Biology subjects

Graybiel, A. M.

Publications and source records attributed to Graybiel, A. M..

At least 19 recordsLinked to original sources

bioRxiv2026

Acute stress reorganizes pregenual cingulate and subthalamic coupling to approach-avoidance decisions in remitted depression

Major depressive disorder (MDD) is highly recurrent, and psychosocial stress is a central precipitant of relapses. Daily choices require weighing potential rewards against costs, a process disrupted in MDD that may contribute to relapse. Here, we tested whether a psychosocial stressor affects neural and computational mechanisms underlying approach-avoidance decision making in individuals with remitted MDD (rMDD, N=50) and healthy controls (N=74), prioritizing pregenual anterior cingulate cortex (pgACC) and subthalamic nucleus (STN) due to their roles in value integration and decision caution, respectively. Participants performed a dynamic approach-avoidance conflict task with fMRI before and after psychosocial stress. Hierarchical Bayesian drift-diffusion modeling evaluated whether stress modulated computational and neural mechanisms, with trial-wise pgACC and STN activity entered as neural regressors on evidence accumulation and decision threshold, respectively. Before stress, groups did not differ in any decision parameter, but pgACC activity contributed to evidence accumulation toward avoidance in controls only. After stress, rMDD showed larger increases than controls in the impact of both reward and aversiveness on accumulation toward approach and avoidance, respectively, predominantly for net-aversive offers. Furthermore, in rMDD, stress rendered both approach and avoidance decisions more sensitive to pgACC activity, and STN activity was more strongly coupled to the decision threshold than in controls. Finally, stress-induced increases in reward sensitivity in rMDD predicted one-year course of depressive symptoms. Thus, MDD remission is not characterized by a generalized blunting of decision-making, but by a latent circuit difference that acute stress reorganizes and predicts future symptoms.

neuroscience↗

bioRxiv2026

Striatal dopamine signals internal states related to behavioral performance over prolonged timescales in monkeys

Slowly varying internal states govern our ability to sustain goal-directed behavior over minutes to hours, imposing fundamental constraints on cognitive performance, yet the neural signals that track these states remain poorly defined. Dopamine is a powerful modulator of motivated behavior, but its best-characterized signals are in the form of reward prediction errors (RPEs) that operate at seconds timescales. Whether these fast signals also carry information about slower, ongoing states of behavioral performance has not been directly tested. Here, we recorded subsecond dopamine concentration changes across multiple sites in the caudate nucleus (CN) and putamen of rhesus monkeys performing a reward-guided saccade task. Task performance oscillated over tens to hundreds of trials, demonstrating fluctuating internal states of sustained engagement. We found that single-trial dopamine signals were strongly modulated by these slowly evolving performance states, in a manner dissociable from both trial-level RPE and cumulative reward rate. This relationship was biased toward future rather than past performance windows, indicating that dopamine tracks motivational state prospectively rather than simply reflecting the reward history on which prediction errors are computed. Furthermore, performance-state modulation was concentrated in the CN rather than the putamen, consistent with the distinct roles of these regions in oculomotor and skeletomotor control and suggesting that state-dependent dopamine signals are organized according to the behavioral demands of the task. These findings demonstrate that phasic dopamine signals in the dorsal striatum simultaneously reflect fast learning signals and slowly evolving internal states, linking dopamines canonical RPE function to its broader role in sustaining motivated performance.

neuroscience↗

bioRxiv2025

Molecular unbalances between striosome and matrix compartments characterize the pathogenesis of Huntington's disease model mouse

