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Cell Reports May 2023Cross-modal plasticity is the repurposing of brain regions associated with deprived sensory inputs to improve the capacity of other sensory modalities. The functional...
Cross-modal plasticity is the repurposing of brain regions associated with deprived sensory inputs to improve the capacity of other sensory modalities. The functional mechanisms of cross-modal plasticity can indicate how the brain recovers from various forms of injury and how different sensory modalities are integrated. Here, we demonstrate that rewiring of the microglia-mediated local circuit synapse is crucial for cross-modal plasticity induced by visual deprivation (monocular deprivation [MD]). MD relieves the usual inhibition of functional connectivity between the somatosensory cortex and secondary lateral visual cortex (V2L). This results in enhanced excitatory responses in V2L neurons during whisker stimulation and a greater capacity for vibrissae sensory discrimination. The enhanced cross-modal response is mediated by selective removal of inhibitory synapse terminals on pyramidal neurons by the microglia in the V2L via matrix metalloproteinase 9 signaling. Our results provide insights into how cortical circuits integrate different inputs to functionally compensate for neuronal damage.
Topics: Animals; Microglia; Neurons; Synapses; Pyramidal Cells; Visual Cortex; Neuronal Plasticity; Vibrissae; Somatosensory Cortex
PubMed: 37086724
DOI: 10.1016/j.celrep.2023.112383 -
The Journal of Experimental Medicine Mar 2022Microglia, the main immunocompetent cells of the brain, regulate neuronal function, but their contribution to cerebral blood flow (CBF) regulation has remained elusive....
Microglia, the main immunocompetent cells of the brain, regulate neuronal function, but their contribution to cerebral blood flow (CBF) regulation has remained elusive. Here, we identify microglia as important modulators of CBF both under physiological conditions and during hypoperfusion. Microglia establish direct, dynamic purinergic contacts with cells in the neurovascular unit that shape CBF in both mice and humans. Surprisingly, the absence of microglia or blockade of microglial P2Y12 receptor (P2Y12R) substantially impairs neurovascular coupling in mice, which is reiterated by chemogenetically induced microglial dysfunction associated with impaired ATP sensitivity. Hypercapnia induces rapid microglial calcium changes, P2Y12R-mediated formation of perivascular phylopodia, and microglial adenosine production, while depletion of microglia reduces brain pH and impairs hypercapnia-induced vasodilation. Microglial actions modulate vascular cyclic GMP levels but are partially independent of nitric oxide. Finally, microglial dysfunction markedly impairs P2Y12R-mediated cerebrovascular adaptation to common carotid artery occlusion resulting in hypoperfusion. Thus, our data reveal a previously unrecognized role for microglia in CBF regulation, with broad implications for common neurological diseases.
Topics: Adult; Aged; Animals; Brain; Calcium Signaling; Carotid Artery Diseases; Cerebrovascular Circulation; Evoked Potentials; Female; Humans; Hypercapnia; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microglia; Neurovascular Coupling; Receptors, Purinergic; Receptors, Purinergic P2Y12; Vasodilation; Vibrissae
PubMed: 35201268
DOI: 10.1084/jem.20211071 -
Nature Jun 2021Tissue stem cells are generated from a population of embryonic progenitors through organ-specific morphogenetic events. Although tissue stem cells are central to organ...
Tissue stem cells are generated from a population of embryonic progenitors through organ-specific morphogenetic events. Although tissue stem cells are central to organ homeostasis and regeneration, it remains unclear how they are induced during development, mainly because of the lack of markers that exclusively label prospective stem cells. Here we combine marker-independent long-term 3D live imaging and single-cell transcriptomics to capture a dynamic lineage progression and transcriptome changes in the entire epithelium of the mouse hair follicle as it develops. We found that the precursors of different epithelial lineages were aligned in a 2D concentric manner in the basal layer of the hair placode. Each concentric ring acquired unique transcriptomes and extended to form longitudinally aligned, 3D cylindrical compartments. Prospective bulge stem cells were derived from the peripheral ring of the placode basal layer, but not from suprabasal cells (as was previously suggested). The fate of placode cells is determined by the cell position, rather than by the orientation of cell division. We also identified 13 gene clusters: the ensemble expression dynamics of these clusters drew the entire transcriptional landscape of epithelial lineage diversification, consistent with cell lineage data. Combining these findings with previous work on the development of appendages in insects, we describe the 'telescope model', a generalized model for the development of ectodermal organs in which 2D concentric zones in the placode telescope out to form 3D longitudinally aligned cylindrical compartments.
