Oligodendrocyte precursor cells (OPCs) play diverse roles in the brain, extending beyond their classically recognized contributions to oligodendrogenesis and myelination.In the developing and adult ...visual system, OPCs have been shown to remodel axons and to eliminate synapses through phagocytic engulfment.The engulfment of synapses by OPCs is influenced by multiple factors, including neural activity and molecular signals from other brain cells.Future work is needed to define the biological consequences and underlying molecular mechanisms of synapse engulfment by OPCs.
Oligodendrocyte precursor cells (OPCs) are non-neuronal brain cells that give rise to oligodendrocytes, glia that myelinate the axons of neurons in the brain. Classically known for their contributions to myelination via oligodendrogenesis, OPCs are increasingly appreciated to play diverse roles in the nervous system, ranging from blood vessel formation to antigen presentation. Here, we review emerging literature suggesting that OPCs may be essential for the establishment and remodeling of neural circuits in the developing and adult brain via mechanisms that are distinct from the production of oligodendrocytes. We discuss the specialized features of OPCs that position these cells to integrate activity-dependent and molecular cues to shape brain wiring. Finally, we place OPCs within the context of a growing field focused on understanding the importance of communication between neurons and glia in the contexts of both health and disease.
In the cat's visual cortex, the responses of simple cells seem to be totally determined by their thalamic input, yet only a few percent of the excitatory synapses in layer 4 arise from the thalamus. ...To resolve this discrepancy between structure and function, we used correlated light and electron microscopy to search individual spiny stellate cells (simple cells) for possible structural features that would explain the biophysical efficacy of the thalamic input, such as synaptic location on dendrites, size of postsynaptic densities, and postsynaptic targets. We find that thalamic axons form a small number of synapses with the spiny stellates (188 on average), that the median size of the synapses is slightly larger than that of other synapses on the dendrites of spiny stellates, that they are not located particularly proximal to the soma, and that they do not cluster on the dendrites. These findings point to alternative mechanisms, such as synchronous activation of the sparse thalamic synapses to boost the efficacy of the thalamic input. The results also support the idea that the thalamic input does not by itself determine the cortical response of spiny stellate cells, allowing the cortical microcircuit to amplify and modulate its response according to the particular context and computation being performed.
Imaging is a dominant strategy for data collection in neuroscience, yielding stacks of images that often scale to gigabytes of data for a single experiment. Machine learning algorithms from computer ...vision can serve as a pair of virtual eyes that tirelessly processes these images, automatically detecting and identifying microstructures. Unlike learning methods, our Flexible Learning-free Reconstruction of Imaged Neural volumes (FLoRIN) pipeline exploits structure-specific contextual clues and requires no training. This approach generalizes across different modalities, including serially-sectioned scanning electron microscopy (sSEM) of genetically labeled and contrast enhanced processes, spectral confocal reflectance (SCoRe) microscopy, and high-energy synchrotron X-ray microtomography (μCT) of large tissue volumes. We deploy the FLoRIN pipeline on newly published and novel mouse datasets, demonstrating the high biological fidelity of the pipeline's reconstructions. FLoRIN reconstructions are of sufficient quality for preliminary biological study, for example examining the distribution and morphology of cells or extracting single axons from functional data. Compared to existing supervised learning methods, FLoRIN is one to two orders of magnitude faster and produces high-quality reconstructions that are tolerant to noise and artifacts, as is shown qualitatively and quantitatively.
A primary cilium is a membrane-bound extension from the cell surface that contains receptors for perceiving and transmitting signals that modulate cell state and activity. Primary cilia in the brain ...are less accessible than cilia on cultured cells or epithelial tissues because in the brain they protrude into a deep, dense network of glial and neuronal processes. Here, we investigated cilia frequency, internal structure, shape, and position in large, high-resolution transmission electron microscopy volumes of mouse primary visual cortex. Cilia extended from the cell bodies of nearly all excitatory and inhibitory neurons, astrocytes, and oligodendrocyte precursor cells (OPCs) but were absent from oligodendrocytes and microglia. Ultrastructural comparisons revealed that the base of the cilium and the microtubule organization differed between neurons and glia. Investigating cilia-proximal features revealed that many cilia were directly adjacent to synapses, suggesting that cilia are poised to encounter locally released signaling molecules. Our analysis indicated that synapse proximity is likely due to random encounters in the neuropil, with no evidence that cilia modulate synapse activity as would be expected in tetrapartite synapses. The observed cell class differences in proximity to synapses were largely due to differences in external cilia length. Many key structural features that differed between neuronal and glial cilia influenced both cilium placement and shape and, thus, exposure to processes and synapses outside the cilium. Together, the ultrastructure both within and around neuronal and glial cilia suggest differences in cilia formation and function across cell types in the brain.
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•Primary cilia extend from visual cortex neurons and select glia•Internal cilia ultrastructure is not stereotyped but varies between cell classes•Cilia are near synapses and surrounded by neurites and glial processes•Cilia placement and structure impact the external environment of cilia
Ott and Torres et al. identify distinguishing anatomical features of neuronal and glial primary cilia in the mouse visual cortex. Internal structural differences determine both cilium shape and the extent of cilium exposure to the extracellular neuropil, where cilia pass near, and even adjacent to, many synapses.
