Biology subjects

Bostan, A. C.

Publications and source records attributed to Bostan, A. C..

6 recordsLinked to original sources

bioRxiv2025

Incentive valence differentially engages open- and closed-loop basal ganglia circuits during movement initiation

Incentives modulate voluntary movement, yet the circuitry channeling these signals into motor output remains unclear. Classical models emphasize a closed-loop circuit (CLC) linking dorsal putamen (PUTd) with motor cortex, but this pathway is anatomically segregated from affective processing regions. Anatomical and clinical evidence point to an alternative: an open-loop circuit (OLC) from ventral putamen (PUTv) that may route affective signals to motor cortex. Here, we conducted two experiments to test whether a functional OLC exists in humans and whether it is differentially engaged by incentive conditions. First, in 7 T resting-state fMRI (multi-echo), PUTv showed robust functional connectivity with both affective and motor regions, including the cingulate motor area (CMA), even after accounting for PUTd variance. This connectivity pattern supports the plausibility of an independent pathway linking affective basal ganglia regions to the motor cortex. Second, in 3 T task fMRI (incentivized reaching), jackpot (high-reward) and robber (high-loss avoidance) incentive conditions produced distinct behavioral and neural signatures. Jackpot produced a speed-accuracy trade-off, with faster movement initiation but more false starts. Neurally, this coincided with engagement (BOLD responses relevant for initiation speed) being reduced in CLC nodes but not in OLC. Robber, in contrast, eliminated engagement in both OLC and CLC nodes, instead recruiting stopping-related regions (e.g., STN), consistent with an avoidance phenomenology. Together, these findings support a versatile architecture for movement initiation that flexibly engages distinct cortico-subcortical circuits depending on incentive phenomenology, and offer a candidate mechanism through which affective salience and valence modulate voluntary movement. Significance StatementAffective signals profoundly influence movement, yet the mechanisms linking motivationally relevant contexts with motor behavior remain unclear. Combining ultra-high field (7 T) connectomics with task-based (3 T) neuroimaging, we provide the first systems-level evidence in humans for such a mechanism: a ventral putamen-centered open-loop circuit (OLC) connecting affective and motor areas, operating alongside the canonical dorsal putamen-centered closed-loop sensorimotor circuit (CLC). Critically, the phenomenological quality of incentive (how it is construed as reward versus threat) rather than magnitude alone, likely determines which circuit dominates during movement initiation. These findings help to explain paradoxical kinesia in Parkinsons disease, where affective contexts can bypass degraded sensorimotor circuits, and establish foundations for context-based therapeutic interventions.

neuroscience↗

bioRxiv2025

A Multimodal Atlas Reveals the Anatomical Distribution of Medium Spiny Neuron Subtypes and a Novel RGS6+ Population in the Primate Striatum

The primate striatum and its principal neuron type, the medium spiny neuron (MSN), integrate cortical and subcortical signals related to movement, cognition, and emotion. These signals are processed through cell type specific circuits traditionally defined by MSN dopamine receptor expression. However, classification by dopamine receptor type alone fails to fully specify MSN diversity and falls short of capturing the functional complexity of the striatum. Here, we combined single-nucleus multi-omic sequencing and high-plex spatial transcriptomics to build a comprehensive atlas of MSNs in the macaque striatum. Using multi-omic sequencing, we profiled MSNs across four anatomically and functionally defined territories, and we mapped these subtypes back into their anatomical context by integrating the multi-omic data with [~]5.4 million spatially resolved cells sampled across the full rostral-caudal and dorsal-ventral extent of the striatum. This approach revealed two previously undocumented ventral striatum (VS) subtypes, D1-VS-RGS6 and D2-VS-RGS6, which are molecularly distinct from known ventral striatal MSNs yet share core limbic features. We also uncovered gradients in matrix-compartment cell types along the rostral-caudal axis. Finally, by integrating MSN subtype-specific transcriptomes and ATAC-seq-derived regulatory annotations with human GWAS data, we demonstrate strong, cell-type-specific enrichment of polygenic risk for Parkinsons disease, substance use disorders, and psychiatric and cognitive traits, including a striking association of D2-VS-RGS6 with schizophrenia and bipolar disorder. Together, this multimodal atlas provides a foundation for linking primate striatal cell types to circuit function and disease mechanisms. HIGHTLIGHTSO_LIMultimodal analysis of NHP striatum reveals heterogeneous cell type distribution C_LIO_LITwo previously uncharacterized MSN subtypes in the ventral striatum express RGS6 C_LIO_LIVentral striatum cell types exhibit similar characteristics across the Rostro-Caudal axis C_LIO_LINHP cell types show strong, cell type specific associations to genomic disease predictors C_LI

