Frontiers in Neural Circuits最新文献

The cerebellar output can trigger whisker movement through indirect projections that pass via several brainstem pre-motor nuclei before reaching the facial nucleus, which directly controls whisker movements in rodents. Although the central pattern generator function of the intermediate reticular formation has been recently clarified, the roles of the other whisker pre-motor nuclei remain unclear. Here, we set out to compare the whisker movement kinematics of the main pre-motor whisker nuclei connecting the cerebellum and the facial nucleus. We optogenetically stimulated neurons located in the cerebellar cortex: Purkinje cells (PCs), the cerebellar nuclei (CN), the red nucleus (RN), the superior colliculus (SC), the spinal trigeminal nucleus (SV), and the reticular formation (RF); in head-fixed awake mice while monitoring the bilateral whisker movement. We show that optogenetic stimulation of the RN, SC, and SV resulted in a predominant midpoint change, whereas optogenetic stimulation of the PCs, CN, and RF resulted in faster whisker movements. In addition, the excitation of PCs, the RN, and SC resulted in symmetric bilateral whisking. In contrast, the excitation of the RF, and SV resulted in initial asymmetric movement, followed by a more dominantly symmetrical bilateral whisking. Importantly, PC excitation generated a robust rhythmic whisking pattern that could not be reproduced by direct CN stimulation, indicating that the cerebellar cortex sculpts CN population output rather than simply gating it. Our results suggest that cerebellar output engages multiple, specialized pre-motor pathways through a divergent-convergent architecture. This system allows different pre-motor nuclei to modulate distinct aspects of whisking kinematics, ultimately shaping whisker motor dynamics.

Brain pericytes play essential roles in vascular homeostasis, including capillary stabilization and maintenance of the blood-brain barrier. Lipopolysaccharide (LPS), a component of the outer membrane of Gram-negative bacteria, is known to trigger inflammatory responses not only systemically but also within the central nervous system. In this study, we investigated the effects of LPS on the phenotype and transcriptome of brain vascular pericytes. LPS promoted bromodeoxyuridine incorporation in the primary culture of human brain pericytes as well as increased the number of Ki67-positive cells, indicating enhanced pericyte proliferation. Morphological analysis revealed that LPS decreased the cellular aspect ratio, suggesting altered cellular elongation. Transcriptomic profiling showed that LPS-induced differentially expressed genes were enriched for terms related to cell proliferation, angiogenesis, and blood-brain barrier function. Because pericytes critically regulate neurovascular coupling and metabolic support for active neurons, these LPS-induced alterations may ultimately perturb the microvascular control of neural circuits. These results suggest that LPS has the potential to regulate brain vascular function by inducing morphological and functional changes in pericytes.

Introduction: Sparse and bright labeling of retinal ganglion cell (RGC) is essential for correlating single-cell morphology with brain-wide visual circuitry. This study aimed to develop a cell-type-specific, sparse labeling strategy for parvalbumin-expressing RGCs (PV⁺ RGCs) in the transgenic mouse retina using recombinant adeno-associated virus (rAAV) and to map the whole-brain projection patterns of single PV⁺ RGCs via fluorescence micro-optical sectioning tomography (fMOST).

Methods: A cell-type-specific dual AAV system was employed, co-packaging a Cre-dependent Flpo plasmid and an Flpo-dependent enhanced yellow fluorescent protein (EYFP) plasmid. Key parameters-including the mixing ratio of core plasmids (ranging from 1/100 to 1/1000), gene copy number of Flpo and EYFP (single versus double), and AAV serotype (AAV2.2 versus engineered AAV2.NN)-were systematically optimized. Transduction efficiency and labeling sparsity under each condition were compared. Whole-retina-to-brain imaging was performed using fMOST on samples injected with the optimal condition (AAV2.2-double-1/1000), enabling the reconstruction of complete axonal trajectories of individual PV⁺ RGCs from the retina to the brain.

Results: The sparsity and signal intensity of labeled RGCs varied significantly with the core plasmid ratio, AAV serotype, and gene copy number. The engineered AAV2.NN serotype increased transduction efficiency and labeling density under equivalent conditions, which facilitated the morphological subclassification of PV⁺ RGCs into ON, ON-OFF, and OFF types based on their stratification relative to ChAT bands. Axonal projections of single PV⁺ RGCs were successfully traced to the superior colliculus (SC), dorsal and ventral lateral geniculate nuclei (dLGN/vLGN).

Discussion: This viral labeling platform effectively resolves the classical trade-off between sparsity and signal intensity, providing a robust methodology for whole-brain mapping of individual RGC projections. The approach establishes a practical foundation for future mechanistic and therapeutic studies investigating subtype-selective vulnerability in RGCs.