The pathogenesis of Huntingtons disease is still incompletely understood, despite the remarkable advances in identifying the molecular effects of the Htt mutation in this disease. When we focus on movement disorders, clinical studies offer us some hints about this issue. Human studies employing positron emission tomography have identified a reduction in phosphodiesterase 10A (PDE10A) as the earliest event in the brain of patients with Huntingtons disease, which occurs about 25 years before symptom onset. A PDE10A mutation is also known to cause childhood-onset chorea. GNAL encodes the olfactory type G-protein subunit (Golf), strongly expressed in the striatum, and its mutation causes familial dystonia. PDE10A and Golf are both critical regulators of cyclic AMP and are abundant in striatal spiny projection neurons. These findings suggest that maintaining cyclic AMP levels in the striatum might be an essential target for the pathogenesis of movement disorders such as chorea and dystonia. Why and how these changes in the striatum cause movement disorder are still a mystery. Here we suggest that a key might be evaluating these messenger systems in light of the circuit-level compartmental organization of the striatum, in which there is particular vulnerability of the striosome compartment. We developed machine learning algorithms to define with high precision and reproducibility the borders of striosomes in the brains of q175 Huntingtons disease model mice from 3-12 months of age. We demonstrate that multiple molecules including Golf, PDE10A, dopamine D1 and D2 receptors, adenosine 2A receptors, and mu-opioid receptors differentially change their expression patterns in striosomes across ages by comparison with their expression patterns in the matrix compartment. An early and pronounced differential vulnerability of striosomes has been demonstrated in studies of post-mortem Huntingtons brains. Our findings here, mapping the molecular distributions across age in a widely studied mouse model of Huntingtons disease, may help to pinpoint the pathogenic mechanisms of Huntingtons disease by demonstrating the differential molecular changes in the striosome compartment.

neuroscience↗

bioRxiv2025

Nociceptin Orphanin F/Q Pathways are Dysregulated by Stress and Modulate Reward Learning and Motivation Across Species

Nociceptin orphanin F/Q has been implicated in stress-related depressive phenotypes. Specifically, exposure to chronic stressors upregulates nociceptin receptors (NOPR), whereas NOPR antagonism has anti-depressant/anti-anhedonic effects. The mechanisms underlying these effects remain, however, unclear. Here, we investigated the role of NOPR in depressive phenotypes alongside potentially prohedonic effects of NOPR antagonism across species. In Study 1, we evaluated whether exposure to early-life adversity (ELA) upregulated ventral tegmental area (VTA) and striatal prepronociceptin (Pnoc) gene expression in adult mice. In Study 2, we tested whether chronic social defeat altered Pnoc gene expression in reward-related regions. To establish whether direct NOPR modulation is implicated in reward-related behaviors, in Study 3, we assessed whether NOPR antagonism alters reward learning in rats. Finally, in Study 4, we tested whether NOPR antagonism boosts motivation among depressed humans. ELA induced anhedonic behavior and increased Pnoc expression in the VTA; in females (but not males), ELA increased Pnoc expression in the dorsal striatum (Study 1). Furthermore, chronic stress reduced Pnoc-expressing cells in the VTA, dorsal striatum and prefrontal cortex and susceptible rats showed reduced VTA NOPR gene (Oprl1)-expressing cells (Study 2). In a behavioral assay, a single 30-mg dose of a NOPR antagonist (BTRX-246040) boosted reward learning in rats (Study 3). Finally, in depressed humans, relative to placebo, 8-week treatment with BTRX-246040 increased incentive motivation (Study 4). Collectively, our findings indicate that chronic stressors alter Pnoc and mRNA levels of Pnoc-expressing cells in a sex-selective and region-specific manner impacting reward structures, and that NOPR antagonism shows anti-anhedonic properties.

neuroscience↗

bioRxiv2025

State-dependent modulation of spiny projection neurons controls levodopa-induced dyskinesia in a mouse model of Parkinson's disease

In the later stages of Parkinsons disease (PD), patients often manifest levodopa-induced dyskinesia (LID), compromising their quality of life. The pathophysiology underlying LID is poorly understood, and treatment options are limited. To move toward filling this treatment gap, the intrinsic and synaptic changes in striatal spiny projection neurons (SPNs) triggered by the sustained elevation of dopamine (DA) during dyskinesia were characterized using electrophysiological, pharmacological, molecular and behavioral approaches. Our studies revealed that the intrinsic excitability and functional corticostriatal connectivity of SPNs in dyskinetic mice oscillate between the on- and off-states of LID in a cell- and state-specific manner. Although triggered by levodopa, these rapid oscillations in SPN properties depended on both dopaminergic and cholinergic signaling. In a mouse PD model, disrupting M1 muscarinic receptor signaling specifically in iSPNs or deleting its downstream signaling partner CalDAG-GEFI blunted the levodopa-induced oscillation in functional connectivity, enhanced the beneficial effects of levodopa and attenuated LID severity.

