The striatum is one of the first brain regions affected in Parkinson's disease (PD), where dopaminergic axons projecting from the substantia nigra undergo dying-back degeneration. Growing evidence shows that dopamine depletion triggers network-level remodeling in the striatum, whose pathological significance extends far beyond acute changes in neuronal excitability. Striatal parvalbumin interneurons (PVINs) have recently been recognized as unique integrators of dopaminergic, neuroinflammatory and electrical network signals and as the principal striatal source of glial-cell-line-derived neurotrophic factor (GDNF). This integrative capacity renders PVINs early targets of parkinsonian injury, yet also allows them to orchestrate compensatory plasticity that shapes subsequent disease progression. Here we review how PVINs, via receptor-specific signaling, drive network reorganization in response to dopaminergic degeneration. We propose that these cells follow a compensatory-to-degenerative trajectory that canalizes abnormal synaptic plasticity and thereby exerts a maladaptive influence on PD pathogenesis. Finally, we discuss the therapeutic potential of interventions targeting these adaptive mechanisms.

Rhythmic neural network activity has been broadly linked to behavior. However, it is unclear how membrane potentials of individual neurons track behavioral rhythms, even though many neurons exhibit pace-making properties in isolated brain circuits. To examine whether single-cell voltage rhythmicity is coupled to behavioral rhythms, we focused on delta-frequencies (1-4 Hz) that are known to occur at both the neural network and behavioral levels. We performed membrane voltage imaging of individual striatal neurons simultaneously with network-level local field potential recordings in mice during voluntary movement. We report sustained delta oscillations in the membrane potentials of many striatal neurons, particularly cholinergic interneurons, which organize spikes and network oscillations at beta-frequencies (20-40 Hz) associated with locomotion. Furthermore, the delta-frequency patterned cellular dynamics are coupled to animals' stepping cycles. Thus, delta-rhythmic cellular dynamics in cholinergic interneurons, known for their autonomous pace-making capabilities, play an important role in regulating network rhythmicity and movement patterning.

Dopamine affects voluntary movement by modulating basal ganglia function. However, the contribution of dopamine on striatopallidal synapses, an initial hub in the indirect pathway connecting the striatum to the GPe, remains poorly understood because of the sparse dopaminergic innervation. Here, we combine optogenetic projection targeting, whole cell patch clamp recordings in acute brain slices from mice, and computational modeling to overcome this limitation. We show that dopamine activates D2 receptors (D2Rs) and D4 receptors (D4Rs) differentially in distinct GPe subregions. In a pinwheel-like fashion, dorsolateral and ventromedial GPe expresses high levels of D2Rs, which exert presynaptic inhibition, while in dorsomedial and ventrolateral GPe D4Rs cause postsynaptic inhibition. Dopamine depletion by 6-OHDA reshapes the region-specific effect of dopamine, shifting it in the opposite direction and contributing to hypokinesia. These findings reveal the mechanism by which the different modality information conveyed spatially through the indirect pathway is differentially modulated by dopamine at striatopallidal synapses.

Somatostatin-expressing low-threshold spiking interneurons (SOM-INs) constitute a key inhibitory population in the dorsal striatum, yet their contribution to parkinsonian states and L-DOPA-induced dyskinesia (LID) remains poorly understood. Here, we combined in vivo behavioral assays, chemogenetics, and ex vivo electrophysiology to examine how nigrostriatal dopamine loss and dopaminergic therapy shape SOM-INs' activity and function. During LID, SOM-INs displayed increased c-Fos expression, revealing their recruitment during dyskinetic states. Patch-clamp recordings showed that SOM-INs in control mice fire tonically with characteristic abrupt pauses. While their firing patterns are preserved after dopamine depletion and L-DOPA therapy, dopamine depletion shifted their interspike interval distribution toward longer intervals, indicating reduced intrinsic activity. This deficit was partially reversed by chronic L-DOPA. Consistent with their expression of Drd1/Drd5 transcripts, SOM-INs were excited by the D1/D5 receptor agonist SKF81297 across groups. Chemogenetic inhibition experiments revealed a functional role for SOM-INs in early rotarod learning, demonstrating their contribution to motor skill acquisition, but did not affect baseline motor output in sham or parkinsonian mice. Moreover, SOM-IN inhibition during chronic L-DOPA treatment modestly but consistently exacerbated LID expression selectively during the wearing-off phase, without altering parkinsonian symptoms or the therapeutic efficacy of L-DOPA. Notably, SOM-IN inhibition did not modify the long-duration antiparkinsonian response that persisted after discontinuing L-DOPA. Together, these findings identify SOM-INs as an intrinsically active striatal interneuron population whose excitability is shaped by dopamine depletion and dopamine receptor stimulation, and whose activity restrains dyskinetic responses to dopaminergic overstimulation. Their selective influence on dyskinesia, but not on the therapeutic actions of L-DOPA, highlights SOM-INs as a potential target for circuit-level interventions aimed at improving the motor side-effect profile of dopaminergic therapies.

