Biology subjects

Hikosaka, O.

Publications and source records attributed to Hikosaka, O..

16 recordsLinked to original sources

bioRxiv2026

Parallel basal ganglia and frontal cortical outputs differentially encode context-dependent evaluation and categorical commitment during choice

Adaptive choice requires transforming the evaluation of available options into commitment to a specific action but understanding how this transformation is implemented across neural circuits remains a central challenge. Here we recorded well-isolated neurons in the substantia nigra pars reticulata (SNr) and frontal eye field (FEF), which send parallel projections to the superior colliculus for driving the eye movement choice, while monkeys performed a sequential-offer choice task designed to partially dissociate scene-defined ordinal rank from the categorical commitment. Before target onset, SNr displayed stronger scene-related modulation than FEF. During target evaluation, SNr activity showed ordered modulation across behavioral outcomes dominated by ordinal rank, whereas FEF activity categorically separated acceptance from rejection and strongly encoded target direction. Behavioral model decomposition revealed that ordinal rank alone best explained SNr activity, outperforming both reward magnitude and even a composite acceptability measure that incorporated rank together with reward, scene context, and waiting cost, whereas FEF activity was best explained by categorical commitment. This dissociation was consistent across multivariable modeling, single-neuron response patterns, and all three monkeys. Together, these findings support a division of labor in which context-dependent evaluation and categorical commitment are distributed across parallel basal ganglia and frontal cortical output pathways to efficiently guide voluntary choices.

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bioRxiv2025

Beyond the Brake: the Subthalamic Nucleus Predominantly Facilitates Action in Non-human Primates

The subthalamic nucleus (STN) is a core component of the basal ganglia circuitry, traditionally viewed as a "brake" that suppresses motor output via the indirect and hyperdirect pathways. While this model explains certain aspects of motor control, it fails to account for the complex involvement of the STN in dynamic, value-based behaviors. Movement-related increases in STN neuronal activity have been well documented across species, but the functional organization of these responses during value-based decisions has remained unclear. Here, we recorded 187 STN neurons from macaque monkeys performing a value-based sequential choice task. Data-driven clustering identified three functionally distinct populations. Two populations (comprising approximately 89% of task-responsive neurons) exhibited facilitative activity modulated by learned object value. Temporal alignment analysis revealed that the majority of these neurons were target-locked, suggesting a predominantly stimulus-driven evaluation signal rather than a strictly movement-locked command. A third, smaller population encoded a negative value signal upon presentation of unrewarded objects, independent of subsequent motor strategy. Response latencies of the facilitative STN populations systematically preceded those of functionally analogous populations in the GPe recorded during the same task paradigm, supporting an STN-GPe facilitative pathway for value-based action selection. These findings reveal a functional organization within the ventral STN in which evaluation of stimulus target value, beyond the traditional motor suppressive model, is the predominant mode of processing.

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bioRxiv2025

Retrograde Optogenetics Reveals Functional Convergence within a Corticotectal Pathway of Non-Human Primates

Understanding how the cerebral cortex communicates with subcortical areas to drive behavior remains a central question in system neuroscience. One key unresolved issue is whether prefrontal cortical outputs to motor-related subcortical regions carry predominantly motor commands or mixed sensory-motor signals. Retrograde optogenetics offers a powerful way to interrogate such projection-defined circuits, but its use in non-human primates has been limited. Here, we applied retrograde optogenetics in awake macaques to directly test the functional organization of the corticotectal projection from the frontal eye field (FEF) to the superior colliculus (SC). We asked whether the FEF output signals to SC are motor-dominant or broadly sensory-motor. Optical activation of this pathway evoked robust, contralateral saccades and selectively modulated reaction times, demonstrating its causal role in saccade generation. Optogenetically tagging FEF neurons projecting to SC revealed a heterogeneous population of visual, visuomotor, and motor neurons. This diverse output converged predominantly onto motor-related neurons in the SC. These findings support a visuomotor convergence model, in which diverse FEF outputs drive motor-selective SC neurons with activity sufficient for saccade generation, and thus resolve long-standing questions over the composition of FEF outputs. Additionally, our results establish retrograde optogenetics as a tool for dissecting projection-defined circuits in primates and for precisely probing the neural pathways that link perception to action. HighlightsRetrograde optogenetics enabled pronounced and selective modulation of behavior in macaques. Selective optical stimulation of the FEF-SC pathway evoked contralateral saccades and modulated reaction times. Opto-tagging revealed diverse visual, visuomotor, and motor FEF outputs converging onto motor-related SC neurons. Findings support a visuomotor convergence model and demonstrate the power of projection-specific optogenetic tools in primates.