neuroscience↗

bioRxiv2024

Striatal Astrocytes Influence Dopamine Dynamics and Behavioral State Transitions

We demonstrate here that astrocytes in the striatum interact with striatal dopamine in bidirectional signaling with dopamine release actively driving surges in astrocytic Ca++, which in turn modulate and reduce subsequent dopamine release. These Ca++ surges accurately predict behavioral state changes from task-engaged to task-disengaged states, but fail to predict detailed action parameters. We propose that interactions between striatal astrocytes and dopamine are strong candidates to modulate nigro-striato-nigral loop function underlying on-going behavioral state dynamics.

neuroscience↗

bioRxiv2024

Functional Dichotomy of Orbitofrontal Cortex and Anterior Cingulate Cortex Subregions in Decision-Making and Brain-Body Regulation

Mood disorders are associated with complex disruptions in brain networks, including those associated with the orbitofrontal cortex (OFC) and pregenual anterior cingulate cortex (pACC). The functional contribution of the caudal OFC (cOFC) has remained largely unexplored. We investigated the functions of the cOFC and pACC in macaques performing an approach-avoidance task by the combination of multimodal recordings and electrical microstimulation (EMS) of the cOFC. We assessed neural, autonomic and behavioral responses. We found the cOFC to be sensitive to both positive and negative stimuli, whereas the pACC was singificantly more active during aversive outcomes. EMS of the cOFC increased avoidance behavior, suggesting a causal role for the OFC subdivision in cost-benefit decision-making. Physiological measurements were positively correlated with behavioral patterns, emphasizing body-brain synchronization during emotionally significant decision-making. We suggest that the cOFC contributes to inducing pessimistic states, thereby making its dysfunction a potential contributor to the etiology of mood disorders.

neuroscience↗

bioRxiv2024

Striosomes Target Nigral Dopamine-Containing Neurons via Direct-D1 and Indirect-D2 Pathways Paralleling Classic Direct-Indirect Basal Ganglia Systems

Balanced activity of canonical direct D1 and indirect D2 basal ganglia pathways is considered a core requirement for normal movement, and their imbalance is an etiologic factor in movement and neuropsychiatric disorders. We present evidence for a conceptually equivalent pair of direct-D1 and indirect-D2 pathways that arise from striatal projection neurons (SPNs) of the striosome compartment rather than from SPNs of the matrix, as do the canonical pathways. These S-D1 and S-D2 striosomal pathways target substantia nigra dopamine-containing neurons instead of basal ganglia motor output nuclei. They modulate movement oppositely to the modulation by the canonical pathways: S-D1 is inhibitory and S-D2 is excitatory. The S-D1 and S-D2 circuits likely influence motivation for learning and action, complementing and reorienting canonical pathway modulation. A major conceptual reformulation of the classic direct-indirect pathway model of basal ganglia function is needed, as well as reconsideration of the effects of D2-targeting therapeutic drugs. HIGHLIGHTSO_LIDirect S-D1 and Indirect S-D2 striosomal pathways target SNpc dopamine cells C_LIO_LIThe S-D2 indirect pathway targets a distinct central external pallidal zone (cGPe) C_LIO_LIStimulation of S-D2 increases, of S-D1 decreases, striatal dopamine and movement C_LIO_LIS-D1 SPNs activity brackets task, inverse to a mid-task peak of dopamine release C_LI

neuroscience↗

bioRxiv2024

Developmental and adult striatal patterning of nociceptin ligand marks striosomal population with direct dopamine projections

Circuit influences on the midbrain dopamine system are crucial to adaptive behavior and cognition. Recent developments in the study of neuropeptide systems have enabled high-resolution investigations of the intersection of neuromodulatory signals with basal ganglia circuitry, identifying the nociceptin/orphanin FQ (N/OFQ) endogenous opioid peptide system as a prospective regulator of striatal dopamine signaling. Using a prepronociceptin-Cre reporter mouse line, we characterized highly selective striosomal patterning of Pnoc mRNA expression in mouse dorsal striatum, reflecting early developmental expression of Pnoc. In the ventral striatum, Pnoc expression was was clustered across the nucleus accumbens core and medial shell, including in adult striatum. We found that PnoctdTomato reporter cells largely comprise a population of dopamine receptor D1 (Drd1) expressing medium spiny projection neurons localized in dorsal striosomes, known to be unique among striatal projections neurons for their direct innervation of midbrain dopamine neurons. These findings provide new understanding of the intersection of the N/OFQ system among basal ganglia circuits with particular implications for developmental regulation or wiring of striatal-nigral circuits.

