Biology subjects

Waugh, J. L.

Publications and source records attributed to Waugh, J. L..

6 recordsLinked to original sources

bioRxiv2026

Hippocampal Projections to the Striatal Compartments, Striosome and Matrix, are Spatially Segregated in CA1

The hippocampus routes information to the striatum through at least four polysynaptic circuits. Striatal projection neurons are organized into two tissue compartments, the matrix and striosome, which differ in their embryologic origins, relative abundance, intra-striate location, and afferent and efferent connectivity. These compartments are embedded in distinct functional networks and are activated by different tasks. Consequently, hippocampal inputs that route preferentially through the striosome may underpin different functions and engage with different remote networks than inputs that route through the matrix. It was unknown whether striosome-bound and matrix-bound projections from the hippocampus followed different polysynaptic circuits. We assessed hippocampo-striate projections in living humans using probabilistic diffusion tractography by first parcellating the striatum into voxels with striosome-like and matrix-like structural connectivity. We then quantified structural connectivity between hippocampal efferents (CA1) to each set of compartment-like voxels. CA1 projections to striosome-like voxels in the dorsal striatum (caudate and putamen) were 3.1-fold more abundant than those to matrix-like voxels, particularly in caudo-lateral CA1. This striosome-favoring bias was similar in three segregated hippocampo-striate circuits, in streamlines routing through the subiculum, lateral septum, or medial prefrontal cortex. However, a small region in rostro-medial CA1 preferentially targeted matrix-like voxels. Functional connectivity between CA1 and compartment-like voxels matched this segregated pattern: CA1 activation was correlated with striosome-like voxels but anti-correlated with matrix-like voxels. Additionally, streamlines from CA1 to nucleus accumbens exhibited hemispheric asymmetries, with the left hemisphere biased towards matrix and the right towards striosome. These findings suggest that hippocampo-striate projections are spatially segregated into compartment-specific circuits.

neuroscience↗

bioRxiv2026

Dissociation of Striosome and Matrix Activation in the Human Striatum During the Cue and Execution Phases of Working Memory

The striatum comprises two neurochemically and anatomically distinct tissue compartments, the striosome and matrix, that are hypothesized to support different aspects of cognition and action. In animal studies, the striosome has been linked to reward evaluation, emotional learning, and decision-making under conflict, whereas the matrix is more closely associated with sensorimotor integration and task execution. However, evidence for compartment-specific function in humans is limited and indirect. Using probabilistic tractography, we identified voxels with striosome-like and matrix-like patterns of structural connectivity in healthy adults. We then examined how these compartment-like voxels responded to task demands during an fMRI n-back working-memory paradigm that visually presented four stimulus categories (body part, face, place, or tool). We assessed activation in a low-load condition (0-back, remembering a just-viewed stimulus) vs. a high-load condition (2-back, remembering a stimulus viewed two prior). Functional activation was temporally segregated and matched our prior findings in motor tasks: striosome-like voxels were preferentially engaged during the cue and initial preparation phases, whereas matrix-like voxels dominated during task execution. Trial accuracy strongly modulated striatal activation, with both compartments showing significantly greater responses during "correct" than in "error" trials. Notably, the accuracy-related increase in activation was larger in striosome-like voxels, consistent with a prominent role for striosomal processing in performance evaluation. Both striosome- and matrix-like voxels significantly increased activation from 0-back to 2-back, indicating sensitivity to working-memory load, with larger increases for matrix-like than for striosome-like voxels. Category-selective responses also differed by compartment and cognitive load. Under low working-memory load (0-back), stimulus-category effects were modest and broadly similar between compartments. Under higher load (2-back), activation in striosome-like voxels remained selective for specific stimulus categories, while matrix-like voxels lost category specificity. Together, these findings suggest that the striosome-matrix distinction generalizes from motor to cognitive domains, reflecting a conserved division between preparatory and execution-related processes that varies systematically with task demands, memory category, and performance accuracy. This convergence of compartment-specific responses across domains points to a core organizational principle of the human striatum with potential implications for neuropsychiatric diseases. Key PointsO_LIStriatal medium spiny neurons are organized into two interdigitated compartments, the striosome and matrix, which are embryologically, pharmacologically, and anatomically distinct. Compartment-specific functions have been demonstrated in animals, but their roles in human cognition are unexplored. C_LIO_LIWe found that in humans, striosome-like voxels preferentially activated during memory cues, while matrix-like voxels preferentially activated during recall and memory maintenance. In both compartments, activation scaled with task difficulty. C_LIO_LIActivation in striosome-like voxels scaled more strongly with task accuracy and difficulty, suggesting a striosome-selective role in vigilance and/or motivation. C_LI

neuroscience↗

bioRxiv2025

In Humans, fMRI Reveals That Striosome-like and Matrix-like Striatal Voxels are Engaged in Different Phases of Movement