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bioRxiv2025

Multiple groups of neurons in the superior colliculus convert value signals into saccadic vigor.

Eye movements directed to high-valued objects in the environment are executed with greater vigor. Superior Colliculus (SC) - a subcortical structure that controls eye movements - contains multiple subtypes of neurons that have distinct functional roles in generating saccades. How does value-related information processed in other parts of the brain affect the responses of these different subtypes of SC neurons to facilitate faster saccades? To test this, we recorded four subtypes of neurons simultaneously while the monkey made saccades to objects they had been extensively trained to associate with large or small rewards (i.e., good or bad). In three subtypes of neurons (visual, visuomotor, and motor), the good objects elicited more spikes than bad objects. More importantly, using a bootstrapping procedure, we identified three separable phases of activity: 1) early visual response (EVIS), 2) late visual response (LVIS), and 3) pre-saccadic (PreSAC) motor response in these neuronal subtypes. In each subtype of neurons, the value of objects (good vs. bad) was positively correlated with the activity in the LVIS and PreSAC phases but not the EVIS phase. These data suggest that the value information from other brain regions modulates the visual (LVIS) and the motor (PreSAC) responses of visual, visuomotor, and motor neurons. This enhanced activation facilitates the faster initiation and execution of the saccade based on the value of each object. In addition, we found a novel class of tonically active neurons that decrease their activity in response to object onset and remain inhibited till the end of the saccade. We suggest that these tonic neurons facilitate the saccade to objects by disinhibiting the interactions between the other three SC neurons.

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bioRxiv2025

Excitatory drive to the globus pallidus external segment facilitates action initiation in non-human primates

The external segment of the globus pallidus (GPe) has conventionally been regarded as a key relay in the indirect pathway of the basal ganglia, primarily mediating movement suppression; however, recent studies in rodents suggest a more complex role, including active facilitation of actions. Therefore, we investigated whether the primate GPe exhibits similar functional diversity by recording single-unit activity in two macaque monkeys performing a sequential choice task. This task separated processes of action initiation and suppression by requiring the monkeys to either accept a "good" object for reward or reject a "bad" object using one of multiple strategies. We identified three distinct neuronal clusters based on their firing patterns. Clusters 1 and 2 displayed elevated activity preceding contralateral saccades toward good objects, strongly correlating with shorter reaction times, suggesting a facilitative contribution. In contrast, Clusters 2 and 3 showed decreased activity during rejection of bad objects, reflecting proactive inhibition. Local pharmacological blockade of glutamate receptors within the caudodorsal GPe prolonged saccade latencies and reduced the frequency of rejection saccades, suggesting a causal role for excitatory drive in saccade facilitation. These findings expand the traditional view of the GPe beyond a purely inhibitory station, indicating that in primates it may simultaneously mediate both motor facilitation and proactive suppression. Our results emphasize the importance of characterizing circuit-specific and cell-type-specific roles of the GPe within basal ganglia networks, with implications for normal motor function and movement disorder pathophysiology under complex reward-based decision processes in non-human primates.

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bioRxiv2024

Contribution of glutamatergic projections to neurons in the nonhuman primate lateral substantia nigra pars reticulata for the reactive inhibition