neuroscience↗

bioRxiv2023

Synchronous Measurements of Extracellular Action Potentials and Neurochemical Activity with Carbon Fiber Electrodes in Nonhuman Primates

Measuring the dynamic relationship between neuromodulators, such as dopamine, and neuronal action potentials is imperative to understand how these fundamental modes of neural signaling interact to mediate behavior. Here, we developed methods to measure concurrently dopamine and extracellular action potentials (i.e., spikes) and applied these in a monkey performing a behavioral task. Standard fast-scan cyclic voltammetric (FSCV) electrochemical (EChem) and electrophysiological (EPhys) recording systems are combined and used to collect spike and dopamine signals, respectively, from an array of carbon fiber (CF) sensors implanted in the monkey striatum. FSCV requires the application of small voltages at the implanted sensors to measure redox currents generated from target molecules, such as dopamine. These applied voltages create artifacts at neighboring EPhys-measurement sensors, producing signals that may falsely be classified as physiological spikes. Therefore, simple automated temporal interpolation algorithms were designed to remove these artifacts and enable accurate spike extraction. We validated these methods using simulated artifacts and demonstrated an average spike recovery rate of 84.5%. This spike extraction was performed on data collected from concurrent EChem and EPhys recordings made in a task-performing monkey to discriminate cell-type specific striatal units. These identified units were shown to correlate to specific behavioral task parameters related to reward size and eye-movement direction. Synchronous measures of spike and dopamine signals displayed contrasting relations to the behavioral task parameters, as taken from our small set of representative data, suggesting a complex relationship between these two modes of neural signaling. Future application of our methods will help advance our understanding of the interactions between neuromodulator signaling and neuronal activity, to elucidate more detailed mechanisms of neural circuitry and plasticity mediating behaviors in health and in disease. Significance statementWe present a simple method for recording synchronous molecular and neuronal spike signals. Conventional electrophysiological and electrochemical instruments are combined without the need for additional hardware. A custom-designed algorithm was made and validated for extracting neuronal action potential signals with high fidelity. We were able to compute cell-type specific spike activity along with molecular dopamine signals related to reward and movement behaviors from measurements made in the monkey striatum. Such combined measurements of neurochemical and extracellular action potentials may help pave the way to elucidating mechanisms of plasticity, and how neuromodulators and neurons are orchestrated to mediate behavior.

neuroscience↗

bioRxiv2023

Rhythm Receptive Fields in Striatum of Mice Executing Complex Continuous Movement Sequences

By the use of a novel experimental system, the step-wheel, we investigated the neural underpinnings of complex and continuous movements. We recorded neural activities from the dorsolateral striatum and found neurons sensitive to movement rhythm parameters. These neurons responded to specific combinations of interval, phase, and repetition of movement, effectively forming what we term "rhythm receptive fields." Some neurons even responsive to the combination of movement phases of multiple body parts. In parallel, cortical recordings in sensorimotor areas highlighted a paucity of neurons responsive to multiple parameter combinations, relative to those in the striatum. These findings have implications for comprehending motor coordination deficits seen in brain disorders including Parkinsons disease. Movement encoding by rhythm receptive fields should streamline the brains capacity to encode temporal patterns, help to resolve the degrees of freedom problem. Such rhythm fields hint at the neural mechanisms governing effective motor control and processing of rhythmic information.

neuroscience↗

bioRxiv2023

Dopamine Release Plateau and Outcome Signals in Dorsal Striatum Contrast with Classic Reinforcement Learning Formulations

We recorded dopamine release signals in medial and lateral sectors of the striatum as mice learned consecutive visual cue-outcome conditioning tasks including cue association, cue discrimination, reversal, and probabilistic discrimination task versions. Dopamine release responses in medial and lateral sites exhibited learning-related changes within and across phases of acquisition. These were different for the medial and lateral sites. In neither sector could these be accounted for by classic reinforcement learning as applied to dopamine-containing neuron activity. Cue responses ranged from initial sharp peaks to modulated plateau responses. In the medial sector, outcome (reward) responses during cue conditioning were minimal or, initially, negative. By contrast, in lateral sites, strong, transient dopamine release responses occurred at both cue and outcome. Prolonged, plateau release responses to cues emerged in both regions when discriminative behavioral responses became required. In most sites, we found no evidence for a transition from outcome to cue signaling, a hallmark of temporal difference reinforcement learning as applied to midbrain dopamine activity. These findings delineate reshaping of dopamine release activity during learning and suggest that current views of reward prediction error encoding need review to accommodate distinct learning-related spatial and temporal patterns of striatal dopamine release in the dorsal striatum.