Topics: Animals; Cell Lineage; Cell Tracking; Ectoderm; Embryo, Mammalian; Epithelial Cells; Female; Flow Cytometry; Gene Expression Regulation, Developmental; Hair Follicle; Male; Mice; Mice, Transgenic; Multigene Family; RNA-Seq; Single-Cell Analysis; Skin; Stem Cells; Tissue Culture Techniques; Transcriptome; Vibrissae
PubMed: 34108685
DOI: 10.1038/s41586-021-03638-5 -
Nature Neuroscience Apr 2020Hyper-reactivity to sensory input is a common and debilitating symptom in individuals with autism spectrum disorders (ASD), but the neural basis underlying sensory...
Hyper-reactivity to sensory input is a common and debilitating symptom in individuals with autism spectrum disorders (ASD), but the neural basis underlying sensory abnormality is not completely understood. Here we examined the neural representations of sensory perception in the neocortex of a Shank3B mouse model of ASD. Male and female Shank3B mice were more sensitive to relatively weak tactile stimulation in a vibrissa motion detection task. In vivo population calcium imaging in vibrissa primary somatosensory cortex (vS1) revealed increased spontaneous and stimulus-evoked firing in pyramidal neurons but reduced activity in interneurons. Preferential deletion of Shank3 in vS1 inhibitory interneurons led to pyramidal neuron hyperactivity and increased stimulus sensitivity in the vibrissa motion detection task. These findings provide evidence that cortical GABAergic interneuron dysfunction plays a key role in sensory hyper-reactivity in a Shank3 mouse model of ASD and identify a potential cellular target for exploring therapeutic interventions.
Topics: Action Potentials; Animals; Autism Spectrum Disorder; Disease Models, Animal; GABAergic Neurons; Mice; Microfilament Proteins; Nerve Tissue Proteins; Physical Stimulation; Pyramidal Cells; Sensory Thresholds; Somatosensory Cortex; Touch; Touch Perception
PubMed: 32123378
DOI: 10.1038/s41593-020-0598-6 -
British Journal of Pharmacology Jun 2021The promotion of hair regeneration and growth heavily depends on the activation of Wnt/β-catenin signalling in the hair follicle, including dermal papilla (DP)....
BACKGROUND AND PURPOSE
The promotion of hair regeneration and growth heavily depends on the activation of Wnt/β-catenin signalling in the hair follicle, including dermal papilla (DP). KY19382, one of the newly synthesized analogues of indirubin-3'-monoxime (I3O), was identified as a Wnt/β-catenin signalling activator via inhibition of the interaction between CXXC-type zinc finger protein 5 (CXXC5) and dishevelled (Dvl). Given the close relationship between the Wnt/β-catenin signalling and hair regeneration, we investigated the effect of KY19382 on hair regrowth and hair follicle neogenesis.
EXPERIMENTAL APPROACH
In vitro hair induction effects of KY19382 were performed in human DP cells. The hair elongation effects of KY19382 were confirmed through the human hair follicle and vibrissa culture system. In vivo hair regeneration abilities of KY19382 were identified in three models: hair regrowth, wound-induced hair follicle neogenesis (WIHN) and hair patch assays using C57BL/6 mice. The hair regeneration abilities were analysed by immunoblotting, alkaline phosphatase (ALP) and immunohistochemical staining.
KEY RESULTS
KY19382 activated Wnt/β-catenin signalling and elevated expression of ALP and the proliferation marker PCNA in DP cells. KY19382 also increased hair length in ex vivo-cultured mouse vibrissa and human hair follicles and induced hair regrowth in mice. Moreover, KY19382 significantly promoted the generation of de novo hair follicles as shown by WIHN and hair patch assays.
CONCLUSION AND IMPLICATIONS
These results indicate that KY19382 is a potential therapeutic drug that exhibits effective hair regeneration ability via activation of the Wnt/β-catenin signalling for alopecia treatments.
Topics: Animals; Hair; Hair Follicle; Mice; Mice, Inbred C57BL; Wnt Signaling Pathway
PubMed: 33751552
DOI: 10.1111/bph.15438 -
Nature Sep 2022Central oscillators are primordial neural circuits that generate and control rhythmic movements. Mechanistic understanding of these circuits requires genetic...
Central oscillators are primordial neural circuits that generate and control rhythmic movements. Mechanistic understanding of these circuits requires genetic identification of the oscillator neurons and their synaptic connections to enable targeted electrophysiological recording and causal manipulation during behaviours. However, such targeting remains a challenge with mammalian systems. Here we delimit the oscillator circuit that drives rhythmic whisking-a motor action that is central to foraging and active sensing in rodents. We found that the whisking oscillator consists of parvalbumin-expressing inhibitory neurons located in the vibrissa intermediate reticular nucleus (vIRt) in the brainstem. vIRt neurons receive descending excitatory inputs and form recurrent inhibitory connections among themselves. Silencing vIRt neurons eliminated rhythmic whisking and resulted in sustained vibrissae protraction. In vivo recording of opto-tagged vIRt neurons in awake mice showed that these cells spike tonically when animals are at rest, and transition to rhythmic bursting at the onset of whisking, suggesting that rhythm generation is probably the result of network dynamics, as opposed to intrinsic cellular properties. Notably, ablating inhibitory synaptic inputs to vIRt neurons quenched their rhythmic bursting, impaired the tonic-to-bursting transition and abolished regular whisking. Thus, the whisking oscillator is an all-inhibitory network and recurrent synaptic inhibition has a key role in its rhythmogenesis.