Advances in optical techniques and two-photon (2P) sensitive genetic voltage indicators (GEVIs) enabled in-depth voltage imaging at single-spike and single-cell resolution. These results were achieved using ASAP-type sensors, while rhodopsin-based GEVIs were mainly used with one-photon (1P) illumination. Here, we demonstrate compatibility of rhodopsin-based GEVIs with 2P illumination. We rationally engineer a fully genetically encoded, rhodopsin-based GEVI, just another voltage indicating sensor (Jarvis), and demonstrate its utility under 1P and 2P illumination. We further show 2P usability of the fluorescence resonance energy transfer (FRET)-opsin GEVIs pAce and Voltron2. Comparing 2P scanless with fast 2P scanning illumination revealed that responses are resolved with both approaches, but FRET-opsin GEVIs show improved signal-to-noise ratio (SNR) with low irradiance, inherent to scanless illumination. Utilizing Jarvis and pAce, we establish high-SNR action potential detection at kilohertz imaging rates in mouse hippocampal slices, zebrafish larvae, and the cortex of awake mice, demonstrating high-contrast action potential detection under 2P illumination with rhodopsin-based GEVIs in vitro and in vivo.

The basal ganglia integrate cortical inputs with dopaminergic signals to potentiate and select actions. The reward-related activity of dopamine neurons is well-studied, but the coding properties of cortical inputs to the basal ganglia remain largely unknown. We examined the activity of neurons in the frontal eye field of monkeys that were optogenetically identified as projecting to the basal ganglia. We found that the projecting neurons contained information about expected rewards and selected actions. The reward-related signal and modulations independent of task condition were stronger in optogenetically identified projecting neurons than in other neurons in the same area. These findings indicate that reward, choice, and sensorimotor information are already integrated into the cortical inputs to the basal ganglia, suggesting that the basal ganglia network integrates reward from both cortical and dopaminergic inputs rather than relying on a dopaminergic source alone.

How the brain signals prediction errors for non-rewarding, yet significant, sensory events remains a central question. Although the cortical mismatch negativity provides a well-known signature for deviance detection, the contribution of subcortical dopamine remains unclear. This study tested the hypothesis that phasic dopamine in the nucleus accumbens encodes the salience associated with the violation of an ongoing statistical regularity. Using fiber photometry in freely moving rats, we contrasted an auditory oddball paradigm with a many-standards control. Deviant stimuli elicited a significantly amplified dopamine response compared with standard stimuli. Crucially, this dopamine response enhancement was absent in the control condition, demonstrating that the nucleus accumbens dopamine responds specifically to rule violation rather than mere stimulus rarity. The long latency of this signal (~500 ms) relative to the cortical mismatch negativity argues against a direct role in the initial detection of deviance. Instead, our findings support a model in which subcortical dopamine acts as a distinct salience signal, operating in parallel with cortical deviance detection, to evaluate unexpected events and guide subsequent behavioral adjustments.

Making appropriate decisions relies on the brain's capacity to evaluate the expected outcomes of available options and select the most rewarding action. The ventral striatum and midbrain dopamine neurons have been implicated in the option valuation process, consistent with the brain's reinforcement learning theory in which these brain structures encode and update value representations of expected outcomes. Extending beyond this framework, we found that the dopamine-ventral striatum system plays a more proactive role in action selection. We recorded single-unit activity from ventral striatum neurons in macaque monkeys as they sequentially evaluated an option, decided whether to perform an action to choose it, and expressed that motor action. The activity of these neurons initially reflected the value of the option but gradually shifted to reflect monkey's action selection, as if the ventral striatum translates the value information into the action. Moreover, optogenetic facilitation of dopamine input to the ventral striatum as well as electrical stimulation of this region altered monkey's action selection. Our findings reveal a previously unappreciated function of the ventral striatum as a neural hub that bridges option valuation and action selection, and demonstrate the contribution of dopamine in the process leading to action selection within this region.

The striatum comprises a network characterized by a highly shared feedforward inhibition (FFI) mediated by fast-spiking interneurons (FSI), which constitute only 1% of the striatal population. We investigated the dynamical consequences of this extensively shared FFI beyond inducing synchrony in a local striatal microcircuit. Our findings reveal that increased FFI sharing enhances the across-trial variability of striatal responses, activity of medium spiny neurons (MSNs), to cortical inputs, and endows the striatal network with the capacity to modulate output correlations in a bidirectional manner. Specifically, weakly shared cortical inputs become more correlated, whereas strongly shared cortical inputs are decorrelated in the presence of FSIs. These dynamic modulatory effects on MSNs, in turn, substantially alter the spiking statistics of downstream neurons in the globus pallidus, regarding across-trial variability and burstiness.