IntroductionThe striatum is organized into two neurochemically and anatomically distinct compartments, the striosome and matrix, that play specialized roles in motor and cognitive functions. While extensive animal research has elucidated compartment-specific contributions to reward, learning and motor control, direct evidence for compartment specialization in humans is lacking. MethodsWe defined human striatal voxels as striosome-like or matrix-like based on biases in structural (diffusion) connectivity. Then we investigated functional activation patterns in those compartment-like voxels using task-based functional MRI (tfMRI) during pre-movement cue and five motor conditions (left/right hand, left/right foot, and tongue movements). ResultsFunctional activation was strikingly segregated: striosome-like voxels were preferentially engaged during the cue phase, while matrix-like voxels dominated activation during motor execution, especially for tongue and foot movement. Motor tasks elicited robust bilateral activation, with contralateral activation dominating during limb movements. Activation was more lateralized in matrix-like than in striosome-like voxels. Both striosome-like and matrix-like voxels exhibited strong activation at the onset of task execution (e.g., within the first few seconds post-cue). However, activation in matrix-like voxels declined modestly over the course of the movement phase, while striosomal activation dropped sharply at task termination, suggesting a role in behavioral transitions. These findings are consistent with the role of the striosome in anticipatory evaluation and dopaminergic modulation, and matrix specialization for executing automatized routines. ConclusionsThis study provides the first task-based fMRI evidence of temporally and functionally distinct striatal compartment dynamics in humans, offering novel insights into striatal microcircuitry in motivated behavior and the planning and execution of movements. Key PointsO_LIStriatal medium spiny neurons develop in two interdigitated tissue compartments, the striosome and matrix, that are embryologically, pharmacologically, and anatomically distinct. Inter-compartmental differences in function have been identified in animals, but never in humans. C_LIO_LIWe found that in humans, the compartments differed in functional activation during movement tasks: during the task cue, activation was greater in striosome-like voxels, while matrix-like activation was greater during each of five distinct types of movement. C_LIO_LIBoth compartments were active at the beginning of movement, but at the termination of movement striosome-like activation fell to below baseline, suggesting a role for the striosome in behavioral transitions. C_LI

neuroscience↗

bioRxiv2024

The striatal compartments, striosome and matrix, are embedded in largely distinct resting state functional networks

The striatum is divided into two interdigitated tissue compartments, the striosome and matrix. These compartments exhibit distinct anatomical, neurochemical, and pharmacological characteristics and have separable roles in motor and mood functions. Little is known about the functions of these compartments in humans. While compartment-specific roles in neuropsychiatric diseases have been hypothesized, they have yet to be directly tested. Investigating compartment-specific functions is crucial for understanding the symptoms produced by striatal injury, and to elucidating the roles of each compartment in healthy human skills and behaviors. We mapped the functional networks of striosome and matrix in humans in vivo. We utilized a diverse cohort of 674 healthy adults, derived from the Human Connectome Project, including all subjects with complete diffusion and functional MRI data and excluding subjects with substance use disorders. We identified striatal voxels with striosome-like and matrix-like structural connectivity using probabilistic diffusion tractography. We then investigated resting state functional connectivity (rsFC) using these compartment-like voxels as seeds. We found widespread differences in rsFC between striosome-like and matrix-like seeds (p < 0.05, FWE corrected for multiple comparisons), suggesting that striosome and matrix occupy distinct functional networks. Slightly shifting seed voxel locations (<4 mm) eliminated these rsFC differences, underscoring the anatomic precision of these networks. Striosome-seeded networks exhibited ipsilateral dominance; matrix-seeded networks had contralateral dominance. Next, we assessed compartment-specific engagement with the triple-network model (default mode, salience, and frontoparietal networks). Striosome-like voxels dominated rsFC with the default mode network bilaterally. The anterior insula (a primary node in the salience network) had higher rsFC with striosome-like voxels. The inferior and middle frontal cortices (primary nodes, frontoparietal network) had stronger rsFC with matrix-like voxels on the left, and striosome-like voxels on the right. Since striosome-like and matrix-like voxels occupy highly segregated rsFC networks, striosome-selective injury may produce different motor, cognitive, and behavioral symptoms than matrix-selective injury. Moreover, compartment-specific rsFC abnormalities may be identifiable before disease-related structural injuries are evident. Localizing rsFC differences provides an anatomic substrate for understanding how the tissue-level organization of the striatum underpins complex brain networks, and how compartment-specific injury may contribute to the symptoms of specific neuropsychiatric disorders.

