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The cortico–basal ganglia–thalamo–cortical loop is one of the fundamental network motifs in the brain. Revealing its structural and functional organization is critical to understanding cognition, sensorimotor behaviour, and the natural history of many neurological and neuropsychiatric disorders. Classically, this network is conceptualized to contain three information channels: motor, limbic and associative 1 – 4 . Yet this three-channel view cannot explain the myriad functions of the basal ganglia. We previously subdivided the dorsal striatum into 29 functional domains on the basis of the topography of inputs from the entire cortex 5 . Here we map the multi-synaptic output pathways of these striatal domains through the globus pallidus external part (GPe), substantia nigra reticular part (SNr), thalamic nuclei and cortex. Accordingly, we identify 14 SNr and 36 GPe domains and a direct cortico-SNr projection. The striatonigral direct pathway displays a greater convergence of striatal inputs than the more parallel striatopallidal indirect pathway, although direct and indirect pathways originating from the same striatal domain ultimately converge onto the same postsynaptic SNr neurons. Following the SNr outputs, we delineate six domains in the parafascicular and ventromedial thalamic nuclei. Subsequently, we identify six parallel cortico–basal ganglia–thalamic subnetworks that sequentially transduce specific subsets of cortical information through every elemental node of the cortico–basal ganglia–thalamic loop. Thalamic domains relay this output back to the originating corticostriatal neurons of each subnetwork in a bona fide closed loop. Mesoscale connectomic mapping of the cortico–basal ganglia–thalamic network reveals key architectural and information processing features.

Understanding the organization of the hippocampus is fundamental to understanding brain function related to learning, memory, emotions, and diseases such as Alzheimer’s disease. Physiological studies in humans and rodents have suggested that there is both structural and functional heterogeneity along the longitudinal axis of the hippocampus. However, the recent discovery of discrete gene expression domains in the mouse hippocampus has provided the opportunity to re-evaluate hippocampal connectivity. To integrate mouse hippocampal gene expression and connectivity, we mapped the distribution of distinct gene expression patterns in mouse hippocampus and subiculum to create the Hippocampus Gene Expression Atlas (HGEA). Notably, previously unknown subiculum gene expression patterns revealed a hidden laminar organization. Guided by the HGEA, we constructed the most detailed hippocampal connectome available using Mouse Connectome Project (http://www.mouseconnectome.org) tract tracing data. Our results define the hippocampus’ multiscale network organization and elucidate each subnetwork’s unique brain-wide connectivity patterns.

The superior colliculus (SC) receives diverse and robust cortical inputs to drive a range of cognitive and sensorimotor behaviors. However, it remains unclear how descending cortical input arising from higher-order associative areas coordinate with SC sensorimotor networks to influence its outputs. Here, we construct a comprehensive map of all cortico-tectal projections and identify four collicular zones with differential cortical inputs: medial (SC.m), centromedial (SC.cm), centrolateral (SC.cl) and lateral (SC.l). Further, we delineate the distinctive brain-wide input/output organization of each collicular zone, assemble multiple parallel cortico-tecto-thalamic subnetworks, and identify the somatotopic map in the SC that displays distinguishable spatial properties from the somatotopic maps in the neocortex and basal ganglia. Finally, we characterize interactions between those cortico-tecto-thalamic and cortico-basal ganglia-thalamic subnetworks. This study provides a structural basis for understanding how SC is involved in integrating different sensory modalities, translating sensory information to motor command, and coordinating different actions in goal-directed behaviors. The superior colliculus (SC) receives diverse cortical inputs to drive many behaviors. Here, based on comprehensive mapping of cortico-tectal projections, the authors refined the superior colliculus into medial, centromedial, centrolateral, and lateral zones, and characterized the input-output connectivity and morphology of neurons in each zone that serve the role of SC in goal-directed behaviors.

