Although learning in response to extrinsic reinforcement is theorized to be driven by dopamine signals that encode the difference between expected and experienced rewards, skills that enable verbal or musical expression can be learned without extrinsic reinforcement. Instead, spontaneous execution of these skills is thought to be intrinsically reinforcing. Whether dopamine signals similarly guide learning of these intrinsically reinforced behaviours is unknown. In juvenile zebra finches learning from an adult tutor, dopamine signalling in a song-specialized basal ganglia region is required for successful song copying, a spontaneous, intrinsically reinforced process. Here we show that dopamine dynamics in the song basal ganglia faithfully track the learned quality of juvenile song performance on a rendition-by-rendition basis. Furthermore, dopamine release in the basal ganglia is driven not only by inputs from midbrain dopamine neurons classically associated with reinforcement learning but also by song premotor inputs, which act by means of local cholinergic signalling to elevate dopamine during singing. Although both cholinergic and dopaminergic signalling are necessary for juvenile song learning, only dopamine tracks the learned quality of song performance. Therefore, dopamine dynamics in the basal ganglia encode performance quality during self-directed, long-term learning of natural behaviours.

Linking activity in specific cell types with perception, cognition, and action, requires quantitative behavioral experiments in genetic model systems such as the mouse. In head-fixed primates, the combination of precise stimulus control, monitoring of motor output, and physiological recordings over large numbers of trials are the foundation on which many conceptually rich and quantitative studies have been built. Choice-based, quantitative behavioral paradigms for head-fixed mice have not been described previously. Here, we report a somatosensory absolute object localization task for head-fixed mice. Mice actively used their mystacial vibrissae (whiskers) to sense the location of a vertical pole presented to one side of the head and reported with licking whether the pole was in a target (go) or a distracter (no-go) location. Mice performed hundreds of trials with high performance (>90% correct) and localized to <0.95 mm (<6 degrees of azimuthal angle). Learning occurred over 1-2 weeks and was observed both within and across sessions. Mice could perform object localization with single whiskers. Silencing barrel cortex abolished performance to chance levels. We measured whisker movement and shape for thousands of trials. Mice moved their whiskers in a highly directed, asymmetric manner, focusing on the target location. Translation of the base of the whiskers along the face contributed substantially to whisker movements. Mice tended to maximize contact with the go (rewarded) stimulus while minimizing contact with the no-go stimulus. We conjecture that this may amplify differences in evoked neural activity between trial types.

The substantia nigra pars reticulata (SNr) functions as the principal inhibitory output of the basal ganglia, with the timing of its spikes critically controlling downstream disinhibition required for movement initiation. The external globus pallidus (GPe) and D1-expressing medium spiny neurons (D1-MSNs) in the striatum provide GABAergic inputs to the SNr that differ in their amplitude and kinetic properties. How these inputs interact with the intrinsic membrane currents that determine SNr firing is only partially understood. Using optogenetics, computational modeling, and electrophysiology in acute mouse brain slices, 47 animals of either sex were used for measurements, and we found an unexpected interaction between GABAergic inputs and hyperpolarization-activated currents (Ih) that tunes inhibitory efficacy in a pathway-specific manner. GPe inputs evoke fast, large IPSCs that transiently suppress SNr firing within a narrow window but whose rapid decay enables depolarization from Ih to restore firing after only a brief pause. In contrast, the slower decay kinetics of striatal IPSCs enables more sustained inhibition that counters the depolarizing drive from Ih to produce longer pauses, despite their lower conductance amplitudes. Pharmacological blockade of Ih with ZD7288 eliminated the rapid recovery of firing after GPe inhibition and equalized the inhibitory efficacy between GPe and striatal pathways. These findings establish an important interplay between synaptic kinetics and intrinsic membrane conductances in establishing pathway-specific inhibitory balance in the basal ganglia. Our study reveals that inhibitory pathways to the substantia nigra pars reticulata are differentially shaped by the interplay between synaptic kinetics and intrinsic membrane conductances. Using optogenetics, electrophysiology, and modeling, we showed that fast-decaying GABAergic inputs from the external globus pallidus are rapidly overcome by Ih, producing only brief pauses in SNr firing, whereas slower striatal inputs generate longer-lasting inhibition. Blocking Ih abolishes this difference, demonstrating that intrinsic currents tune inhibitory efficacy in a pathway-specific manner. These results identify a biophysical mechanism that helps set the balance of basal ganglia output essential for movement control.