The basal ganglia play a crucial role in action selection by facilitating desired movements and suppressing unwanted ones. The substantia nigra pars reticulata (SNr), a key output nucleus, facilitates movement through disinhibition of the superior colliculus (SC). However, its role in action suppression, particularly in primates, remains less clear. We investigated whether individual SNr neurons in three male macaque monkeys bidirectionally modulate their activity to both facilitate and suppress actions and examined the role of glutamatergic inputs in suppression. Monkeys performed a sequential choice task, selecting or rejecting visually presented targets. Electrophysiological recordings showed SNr neurons decreased firing rates during target selection and increased firing rates during rejection, demonstrating bidirectional modulation. Pharmacological blockade of glutamatergic inputs to the lateral SNr disrupted saccadic control and impaired suppression of reflexive saccades, providing causal evidence for the role of excitatory input in behavioral inhibition. These findings suggest that glutamatergic projections, most likely from the subthalamic nucleus, drive the increased SNr activity during action suppression. Our results highlight conserved basal ganglia mechanisms across species and offer insights into the neural substrates of action selection and suppression in primates, with implications for understanding disorders such as Parkinsons disease. Significance StatementUnderstanding how the basal ganglia facilitate desired actions while suppressing unwanted ones is fundamental to neuroscience. This study shows that neurons in the primate substantia nigra pars reticulata (SNr) bidirectionally modulate activity to control action, decreasing firing rates to facilitate movements and increasing rates to suppress them. Importantly, we provide causal evidence that glutamatergic inputs to the lateral SNr mediate action suppression. These findings reveal a conserved mechanism of action control in primates and highlight the role of excitatory inputs in behavioral inhibition. This advances our understanding of basal ganglia function and has significant implications for treating movement disorders like Parkinsons disease.

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bioRxiv2024

Periaqueductal gray passes over disappointment and signals continuity of remaining reward expectancy

Disappointment is a vital factor in the learning and adjustment of strategies in reward-seeking behaviors. It helps them conserve energy in environments where rewards are scarce, while also increasing their chances of maximizing rewards by prompting them to escape to environments where richer rewards are anticipated (e.g., migration). However, another key factor in obtaining the reward is the ability to monitor the remaining possibilities of obtaining the outcome and to tolerate the disappointment in order to continue with subsequent actions. The periaqueductal gray (PAG) has been reported as one of the key brain regions in regulating negative emotions and escape behaviors in animals. The present study suggests that the PAG could also play a critical role in inhibiting escape behaviors and facilitating ongoing motivated behaviors to overcome disappointing events. We found that PAG activity is tonically suppressed by reward expectancy as animals engage in a task to acquire a reward outcome. This tonic suppression of PAG activity was sustained during a series of sequential task procedures as long as the expectancy of reward outcomes persisted. Notably, the tonic suppression of PAG activity showed a significant correlation with the persistence of animals reward-seeking behavior while overcoming intermittent disappointing events. This finding highlights that the balance between distinct tonic signaling in the PAG, which signals remaining reward expectancy, and phasic signaling in the LHb, which signals disappointment, could play a crucial role in determining whether animals continue or discontinue reward-seeking behaviors when they encounter an unexpected negative event. This mechanism would be essential for animals to efficiently navigate complex environments with various reward volatilities and ultimately contributes to maximizing their reward acquisition.

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bioRxiv2024

Formation of brain-wide neural geometry during visual item recognition in monkeys

Neural dynamics assumes to reflect computations that relay and transform information in the brain. Previous studies have identified the neural population dynamics in many individual brain regions as a trajectory geometry, preserving a manifest of computational motifs. However, whether these populations share particular geometric patterns across brain-wide neural populations remains unclear. Here, by mapping neural dynamics widely across temporal/frontal/limbic regions in the cortical and subcortical structures of monkeys, we show that 10 neural populations, including 2,500 neurons, propagate visual item information in a stochastic manner. We found that visual inputs predominantly evoked rotational dynamics in the higher-order visual area, TE and its downstream striatum tail, while curvy/straight dynamics appeared frequently downstream in the orbitofrontal/hippocampal network. These geometric changes were not deterministic but rather stochastic according to their respective emergence rates. Our meta-analysis results indicated that visual information propagates as a heterogeneous mixture of stochastic neural population signals in the brain.

