensions. Using fiber photometry in Calb1-IRES-Cre (n = 7) and Pdyn-IRES-Cre (n = 6) mice, we recorded calcium signals from matrix and striosomal neurons. Associations between neural activity, target position, and behavioral variables were quantified using linear mixed-effects modeling with cross-validation. Matrix activity prior to the first detected lick was associated with reaction time and the dorsal-ventral target position. During licking, matrix activity was associated with the anterior-posterior and medial-lateral positions, independent of reaction time and lick count, whereas striosomal activity was associated with the dorsal-ventral position. These associations were correlational and differed in strength. The association between matrix activity and the anterior-posterior and medial-lateral positions was the most robust. The present findings are limited to male mice and to the hemisphere ipsilateral to the spout.

The lamprey belongs to the phylogenetically oldest group of vertebrates that diverged from the mammalian evolutionary line 560 million years ago. A comparison between the lamprey and mammalian basal ganglia establishes a detailed similarity regarding its input from cortex/pallium and thalamus, as well as its intrinsic organisation and projections of the output nuclei. This means that the basal ganglia circuits now present in rodents and primates most likely had evolved already at the dawn of vertebrate evolution. This includes the 'direct pathway' with striatal projection neurons (SPNs) expressing dopamine D1 receptors, which act to inhibit the tonically active GABAergic output neurons in globus pallidus interna and substantia nigra pars reticulata that at rest keep the brainstem motor centres under tonic inhibition. The 'indirect pathway' with dopamine D2 receptor-expressing SPNs and intrinsic basal ganglia nuclei is also conserved. The net effect of the direct pathway is to disinhibit brainstem motor centres and release motor programs, while the indirect pathway instead will suppress motor activity. Transmitters, connectivity and membrane properties are virtually identical in lamprey and rodent basal ganglia. We predict that the basal ganglia contains a series of modules each controlling a given pattern of behaviour including locomotion, eye-movements, posture, and chewing that contain both the direct pathway to release a motor program and the indirect pathway to inhibit competing behaviours. The phasic dopamine input serves value-based decisions and motor learning. During vertebrate evolution with a progressively more diverse motor behaviour, the number of modules will have increased progressively. These new modules with a similar design will be used to control newly developed patterns of behaviour - a process referred to as exaptation.