The basolateral amygdalar complex (BLA) is implicated in behaviors ranging from fear acquisition to addiction. Optogenetic methods have enabled the association of circuit-specific functions to uniquely connected BLA cell types. Thus, a systematic and detailed connectivity profile of BLA projection neurons to inform granular, cell type-specific interrogations is warranted. Here, we apply machine-learning based computational and informatics analysis techniques to the results of circuit-tracing experiments to create a foundational, comprehensive BLA connectivity map. The analyses identify three distinct domains within the anterior BLA (BLAa) that house target-specific projection neurons with distinguishable morphological features. We identify brain-wide targets of projection neurons in the three BLAa domains, as well as in the posterior BLA, ventral BLA, posterior basomedial, and lateral amygdalar nuclei. Inputs to each nucleus also are identified via retrograde tracing. The data suggests that connectionally unique, domain-specific BLAa neurons are associated with distinct behavior networks. The basolateral amygdala is implicated in several behavior-related states including anxiety, autism, and addiction. The authors apply circuit-level pathway tracing methods combined with computational techniques to provide a comprehensive connectivity atlas of the mouse basolateral amygdala complex.

Currently, classification of neuron types in the mouse thalamus remains largely incomplete. The anterior thalamic nuclei (ATN), a Papez circuit component, encompass the anterodorsal (AD), anteroventral (AV), and anteromedial (AM) thalamic nuclei. Structurally, the ATN facilitate communication among the neocortex, hippocampus, amygdala, and hypothalamus. Functionally, they play pivotal roles in learning, memory, spatial navigation, and goal-directed behaviors. Therefore, the ATN provide a promising avenue to investigate the relationship between structural and functional complexity with neuron type diversity. In male mice, comprehensive, systematically collected, pathway tracing data revealed several connectionally unique ATN cell populations, suggesting multiple parallel subnetworks run through each nucleus. Further, we applied genetic sparse labeling, brain clearing, 3D microscopic imaging, and computational informatics to morphologically characterize and catalog ATN neuron types. This study provides insights into how the prefrontal cortex, hippocampus, and amygdala interact through neuron type-specific ATN subnetworks to coordinate cognitive and emotional aspects of goal-directed behavior. Neural networks fundamentally dictate function. Here, the authors show thirteen uniquely connected neuron populations within the anterior thalamic nuclei, suggesting multiple parallel subnetworks support its emotional and cognitive functions.

An essential step toward understanding brain function is to establish a structural framework with cellular resolution on which multi-scale datasets spanning molecules, cells, circuits and systems can be integrated and interpreted 1 . Here, as part of the collaborative Brain Initiative Cell Census Network (BICCN), we derive a comprehensive cell type-based anatomical description of one exemplar brain structure, the mouse primary motor cortex, upper limb area (MOp-ul). Using genetic and viral labelling, barcoded anatomy resolved by sequencing, single-neuron reconstruction, whole-brain imaging and cloud-based neuroinformatics tools, we delineated the MOp-ul in 3D and refined its sublaminar organization. We defined around two dozen projection neuron types in the MOp-ul and derived an input–output wiring diagram, which will facilitate future analyses of motor control circuitry across molecular, cellular and system levels. This work provides a roadmap towards a comprehensive cellular-resolution description of mammalian brain architecture. Multi-modal analysis is used to generate a 3D atlas of the upper limb area of the mouse primary motor cortex, providing a framework for future studies of motor control circuitry.

Purpose Total and reverse total shoulder arthroplasty (TSA) are used to treat patients with glenohumeral joint osteoarthritis. The revision rate remains high compared with hip and knee arthroplasty. Glenoid component loosening is an important complication and may be caused by poor positioning of the component. We aimed to evaluate the safety and accuracy of a custom glenoid jig created using preoperative computed tomography (CT) imaging with 3D modelling for glenoid component implantation. Methods Preoperative CT scans of each shoulder ( N  = 7) were obtained. Implants were virtually aligned and custom templates were created for intraoperative use. A two-part custom jig was manufactured for alignment of the central peg and the peripheral screws. Three-dimensional orientation of the component and screws was evaluated in postoperative CT scans. The difference between the preoperative plan and the result was then calculated. Results No technical difficulties or complications occurred. The mean absolute difference between the planned alignment and the postoperative placement of the glenoid component in the three-dimensional space was 3.4 mm (SD = 1 mm). The total average difference for all screws ( N  = 10) was 6.3° (SD = 3.2°). Conclusion A CT-based custom glenoid component alignment can reliably guide the placement of the glenoid component during conventional and reverse TSA. This custom jig may be useful for optimizing glenoid component position in the setting of reverse and TSA. Level of evidence IV.