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bioRxiv2024

Involvement of neurons in the non-human primate anterior striatum in proactive inhibition

Behaving as desired requires selecting the appropriate behavior and inhibiting the selection of inappropriate behavior. This inhibitory function involves multiple processes, such as reactive and proactive inhibition, instead of a single process. In this study, macaque monkeys were required to perform a task in which they had to sequentially select (accept) or refuse (reject) a choice. Neural activity was recorded from the anterior striatum, which is considered to be involved in behavioral inhibition, focusing on the distinction between proactive and reactive inhibitions. We identified neurons with significant activity changes during the rejection of bad objects. Cluster analysis revealed three distinct groups, of which one showed obviously increased activity during object rejection, suggesting its involvement in proactive inhibition. This activity pattern was consistent irrespective of the rejection method, indicating a role beyond mere saccadic suppression. Furthermore, minimal activity changes during the fixation task indicated that these neurons were not primarily involved in reactive inhibition. In conclusion, these findings suggest that the anterior striatum plays a crucial role in cognitive control and orchestrates goal-directed behavior through proactive inhibition, which may be critical in understanding the mechanisms of behavioral inhibition dysfunction that occur in patients with basal ganglia disease.

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bioRxiv2023

Prefrontal cortex signals value category while basal ganglia represent learned values in value learning

Value learning can be variable for objects with the exact same reward but the underlying neural mechanism for such variability is not known. We have addressed this question by recording single-unit activity in the prefrontal cortex (PFC) and substantia nigra reticulata (SNr), two key nodes in cortex-basal ganglia circuitry with crucial roles in value learning, as macaque monkeys learned to associate novel objects with either high or low rewards. Estimating the trial by trial learned values based on choice performance, revealed stark differences between learned values across objects with the same reward outcome. Importantly, while PFC neurons rapidly learned to differentiate objects based on their value category, the firing in SNr correlated with the variability in learned values within a value category. Our results suggest that the variation in objects learned values is more likely to be a readout of SNr firing while PFC may provide a top-down teaching signal to basal ganglia to demarcate the value categories.

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bioRxiv2023

Opposing functions of glutamatergic inputs between the globus pallidus external segment and substantia nigra pars reticulata

The indirect pathway of the basal ganglia, including the subthalamic nucleus (STN) and globus pallidus external segment (GPe), is believed to play a crucial role in suppressing involuntary movements. However, recent evidence suggests the STN and GPe also facilitate voluntary movements. This study hypothesized that excitatory inputs from the STN to the GPe contribute to this facilitation, and that excitatory projections to the substantia nigra pars reticulata (SNr) are involved in the inhibition. To disrupt the STN-GPe or STN-SNr projections in monkeys during choice and fixation tasks, glutamate receptor inhibitors were injected into the GPe or SNr, which induced delayed saccade latencies toward good choices in the choice task (GPe) and caused frequent reflexive saccades to objects in the fixation task (SNr). Our findings suggest excitatory inputs to the GPe and SNr work in opposing manners, providing new insights that redefine our understanding of the functions of basal ganglia pathways. HighlightsO_LISTN and GPe neuronal activity increased when good objects were chosen C_LIO_LISNr activity increased when rejecting bad objects and decreased when accepting good objects C_LIO_LIExcitatory inputs inactivation in the GPe caused delayed saccade to good objects C_LIO_LIExcitatory projection inhibition to the SNr suppressed involuntary saccade control C_LI

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bioRxiv2022

Primate dopamine neurons activated in rewarding environment by tonic disinhibition from amygdala

Seeking out good and avoiding bad objects is critical for survival. In practice, objects are rarely good every time or everywhere, but only at the right time or place. Whereas the basal ganglia (BG) are known to mediate goal-directed behavior, for example, saccades to rewarding objects, it remains unclear how such simple behaviors are rendered contingent on higher-order factors, including environmental context. Here we show that amygdala neurons are sensitive to environments and regulate dopamine (DA) neurons via an inhibitory projection to substantia nigra pars reticulata (SNr) neurons. We combined optogenetics and multi-channel recording to demonstrate that rewarding environments induce tonic firing changes in DA neurons. These tonic responses are mediated by disinhibition via GABAergic projection onto DA neurons from SNr, which in turn are suppressed by inhibitory projection from the amygdala. Thus, the amygdala provides an additional source of learning to BG circuits, namely contingencies imposed by the environment.