The subiculum is a critical node of the hippocampal formation, integrating multiple circuits-including thalamic inputs and afferents from CA1 and medial entorhinal cortex-and projecting broadly to cortical and subcortical targets. Yet its contribution to spatial coding remains incompletely understood. We recorded single-unit activity in freely moving mice using two complementary electrophysiological approaches: (i) chronic tetrodes targeting CA1 and the dorsal subiculum (SUB), and (ii) 64-channel linear silicon probes targeting dorsal SUB. In addition to place cells, boundary-vector cells (BVCs) and corner cells (CCs), we identified a subset of subicular neurons that exhibited spatially periodic, grid-like firing patterns. This phenomenon was replicated across recording technologies, indicating that periodic coding is a consistent feature of the mouse subiculum. Compared with CA1 place cells, SUB spatial neurons exhibited lower spatial information and reduced within-session stability, suggesting distinct coding regimes across hippocampal subregions. Sampling along the proximodistal axis with probe arrays further revealed that burst propensity correlated positively with spatial information at more distal recording sites, consistent with known physiological gradients in subiculum and echoing relationships seen in CA1. Together, these results expand the repertoire of identified spatial codes in SUB and support the view in which subiculum contributes to geometry- and periodicity-based representations that complement CA1 and entorhinal spatial coding, thereby shaping downstream computations in cortico-subcortical circuits.

Introduction: Prader-Willi syndrome (PWS) results from a lack of expression in several paternally inherited, imprinted contiguous genes. Among the genes inactivated in PWS, the Magel2 gene is considered a significant contributor to the etiology of the syndrome. The loss of the Magel2 gene causes abnormalities in growth and fertility and increased adiposity with altered metabolism in adulthood, which aligns with some of the pathologies observed in PWS. Given that anxiety is a prominent phenotypic behavior in PWS, we investigate the role of the Magel2 gene, particularly in hypothalamic POMC neurons innervating the medial amygdala (MeA), in the behavioral phenotypes associated with Prader-Willi Syndrome (PWS).

Methods: In this study, we used a retrograde AAV containing the Cre recombinase under the control of neuronal Pomc enhancers to genetically eliminate the Magel2 gene in MeA-innervating ARCPomc neurons.

Results: Both male and female mice lacking the Magel2 gene in MeA-innervating ARC^Pomc neurons display no alterations in anxiety-like behavior during the open field test, light/dark test, and elevated plus maze test in the absence of exposure to acute stress. However, male mice with a Magel2 gene deletion in these particular neurons exhibit increased stress-induced anxiety-like behavior and reduce motivation/spatial learning, while female mice do not show these behavioral changes. Our results suggest that the Magel2 gene in ARC^Pomc neurons, especially in males, influences the impact of stress on anxiety-like behavior and spatial learning deficits associated with a food reward.

Discussion: With the recent approval of a novel treatment for hyperphagia in PWS by the FDA that seems to target the hypothalamic melanocortin system, understanding the cellular mechanisms by which MAGEL2 in ARC^Pomc neurons innervating the MeA regulates emotional behaviors might help the development of new therapeutic strategies for addressing mental illness in individuals with PWS.

Introduction: Motor tasks require the flexible selection and coordination of multiple muscles, which may be achieved through the organization and combination of muscle synergies. Although multiple muscles may receive a shared neural drive, and each muscle may also receive distinct neural inputs, there is ongoing debate about whether synergies accurately reflect shared neural drives. This study aimed to compare the spectral characteristics of the common drive shared among muscles within the same synergy to those shared among muscles belonging to different synergies.

Methods: Electromyographic signals were recorded from upper limb muscles during an isometric multi-directional force generation task. Synergies were identified using non-negative matrix factorization (NMF), and coherence analysis was conducted to evaluate common drives among muscles within and across synergies. A methodological limitation of previous studies was to segment muscle activity into standard frequency bands. Here, we overcome it by proposing to automatically detect subject-specific and physiologically relevant frequency layers. The application of NMF on the coherence spectra of muscle pairs as a method for automatically detecting physiologically relevant frequency bands sheds light into the neural basis of muscle coordination.

Results: Six frequency layers were identified, and muscle recruited within the same synergy showed a higher coherence within layers in the delta, alpha, and low-beta bands.

Discussion: Our findings enhance the understanding of physiological mechanisms of motor coordination by elucidating the relationship between muscle synergies and the spectral characteristics of intermuscular coherence.