The superior colliculus (SC) is a midbrain structure that receives diverse and robust cortical inputs to drive a range of cognitive and sensorimotor behaviors. However, it remains unclear how descending cortical inputs arising from higher-order associative areas coordinate with SC sensorimotor networks to influence its outputs. In this study, we constructed a comprehensive map of all cortico-tectal projections and identified four collicular zones with differential cortical inputs: medial (SC.m), centromedial (SC.cm), centrolateral (SC.cl) and lateral (SC.l). Computational analyses revealed that cortico-tectal projections are organized as multiple subnetworks that are consistent with previously identified cortico-cortical and cortico-striatal subnetworks. Furthermore, we delineated the brain-wide input/output organization of each collicular zone and described a subset of their constituent neuronal cell types based on distinct connectional and morphological features. Altogether, this work provides a novel structural foundation for the integrative role of the SC in controlling cognition, orientation, and other sensorimotor behaviors.

ABSTRACT The cortico-basal ganglia-thalamic loop is one of the fundamental network motifs in the brain. Revealing its structural and functional organization is critical to understanding cognition, sensorimotor behavior, and the natural history of many neurological and neuropsychiatric diseases. Classically, the basal ganglia is conceptualized to contain three primary information output channels: motor, limbic, and associative. However, given the roughly 65 cortical areas and two dozen thalamic nuclei that feed into the dorsal striatum, a three-channel view is overly simplistic for explaining the myriad functions of the basal ganglia. Recent works from our lab and others have subdivided the dorsal striatum into numerous functional domains based on convergent and divergent inputs from the cortex and thalamus. To complete this work, we generated a comprehensive data pool of ∼700 injections placed across the striatum, external globus pallidus (GPe), substantia nigra pars reticulata (SNr), thalamic nuclei, and cortex. We identify 14 domains of SNr, 36 in the GPe, and 6 in the parafascicular and ventromedial thalamic nuclei. Subsequently, we identify 6 parallel cortico-basal ganglia-thalamic subnetworks that sequentially transduce specific subsets of cortical information with complex patterns of convergence and divergence through every elemental node of the entire cortico-basal ganglia loop. These experiments reveal multiple important novel features of the cortico-basal ganglia network motif. The prototypical sub-network structure is characterized by a highly interconnected nature, with cortical information processing through one or more striatal nodes, which send a convergent output to the SNr and a more parallelized output to the GPe; the GPe output then converges with the SNr. A domain of the thalamus receives the nigral output, and is interconnected with both the striatal domains and the cortical areas that filter into its nigral input source. This study provides conceptual advancement of our understanding of the structural and functional organization of the classic cortico-basal ganglia network. Competing Interest Statement The authors have declared no competing interest.

The basolateral amygdalar complex (BLA) is implicated in behavioral processing ranging from fear acquisition to addiction. Newer methods like optogenetics have enabled the association of circuit-specific functionality to uniquely connected BLA cell types. Thus, a systematic and detailed connectivity profile of BLA projection neurons to inform granular, cell type-specific interrogations is warranted. In this work, we applied computational analysis techniques to the results of our circuit-tracing experiments to create a foundational, comprehensive, multiscale connectivity atlas of the mouse BLA. The analyses identified three domains within the classically defined anterior BLA (BLAa) that house target-specific projection neurons with distinguishable cell body and dendritic morphologies. Further, we identify brain-wide targets of projection neurons located in the three BLAa domains as well as in the posterior BLA (BLAp), ventral BLA (BLAv), lateral (LA), and posterior basomedial (BMAp) nuclei. Projection neurons that provide input to each nucleus are also identifed. Functional characterization of some projection-defined BLA neurons were demonstrated via optogenetic and recording experiments. Hypotheses relating function to connection-defined BLA cell types are proposed.