Parkinson's disease (PD) is a movement disorder caused by the loss of dopaminergic innervation, particularly to the striatum. PD patients often exhibit sensory impairments, yet the underlying network mechanisms are unknown. Here we examined how dopamine (DA) depletion affects sensory processing in the mouse striatum. We used the optopatcher for online identification of direct and indirect pathway projection neurons (MSNs) during in vivo whole-cell recordings. In control mice, MSNs encoded the laterality of sensory inputs with larger and earlier responses to contralateral than ipsilateral whisker deflection. This laterality coding was lost in DA-depleted mice due to adaptive changes in the intrinsic and synaptic properties, mainly, of direct pathway MSNs. L-DOPA treatment restored laterality coding by increasing the separation between ipsilateral and contralateral responses. Our results show that DA depletion impairs bilateral tactile acuity in a pathway-dependent manner, thus providing unexpected insights into the network mechanisms underlying sensory deficits in PD. VIDEO ABSTRACT.

The dorsolateral striatum (DLS) receives excitatory inputs from both sensory and motor cortical regions. In the neocortex, sensory responses are affected by motor activity, however, it is not known whether such sensorimotor interactions occur in the striatum and how they are shaped by dopamine. To determine the impact of motor activity on striatal sensory processing, we performed in vivo whole-cell recordings in the DLS of awake mice during the presentation of tactile stimuli. Striatal medium spiny neurons (MSNs) were activated by both whisker stimulation and spontaneous whisking, however, their responses to whisker deflection during ongoing whisking were attenuated. Dopamine depletion reduced the representation of whisking in direct-pathway MSNs, but not in those of the indirect-pathway. Furthermore, dopamine depletion impaired the discrimination between ipsilateral and contralateral sensory stimulation in both direct and indirect pathway MSNs. Our results show that whisking affects sensory responses in DLS and that striatal representation of both processes is dopamine- and cell type-dependent.

Striatal cholinergic interneurons (CINs) can drive local dopamine release via nicotinic acetylcholine receptors (nAChRs) expressed on dopaminergic axons, but their role in modulating serotonin (5-HT) signaling is poorly understood. Here, we show that synchronous activation of CINs directly triggers local 5-HT release in the dorsal striatum via nAChRs expressed on serotonergic axons. This CIN-5-HT coupling is not detectable in the ventral striatum, despite its substantially denser serotonergic innervation. The nAChR-dependent release not only increases 5-HT levels in the dorsal striatum, but also expands the spatial footprint of serotonergic signaling. In Sapap3 mice, a model of obsessive-compulsive disorder (OCD)-like behavior, this mechanism is exaggerated due to a hypercholinergic state, selectively amplifying the nAChR-dependent component of monoamine release. These findings demonstrate a regionally confined form of acetylcholine-5-HT crosstalk in the striatum and identify CINs as regulators of 5-HT dynamics in both healthy and pathological states.

Midbrain dopamine neurons promote reinforcement learning and movement vigor. An outstanding question is how dopamine-recipient neurons in the striatum parse these heterogeneous signals. Previous work suggests that cholinergic striatal interneurons may gate dopamine-dependent plasticity, but this has not been tested in behaving animals. Here we studied rats performing a decision-making task with reward-related and movement-related events. Optical measurement of dopamine and acetylcholine release in the dorsomedial striatum (DMS) revealed that reward cues evoked cholinergic pauses with different phase relationships relative to dopamine. When dopamine lagged cholinergic dips, dopamine predicted future behavior and DMS firing rates on subsequent trials. In contrast, when dopamine preceded cholinergic dips, there was no observable relationship between dopamine and learning. Finally, when dopamine was coincident with cholinergic bursts, it preceded and predicted the vigor of contralateral orienting movements. Our findings suggest that cholinergic dynamics determine whether dopamine promotes vigor or learning, depending on the instantaneous behavioral context.

Tissue clearing has been widely used for fluorescence imaging of fixed tissues, but its application to live tissues has been limited by toxicity. Here we develop minimally invasive optical clearing media for fluorescence imaging of live mammalian tissues. Light scattering is minimized by adding spherical polymers with low osmolarity to the extracellular medium. A clearing medium containing bovine serum albumin (SeeDB-Live) is compatible with live cells, enabling structural and functional imaging of live tissues, such as spheroids, organoids, acute brain slices and the mouse brains in vivo. SeeDB-Live minimally affects neuronal electrophysiological properties and sensory responses in vivo, and facilitates fluorescence imaging of deep cortical layers in live animals without detectable toxicity to neurons or behavior. We further demonstrate its utility to epifluorescence voltage imaging in acute brain slices and in vivo preparations. Thus, SeeDB-Live expands both the depth and modality range of fluorescence imaging in live mammalian tissues.