Unlike digital computers, the brain exhibits spontaneous activity even during complete rest, despite the evolutionary pressure for energy efficiency. Inspired by the critical brain hypothesis, which proposes that the brain operates optimally near a critical point of phase transition in the dynamics of neural networks to improve computational efficiency, we postulate that spontaneous activity plays a homeostatic role in the development and maintenance of criticality. Criticality in the brain is associated with the balance between excitatory and inhibitory synaptic inputs (EI balance), which is essential for maintaining neural computation performance. Here, we hypothesize that both criticality and EI balance are stabilized by appropriate noise levels and spike-timing-dependent plasticity (STDP) windows. Using spiking neural network (SNN) simulations and in vitro experiments with dissociated neuronal cultures, we demonstrated that while repetitive stimuli transiently disrupt both criticality and EI balance, spontaneous activity can develop and maintain these properties and prolong the fading memory of past stimuli. Our findings suggest that the brain may achieve self-optimization and memory consolidation as emergent functions of noise-driven spontaneous activity. This noise-harnessing mechanism provides insights for designing energy-efficient neural networks, and suggest a potential link between the emergent function of spontaneous activity and sleep function in maintaining homeostasis and consolidating memory.

This article aims to provide a synaptic input database called, dendritic synaptome for dendrites of calcium-binding protein-containing interneurons [calbindin-D28K (CB+), calretinin (CR+), parvalbumin (PV+)] employing a modified correlated light and EM method, the "mirror-technique" that allows for investigating neuronal compartments while preserving utmost ultrastructural quality (Talapka et al., 2021). Nine dendrites and all presynaptic boutons (n = 815) impinging on their surface were traced and reconstructed in three-dimensions (3D) using serial section transmission electron microscopy (ssTEM). The following basic parameters of the synapses were determined: The ratio of symmetric ("ss" or putative inhibitory) and asymmetric ("as" or putative excitatory) synapses, the number of synapses per unit length of dendrite (i.e., density of "as" and "ss"), surface area and volume of presynaptic boutons, and area of the active zones of synapses. Significant differences in the morphometric parameters of asymmetric, but not in symmetric, synapses were detected between the three interneuron subtypes. Surface extent and the number of synapses on PV+ dendrites were the largest compared to the other two subtypes. Although the distribution of presynaptic boutons differed between dendrites, clustering of the presynaptic boutons could be revealed only for PV+ dendrites. Based on our serial-section electron microscopy (ssEM) reconstructions and corresponding light microscopy (LM) databases of CBP dendrites, it was calculated that on average a single CB+, CR+, and PV+ interneuron receives 2,136, 2,148, and 2,589 synapses, respectively, of which 74.6, 81.5, and 85.3% are excitatory, that is, asymmetric, and the remaining inhibitory, that is, symmetric. Carriage return findings provide essential quantitative information to establish realistic computational models for studying the synaptic function of neuronal ensembles in the mouse primary visual cortex.

Neurons throughout the neocortex exhibit selective sensitivity to particular features of sensory input patterns. According to the prevailing views, cortical strategy is to choose features that exhibit predictable relationship to their spatial and/or temporal context. Such contextually predictable features likely make explicit the causal factors operating in the environment and thus they are likely to have perceptual/behavioral utility. The known details of functional architecture of cortical columns suggest that cortical extraction of such features is a modular nonlinear operation, in which the input layer, layer 4, performs initial nonlinear input transform generating proto-features, followed by their linear integration into output features by the basal dendrites of pyramidal cells in the upper layers. Tuning of pyramidal cells to contextually predictable features is guided by the contextual inputs their apical dendrites receive from other cortical columns via long-range horizontal or feedback connections. Our implementation of this strategy in a model of prototypical V1 cortical column, trained on natural images, reveals the presence of a limited number of contextually predictable orthogonal basis features in the image patterns appearing in the column's receptive field. Upper-layer cells generate an overcomplete Hadamard-like representation of these basis features: i.e., each cell carries information about all basis features, but with each basis feature contributing either positively or negatively in the pattern unique to that cell. In tuning selectively to contextually predictable features, upper layers perform selective filtering of the information they receive from layer 4, emphasizing information about orderly aspects of the sensed environment and downplaying local, likely to be insignificant or distracting, information. Altogether, the upper-layer output preserves fine discrimination capabilities while acquiring novel higher-order categorization abilities to cluster together input patterns that are different but, in some way, environmentally related. We find that to be fully effective, our feature tuning operation requires collective participation of cells across 7 minicolumns, together making up a functionally defined 150 μm diameter "mesocolumn." Similarly to real V1 cortex, 80% of model upper-layer cells acquire complex-cell receptive field properties while 20% acquire simple-cell properties. Overall, the design of the model and its emergent properties are fully consistent with the known properties of cortical organization. Thus, in conclusion, our feature-extracting circuit might capture the core operation performed by cortical columns in their feedforward extraction of perceptually and behaviorally significant information.