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bioRxiv2021

Visualization of subcortical structures in non-human primates in vivo by Quantitative Susceptibility Mapping at 3T MRI

Magnetic resonance imaging (MRI) is now an essential tool in the field of neuroscience involving non-human primates (NHP). Structural MRI scanning using T1-weighted (T1w) or T2-weighted (T2w) images provides anatomical information, particularly for experiments involving deep structures such as the basal ganglia and cerebellum. However, for certain subcortical structures, T1w and T2w images fail to reveal important anatomical details. To better visualize such structures in the macaque brain, we applied a relatively new method called quantitative susceptibility mapping (QSM), which enhances tissue contrast based on the local tissue magnetic susceptibility. To evaluate the visualization of important structures, we quantified the the contrast-to-noise ratios (CNRs) of the ventral pallidum (VP), globus pallidus external and internal segments (GPe and GPi), substantia nigra (SN), subthalamic nucleus (STN) in the basal ganglia and the dentate nucleus (DN) in the cerebellum. For these structures, the QSM method significantly increased the CNR, and thus the visibility, beyond that in either the T1w or T2w images. In addition, QSM values of some structures were correlated to the age of the macaque subjects. These results indicate that the QSM method can enable the clear identification of certain subcortical structures that are invisible in more traditional scanning sequences. HighlightsO_LINHP subcortical structures are challenging to see in conventional T1w and T2w images C_LIO_LIWe applied quantitative susceptibility mapping (QSM) to identify them easily C_LIO_LIQSM clearly visualized basal ganglia and cerebellar nucleus of high brain iron content C_LIO_LICNRs of some subcortical nucleus were significantly higher in QSM C_LIO_LIQSM values of several subcortical nucleus increased with age C_LI

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bioRxiv2019

Object novelty and value coding segregate across functionally connected brain networks

Novel and valuable objects are motivationally attractive for animals including primates. However, little is known about how novelty and value processing is organized across the brain. We used fMRI in macaques to map brain activity to fractal patterns varying in either novelty or value dimensions in the context of functionally connected brain networks determined at rest. Results show unique combinations of novelty and value coding across the brain networks. Networks in the ventral temporal cortex and in the parietal cortex showed preferential coding of novelty and value dimensions, respectively, while a wider network composed of temporal and prefrontal areas (TP network), along with functionally connected portions of the striatum, amygdala, and claustrum, responded to both dimensions with similar activation dynamics. Our results support emergence of a common currency signal in the TP network that may underlie the common attitudes toward novel and valuable objects.

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bioRxiv2019

Amygdala controls saccade and gaze physically, motivationally, and socially

The amygdala is uniquely sensitive to emotional events. However, it is not understood whether and how the amygdala uses such emotional signals to control behavior, especially eye movements. We therefore injected muscimol (GABAA agonist) into the central nucleus of amygdala (CeA) in monkeys. This unilateral temporary inactivation suppressed saccades to contralateral but not ipsilateral targets, resulting in longer latencies, hypometric amplitudes, and slower velocity. During free viewing of movies, gaze was distributed mostly in the ipsilateral hemifield. Moreover, CeA inactivation disrupted the tendency of gaze toward social interaction images, which were normally focused on continuously. Conversely, optogenetic stimulation of CeA facilitated saccades to the contralateral side. These findings suggest that CeA controls spatially selective gaze and attention in emotional contexts, and provide a new framework for understanding psychiatric disorders related to amygdala dysfunction.\n\nHighlightsO_LICentral amygdala facilitates contralateral saccades selectively.\nC_LIO_LISaccade facilitation is related to motivational goals and social interaction.\nC_LIO_LIThe amygdala thus controls goal-directed behavior based on emotional contexts.\nC_LI

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bioRxiv2019

Indirect pathway of caudate tail for choosing good objects in periphery

Choosing good objects is essential for real life, which is controlled mainly by the basal ganglia. For that, a subject need to not only find good objects, but reject bad objects. To reveal this rejection mechanism, we created a sequential saccade choice task for monkeys and studied the indirect pathway of caudate tail mediated by cvGPe (caudal-ventral globus pallidus externus). The inhibitory responses of cvGPe neurons to bad objects were smaller when the monkey made saccades to them by mistake. Moreover, experimental reduction of the inhibitory response by local injection of bicuculline (GABAA antagonist) disabled the monkey to reject bad objects. In conclusion, rejecting bad objects is crucial for goal-directed behavior, which is controlled by the indirect pathway in the basal ganglia.

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