neuroscience↗

bioRxiv2024

Cell Type Specific Enhancers for Dorsolateral Prefrontal Cortex.

The dorsolateral prefrontal cortex (DLPFC) is crucial to primate cognitive functions, but a paucity of cell type specific tools limits studies of DLPFC neurocomputational principles. Therefore, we set out to identify enhancers that fit inside Adeno-Associated Virus (AAV) vectors and that elicited functional, cell type specific gene expression in the non-human primate (NHP) DLPFC. We used single nucleus RNA-Seq and ATAC-Seq from rhesus macaque tissue samples to define DLPFC cell types and their associated open chromatin regions (OCRs). We trained machine learning (ML) models to recognize the unique regulatory grammar associated with each DLPFC neuron type, performed in silico screening of all OCRs, and identified candidate enhancers most likely to elicit cell type specific transgene expression in each neuron type. For layer 3 pyramidal neurons (L3PNs) and layer 5 extratelencephalic neurons (L5ETs), we cloned the top twelve identified candidates into AAVs and injected them into NHP DLPFC. In situ observation of enhancer-driven expression revealed the best performers, RMacL3-01 and RMacL5ET-01. We validated RMacL3-01 and RMacL5ET-01 using one-at-a-time injections in NHP DLPFC. RMacL3-01 restricted GFP expression to pyramidal neurons in layers 2 and 3, whereas RMacL5ET-01 restricted expression to POU3F1+ neurons in layer 5. RMacL3-01 elicited functional levels of channelrhodopsin expression that enabled optical activation of single- and multi-unit activity in NHP DLFPC. Together, these results and resources establish a solid foundation to study cell type specific principles of primate cognitive functions.

neuroscience↗

bioRxiv2024

Movement-related activity in the internal globus pallidus of the parkinsonian macaque

Although the basal ganglia (BG) plays a central role in the motor symptoms of Parkinsons disease, few studies have investigated the influence of parkinsonism on movement-related activity in the BG. Here, we studied the perimovement activity of neurons in globus pallidus internus (GPi) of non-human primates during performance of a choice reaction time reaching task before and after the induction of parkinsonism by administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Neuronal responses, including increases or decreases in firing rate, were equally common in the parkinsonian brain as seen prior to MPTP and the distribution of different response types was largely unchanged. The slowing of behavioral reaction times and movement durations following the induction of parkinsonism was accompanied by a prolongation of the time interval between neuronal response onset and movement initiation. Neuronal responses were also reduced in magnitude and prolonged in duration after the induction of parkinsonism. Importantly, those two effects were more pronounced among decrease-type responses, and they persisted after controlling for MPTP-induced changes in the between-trial variability in response timing. Following MPTP the trial-to-trial timing of neuronal responses also became uncoupled from the time of movement onset and more variable in general. Overall, the effects of MPTP on temporal features of GPi responses were related to the severity of parkinsonian motor impairments whereas changes in response magnitude and duration did not reflect symptom severity consistently. These findings point to a previously underappreciated potential role for abnormalities in the timing of GPi task-related activity in the generation of parkinsonian motor signs. New & NoteworthyAlthough the globus pallidus internus (GPi) plays a central role in the cardinal symptoms of Parkinsons disease (PD), how parkinsonism alters the movement-related activity of GPi neurons remains understudied. Using a monkey model of PD, we found that: 1) the timing of GPi responses became uncoupled from movement onset. And 2) responses, especially decrease-type responses, became attenuated and prolonged. These abnormalities in GPi perimovement activity may contribute to the generation of parkinsonian motor signs.