Maps of the nervous system that identify individual cells along with their type, subcellular components and connectivity have the potential to elucidate fundamental organizational principles of ...neural circuits. Nanometer-resolution imaging of brain tissue provides the necessary raw data, but inferring cellular and subcellular annotation layers is challenging. We present segmentation-guided contrastive learning of representations (SegCLR), a self-supervised machine learning technique that produces representations of cells directly from 3D imagery and segmentations. When applied to volumes of human and mouse cortex, SegCLR enables accurate classification of cellular subcompartments and achieves performance equivalent to a supervised approach while requiring 400-fold fewer labeled examples. SegCLR also enables inference of cell types from fragments as small as 10 μm, which enhances the utility of volumes in which many neurites are truncated at boundaries. Finally, SegCLR enables exploration of layer 5 pyramidal cell subtypes and automated large-scale analysis of synaptic partners in mouse visual cortex.
One of the hallmarks of neocortical circuits is the predominance of recurrent excitation between pyramidal neurons, which is balanced by recurrent inhibition from smooth GABAergic neurons. It has ...been previously described that in layer 2/3 of primary visual cortex (V1) of cat and monkey, pyramidal cells filled with horseradish peroxidase connect approximately in proportion to the spiny (excitatory, 95% and 81%, respectively) and smooth (GABAergic, 5% and 19%, respectively) dendrites found in the neuropil. By contrast, a recent ultrastructural study of V1 in a single mouse found that smooth neurons formed 51% of the targets of the superficial layer pyramidal cells. This suggests that either the neuropil of this particular mouse V1 had a dramatically different composition to that of V1 in cat and monkey, or that smooth neurons were specifically targeted by the pyramidal cells in that mouse. We tested these hypotheses by examining similar cells filled with biocytin in a sample of five mice. We found that the average composition of the neuropil in V1 of these mice was similar to that described for cat and monkey V1, but that the superficial layer pyramidal cells do form proportionately more synapses with smooth dendrites than the equivalent neurons in cat or monkey. These distributions may underlie the distinct differences in functional architecture of V1 between rodent and higher mammals.
Inside one voxel of a cubic millimeter of neocortex, fifty to hundred thousand neurons use 4km of axonal cable to form three to fifteen hundred million synapses with each other. While in the human, ...such voxel is a small fragment of a cortical area, in the mouse an entire cortical area, like the primary auditory cortex, can be contained in a voxel of this size. This raises the fundamental question of what happens inside such a voxel? Are the circuits contained in this voxel, and their operations, different in every area, or are there general principles that are conserved across cortical areas and species? Such questions go to the heart of understanding how the neocortex wires itself and works. One proposal is to answer these questions by mapping the entire circuit at synaptic resolution to produce a ‘connectome’ — of the cortical column, or even of the entire brain. However, such a high-resolution connectome is self-evidently unachievable with the tools available and as a strategy it still leaves us short of understanding the ‘principles of neural engineering’. We offer an alternative route that uses physiology and computational modeling as a means of generating ‘predictive anatomy’, where the questions about underlying structure are directed to fundamental principles of organization and operation of the cortical circuits. This approach involves ‘sparse’ rather than ‘dense’ reconstructions at light and electron microscope resolution to keep the questions well-matched to current experimental tools. Rather than providing a snap-shot of an entire wiring diagram, our strategy provides for a statistical description of the circuit and integrates theory, function, and structure in a common framework.
•Historically cortical circuits have been variously thought to be random or specific.•‘Dense reconstruction’ of a connectome is limited by lack of automated methods.•Theory predicts form from function, steering circuit mapping by sparse reconstruction.•The concept of “canonical circuits” unifies form, function, and theory in neocortex.
Pyramidal cells of layer 6 in cat visual cortex are the source of the corticothalamic projection, and their recurrent collaterals provide substantially more excitatory synapses in layer 4 than does ...the thalamic input. They have predominantly simple receptive fields and can be driven monosynaptically by electrically stimulating thalamic relay cells. Layer 6 cells could thus provide a significant disynaptic amplification of the thalamic input to layer 4, particularly since their synapses facilitate, unlike the thalamic afferents whose synapses depress. However, purely geometric considerations of the relation of their dendritic trees to the thalamic input indicate that they should form a far smaller number of synapses with thalamic afferents than do the simple cells of layer 4. We thus analyzed quantitatively the thalamic input to identified corticothalamic cells by labeling the thalamic afferents and corticothalamic cells in vivo. We made a correlated light and electron microscopic study of 73 "contacts" between thalamic afferents and five corticothalamic cells. The electron microscope revealed that only 24 of the contacts identified at light microscope level were indeed synapses and, contrary to geometric predictions, virtually all were located on spines on the basal dendrites. Our quantitative estimates indicate that the corticothalamic cells form even fewer synapses with the thalamic afferents than predicted by geometric considerations and only 1/10 as many as do the layer 4 simple cells. These data strongly suggest it is the collective computation of cortical neurons, not the monosynaptic thalamic input, that determines the output of the corticothalamic cells.
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