neuroscience↗

bioRxiv2023

Scalable, flexible carbon fiber electrode thread arrays for three-dimensional spatial profiling of neurochemical activity in deep brain structures of rodents

We developed a flexible "electrode-thread" array for recording dopamine neurochemical activity from a lateral distribution of subcortical targets (up to 16) transverse to the axis of insertion. Ultrathin ([~] 10 {micro}m diameter) carbon fiber (CF) electrode-threads (CFETs) are clustered into a tight bundle to introduce them into the brain from a single entry point. The individual CFETs splay laterally in deep brain tissue during insertion due to their innate flexibility. This spatial redistribution allows navigation of the CFETs towards deep brain targets spreading horizontally from the axis of insertion. Commercial "linear" arrays provide single entry insertion but only allow measurements along the axis of insertion. Horizontally configured neurochemical recording arrays inflict separate penetrations for each individual channel (i.e., electrode). We tested functional performance of our CFET arrays in vivo for recording dopamine neurochemical dynamics and for providing lateral spread to multiple distributed sites in the striatum of rats. Spatial spread was further characterized using agar brain phantoms to measure electrode deflection as a function of insertion depth. We also developed protocols to slice the embedded CFETs within fixed brain tissue using standard histology techniques. This method allowed extraction of the precise spatial coordinates of the implanted CFETs and their recording sites as integrated with immunohistochemical staining for surrounding anatomical, cytological, and protein expression labels. Neurochemical recording operations tested here can be integrated with already widely established capabilities of CF-based electrodes to record single neuron activity and local field potentials, to enable multi-modal recording functions. Our CFET array has the potential to unlock a wide range of applications, from uncovering the role of neuromodulators in synaptic plasticity, to addressing critical safety barriers in clinical translation towards diagnostic and adaptive treatment in Parkinsons disease and major mood disorders.

bioengineering↗

bioRxiv2023

Emergence of rhythmic chunking in complex stepping of mice

Motor chunking is important for motor execution, allowing atomization and efficiency of movement sequences. However, it remains unclear why and how chunks contribute to motor execution. To analyze the structure of naturally occurring chunks, we trained mice to run in a complex series of steps and identified the formation of chunks. We found that intervals (cycle) and the positional relationship between the left and right limbs (phase) of steps inside the chunks, unlike those outside the chunks, were consistent across occurrences. Further, licking by the mice was also more periodic and linked to the specific phases of limb movements within the chunk. Based on these findings, we propose the rhythm chunking hypothesis, whereby within chunks, the repetitive movements of many body parts are linked by the rhythm parameters: cycle and phase. The computational complexity of movement may thereby be reduced by adjusting movements as the combination of rhythms.

animal behavior and cognition↗

bioRxiv2022

Huntington's Disease Produces Multiplexed Transcriptional Vulnerabilities of StriatalD1-D2 and Striosome-Matrix Neurons

Striatal cell-type-specific vulnerability in Huntingtons disease (HD) preferentially affects dopamine D2R-expressing projection neurons (SPNs), compatible with manifest motor symptomatology in HD. Transcriptional studies of striatal striosome-matrix compartmentalization in HD are, however, limited, despite pathologic evidence for striosome vulnerability aligning with early mood symptomatology. We used single-nucleus RNA-sequencing on striatal samples from two murine models, and rare Grade 1 HD patient tissues, to examine striosome and matrix sub-clusters within parent D1 and D2 SPN clusters. In human HD, striosomal SPNs were the most depleted SPN population. Surprisingly, for both mouse models, transcriptomic distinctiveness was diminished more for striosome-matrix SPNs than for D1-D2 SPNs. Compartmental markers were dysregulated so as to cancel endogenous identities as striosomal or matrix SPNs, but markers for D1-D2 exhibited less identity obscuring. The canonical striosome-matrix as well as D1-D2 organizations of the striatum thus are both strongly, but differentially, compromised in HD and are targets for therapeutics.