neuroscience↗

bioRxiv2024

Dissociation of novel open loop from ventral putamen to motor areas from classic closed loop in humans II: task-based function

Humans ubiquitously increase the speed of their movements when motivated by incentives (i.e., capturing reward or avoiding loss). The complex interplay between incentivization and motor output is pertinent for unpacking the functional profiles of different circuits that link the basal ganglia with motor cortical areas. Here, we analyzed the functional profile of nodes forming two circuits involving putamen and motor cortical areas: the traditional "closed-loop circuit" (CLC) from sensorimotor dorsal putamen (PUTd) and a putative "open-loop circuit" (OLC) from ventral putamen (PUTv). Establishing differential function between CLC and OLC is particularly relevant for therapeutic approaches to Parkinsons disease, where OLC function is hypothesized to be relatively spared by the disease process. In a large sample fMRI study, 68 healthy controls executed speeded reaches with a joystick under different levels of incentivization to accurately hit precision targets. We dissociated effects of "incentive per se" (i.e., changes in brain activity when an upcoming movement obtains a reward or avoids a loss) from "RT effects" (i.e., brain activity that directly scales with adjustments to movement initiation time). Incentive per se was observed across sites in both CLC and OLC. However, RT effects were primarily in nodes of the OLC and motor sites, consistent with the hypothesized anatomy and function of OLC. Our findings additionally suggest valence might mediate when incentives recruit OLC to more prominent control of motor behavior.

neuroscience↗

bioRxiv2024

An open-source MRI compatible frame for multimodal presurgical mapping in macaque and capuchin monkeys

HighlightsO_LIWe present a compact MRI-compatible stereotaxic frame for large nonhuman primates. C_LIO_LIThe design is 3D printable, inexpensive, and matches size of an adult human head. C_LIO_LIEnabled real-time, accurate, MRI-guided deep-brain viral vector injection. C_LIO_LIFacilitated multimodal alignment for deep-brain electrophysiology planning. C_LIO_LIAll computer-aided-design files are modularized and publicly available and editable. C_LI BackgroundHigh-precision neurosurgical targeting in nonhuman primates (NHPs) often requires presurgical anatomy mapping with noninvasive neuroimaging techniques (MRI, CT, PET), allowing for translation of individual anatomical coordinates to surgical stereotaxic apparatus. Given the varied tissue contrasts that these imaging techniques produce, precise alignment of imaging-based coordinates to surgical apparatus can be cumbersome. MRI-compatible stereotaxis with radiopaque fiducial markers offer a straight-forward and reliable solution, but existing commercial options do not fit in conformal head coils that maximize imaging quality. New methodWe developed a compact MRI-compatible stereotaxis suitable for a variety of NHP species (Macaca mulatta, Macaca fascicularis, and Cebus apella) that allows multimodal alignment through technique-specific fiducial markers. Comparison with existing methodsWith the express purpose of compatibility with clinically available MRI, CT, and PET systems, the frame is no larger than a human head, while allowing for imaging NHPs in the supinated position. This design requires no marker implantation, special software, or additional knowledge other than the operation of a common large animal stereotaxis. ResultsWe demonstrated the applicability of this 3D-printable apparatus across a diverse set of experiments requiring presurgical planning: 1) We demonstrate the accuracy of the fiducial system through a within-MRI cannula insertion and subcortical injection of viral vectors. 2) We also demonstrated accuracy of multimodal (MRI and CT) alignment and coordinate transfer to guide a surgical robot electrode implantation for deep-brain electrophysiology. ConclusionsThe computer-aided design files and engineering drawings are publicly available, with the modular design allowing for low cost and manageable manufacturing.

bioengineering↗