Frontal Cortex (FC) plays a pivotal role in adaptively controlling actions and their dynamics in response to incoming sensory signals. We explored FC encoding of identical stimuli and their behavioral consequences when they signified diametrically opposite responses depending on task context. Two groups of female ferrets performed Go-NoGo auditory categorization tasks with opposite contingencies and rewards, and diverse stimuli. Remarkably, despite opposite stimulus-action associations, single-unit responses were similar across all tasks, being more sustained and stronger to Target sounds (signaling a change in action) than to Reference sounds (indicating maintenance of ongoing actions) especially during task engagement. Overall activity was composed of three distinct dynamic response profiles. Each corresponded to a separate neuronal cluster and exhibited a different role in relation to the succession of task events. Decoding based on the temporal structure of population responses revealed distinct decoders that were aligned to different task events. Similar to single unit findings, the β-band power extracted from the FC local field potentials (LFPs) was strongly and similarly modulated during Target stimuli across all tasks despite opposite behavioral actions. In contrast, power in all other LFP frequency bands varied significantly across task stimuli and actions. Based on these findings, we propose the FC encodes a common, highly abstract representation of all the different behavioral tasks. We further outline a hypothetical model of pathway-specific functional projections from the tripartite FC neuronal clusters to the basal ganglia, consistent with previous evidence for the conjoint roles of the FC and striatum in adaptive motor control. The frontal cortex (FC) encodes an abstract representation of perception and action with associated rewards and cognitive functions. Thus, even when ferrets perform opposite Go/NoGo behaviors, FC responses exhibit similar sequences of dynamic patterns from 3 cell clusters. The first component is phasic encoding stimulus category and the decision to maintain or change ongoing actions. The second is a rapid response suppression, initiated if the animal switches to a new action. The third is a buildup of excitatory activity as the animal sustains its new action. We propose a model for how such an abstract FC representation may emerge from separate functional projections from the FC clusters to the striatum, offering new insights into the FC role in behavioral control.

Acetylcholine (ACh) release in the medial prefrontal cortex (mPFC) is a major contributor to the balance between attention and inhibitory control, which is crucial for the execution of adaptive goal-directed behaviors. Yet, our understanding of the functional heterogeneity within the mPFC, particularly how distinct cholinergic afferences and circuits regulate these processes, remains limited. Here, we used in vivo fiber photometry, neuronal tracing, and chemogenetics manipulations to demonstrate the role of the prelimbic sub-region of the mPFC (PrL) and its ascending cholinergic projections in a cued-Fixed Consecutive Number task (FCNcue task) in male mice. We found that following a transient activation at the initiation of the behavioral response (cue detection), persistent inhibition of PrL neuronal activity, measured by fiber photometry, may be necessary to maintain engagement in the task and completion of the chain of required responses (i.e., optimal responses). Moreover, we found that the PrL receives dense ACh projections almost exclusively from the most anterior-medial part of the basal forebrain (BF) comprising the horizontal and ventral parts of the diagonal band of Broca (HDB and VDB) and the substantia innominata (SI) nuclei. Finally, chemogenetic activation of this ACh pathway inhibited PrL activity and enhanced behavioral performance of the mice by increasing the percentage of optimal responses. Overall, this study provides insights into the spatial and temporal dynamics of cholinergic signaling to the PrL and its causal role on attentional control.