neuroscience↗

bioRxiv2022

Cannabinoid receptor 1 is required for neurodevelopment of striosome-dendron bouquets

Cannabinoid receptor 1 (CB1R) has strong effects on neurogenesis and axon pathfinding in the prenatal brain. Endocannabinoids that activate CB1R are abundant in the early postnatal brain and in mothers milk, but few studies have investigated their function in newborns. We examined postnatal CB1R expression in the major striatonigral circuit from striosomes of the striatum to the dopamine-containing neurons of the substantia nigra. CB1R enrichment was first detectable between postnatal days 5 and 7, and this timing coincided with the formation of striosome-dendron bouquets, the elaborate anatomical structures by which striosomal neurons control dopaminergic cell activity through inhibitory synapses. In Cnr1-/- knockouts lacking CB1R expression, striosome-dendron bouquets were markedly disorganized by postnatal day 11 and at adulthood, suggesting a postnatal pathfinding connectivity function for CB1R in connecting striosomal axons and dopaminergic neurons analogous to CB1Rs prenatal function in other brain regions. Our finding that CB1R plays a major role in postnatal wiring of the striatonigral dopamine system, with lasting consequences at least in mice, points to a crucial need to determine whether lactating mothers use of CB1R agonists (e.g., in marijuana) or antagonists (e.g., type 2 diabetes therapies) can disrupt brain development in nursing offspring.

neuroscience↗

bioRxiv2021

Effects of acute and repeated administration of the selective M4 PAM VU0152099 on cocaine vs. food choice in male rats

AO_SCPLOWBSTRACTC_SCPLOWLigands that stimulate muscarinic acetylcholine receptors 1 and 4 (M1, M4) have shown promising effects as putative pharmacotherapy for cocaine use disorder in rodent assays. We have previously shown reductions in cocaine effects with acute M4 stimulation, as well as long-lasting, delayed, reductions in cocaine taking and cocaine seeking with combined M1/M4 receptor stimulation or with M1 stimulation alone. M4 stimulation opposes dopaminergic signaling acutely, but direct dopamine receptor antagonists have proved unhelpful in managing cocaine use disorder because they lose efficacy with long-term administration. It is therefore critical to determine whether M4 approaches themselves can remain effective with repeated or chronic dosing. We assessed the effects of repeated administration of the M4 positive allosteric modulator (PAM) VU0152099 in rats trained to choose between intravenous cocaine and a liquid food reinforcer, to obtain quantitative measurement of whether M4 stimulation could produce delayed and lasting reduction in cocaine taking. VU0152099 produced progressively augmenting suppression of cocaine choice and cocaine intake, but produced neither rebound nor lasting effects after treatment ended. To compare and contrast effects of M1 vs. M4 stimulation, we tested whether the M4 PAM VU0152100 suppressed cocaine self-administration in mice lacking CalDAG-GEFI signaling factor, required for M1-mediated suppression of cocaine self-administration. CalDAG-GEFI ablation had no effect on M4-mediated suppression of cocaine self-administration. These findings support the potential usefulness of M4 PAMs as pharmacotherapy to manage cocaine use disorder, alone or in combination with M1-selective ligands, and show that M1 and M4 stimulation modulate cocaine-taking behavior by distinct mechanisms.

neuroscience↗

bioRxiv2021

Multiplexed action-outcome representation by striatal striosome-matrix compartments detected with a novel cost-benefit foraging task

Learning about positive and negative outcomes of actions is crucial for survival and underpinned by conserved circuits including the striatum. How associations between actions and outcomes are formed is not fully understood, particularly when the outcomes have mixed positive and negative features. We developed a novel foraging ( bandit) task requiring mice to maximize rewards while minimizing punishments. By 2-photon Ca++ imaging, we monitored activity of 5831 identified anterodorsal striatal striosomal and matrix neurons. Surprisingly, we found that action-outcome associations for reward and punishment were combinatorially encoded rather than being integrated as overall outcome value. Single neurons could, for one action, encode outcomes of opposing valence. Striosome compartments consistently exhibited stronger representations of reinforcement outcomes than matrix, especially for high reward or punishment prediction errors. These findings demonstrate a remarkable multiplexing of action-outcome contingencies by single identified striatal neurons and suggest that striosomal neurons are differentially important in action-outcome learning.

neuroscience↗