neuroscience↗

bioRxiv2024

In humans, insulo-striate structural connectivity is largely biased toward either striosome-like or matrix-like striatal compartments

The insula is an integral component of sensory, motor, limbic, and executive functions, and insular dysfunction is associated with numerous human neuropsychiatric disorders. Insular afferents project widely, but insulo-striate projections are especially numerous. The targets of these insulo-striate projections are organized into tissue compartments, the striosome and matrix. These striatal compartments have distinct embryologic origins, afferent and efferent connectivity, dopamine pharmacology, and susceptibility to injury. Striosome and matrix appear to occupy separate sets of cortico-striato-thalamo-cortical loops, so a bias in insulo-striate projections towards one compartment may also embed an insular subregion in distinct regulatory and functional networks. Compartment-specific mapping of insulo-striate structural connectivity is sparse; the insular subregions are largely unmapped for compartment-specific projections. In 100 healthy adults, we utilized probabilistic diffusion tractography to map and quantify structural connectivity between 19 structurally-defined insular subregions and each striatal compartment. Insulo-striate streamlines that reached striosome-like and matrix-like voxels were concentrated in distinct insular zones (striosome: rostro- and caudoventral; matrix: caudodorsal) and followed different paths to reach the striatum. Though tractography was generated independently in each hemisphere, the spatial distribution and relative bias of striosome-like and matrix-like streamlines were highly similar in the left and right insula. 16 insular subregions were significantly biased towards one compartment: seven toward striosome-like voxels and nine toward matrix-like voxels. Striosome-favoring bundles had significantly higher streamline density, especially from rostroventral insular subregions. The biases in insulo-striate structural connectivity we identified mirrored the compartment-specific biases identified in prior studies that utilized injected tract tracers, cytoarchitecture, or functional MRI. Segregating insulo-striate structural connectivity through either striosome or matrix may be an anatomic substrate for functional specialization among the insular subregions.

neuroscience↗

bioRxiv2017

Molecular map of GNAO1-related disease phenotypes and reactions to treatment

The GNAO1 gene codes for the most commonly expressed G protein in the central nervous system. Pathogenic GNAO1 variants result in early-onset neurological phenotypes, sometimes with distinct epilepsy or movement disorder, and sometimes with both mani-festations in the same patient. The existing extensive knowledge about G-protein coupled receptor (GPCR) signaling provides the input needed to describe quantitatively how mutations modify the GPCR signal. This in turn allows rational interpretation of distinct phenotypes arising from mutations in GNAO1. In this work we outline a model that enables understanding of clinical phenotypes at a molecular level. The mutations affecting the catalytic pocket of GNAO1, we show, result in the improper withdrawal of the signal, and give rise to epileptic phenotypes (EPs). The converse is not true - some pure EPs are caused by mutations with no obvious impact on catalysis. Mutations close to the interface with GNAO1s downstream effector block the signal propagation in that direction, and manifest as a movement disorder phenotype without epilepsy. Quantifying the reported reaction to therapy highlights the tendency of the latter group to be unresponsive to the therapies currently in use. We argue, however, that the majority of clinically described mutations can impact several aspects of GNAO1 function at once, resulting in the continuum of phenotypes observed in patients. The reasoning based on GNAO1 signaling model provides a precision medicine paradigm to aid clinicians in selecting effective categories of medication, and in addition, can suggest pragmatic targets for future therapies.

molecular biology↗