Topics: Animals; Brain Stem; Mice; Movement; Neural Inhibition; Neural Pathways; Neurons; Parvalbumins; Periodicity; Rest; Synapses; Vibrissae; Wakefulness
PubMed: 36045290
DOI: 10.1038/s41586-022-05144-8 -
Neuroscience and Biobehavioral Reviews Jun 2023Since the discovery 50 years ago of the precisely ordered representation of the whiskers in somatosensory cortex, the rodent tactile sensory system has been a fertile... (Review)
Review
Since the discovery 50 years ago of the precisely ordered representation of the whiskers in somatosensory cortex, the rodent tactile sensory system has been a fertile ground for the study of sensory processing. With the growing sophistication of touch-based behavioral paradigms, together with advances in neurophysiological methodology, a new approach is emerging. By posing increasingly complex perceptual and memory problems, in many cases analogous to human psychophysical tasks, investigators now explore the operations underlying rodent problem solving. We define the neural basis of tactile cognition as the transformation from a stage in which neuronal activity encodes elemental features, local in space and in time, to a stage in which neuronal activity is an explicit representation of the behavioral operations underlying the current task. Selecting a set of whisker-based behavioral tasks, we show that rodents achieve high level performance through the workings of neuronal circuits that are accessible, decodable, and manipulatable. As a means towards exploring tactile cognition, this review presents leading psychophysical paradigms and, where known, their neural correlates.
Topics: Animals; Humans; Touch; Rodentia; Touch Perception; Somatosensory Cortex; Cognition
PubMed: 37028580
DOI: 10.1016/j.neubiorev.2023.105161 -
Nature Communications Apr 2024In artificial nervous systems, conductivity changes indicate synaptic weight updates, but they provide limited information compared to living organisms. We present the...
In artificial nervous systems, conductivity changes indicate synaptic weight updates, but they provide limited information compared to living organisms. We present the pioneering design and production of an electrochromic neuromorphic transistor employing color updates to represent synaptic weight for in-sensor computing. Here, we engineer a specialized mechanism for adaptively regulating ion doping through an ion-exchange membrane, enabling precise control over color-coded synaptic weight, an unprecedented achievement. The electrochromic neuromorphic transistor not only enhances electrochromatic capabilities for hardware coding but also establishes a visualized pattern-recognition network. Integrating the electrochromic neuromorphic transistor with an artificial whisker, we simulate a bionic reflex system inspired by the longicorn beetle, achieving real-time visualization of signal flow within the reflex arc in response to environmental stimuli. This research holds promise in extending the biomimetic coding paradigm and advancing the development of bio-hybrid interfaces, particularly in incorporating color-based expressions.
Topics: Animals; Coleoptera; Transistors, Electronic; Biomimetics; Neural Networks, Computer; Color; Vibrissae; Bionics; Synapses
PubMed: 38658551
DOI: 10.1038/s41467-024-47630-9 -
Nature Mar 2020Proper brain function depends on neurovascular coupling: neural activity rapidly increases local blood flow to meet moment-to-moment changes in regional brain energy...
Proper brain function depends on neurovascular coupling: neural activity rapidly increases local blood flow to meet moment-to-moment changes in regional brain energy demand. Neurovascular coupling is the basis for functional brain imaging, and impaired neurovascular coupling is implicated in neurodegeneration. The underlying molecular and cellular mechanisms of neurovascular coupling remain poorly understood. The conventional view is that neurons or astrocytes release vasodilatory factors that act directly on smooth muscle cells (SMCs) to induce arterial dilation and increase local blood flow. Here, using two-photon microscopy to image neural activity and vascular dynamics simultaneously in the barrel cortex of awake mice under whisker stimulation, we found that arteriolar endothelial cells (aECs) have an active role in mediating neurovascular coupling. We found that aECs, unlike other vascular segments of endothelial cells in the central nervous system, have abundant caveolae. Acute genetic perturbations that eliminated caveolae in aECs, but not in neighbouring SMCs, impaired neurovascular coupling. Notably, caveolae function in aECs is independent of the endothelial NO synthase (eNOS)-mediated NO pathway. Ablation of both caveolae and eNOS completely abolished neurovascular coupling, whereas the single mutants exhibited partial impairment, revealing that the caveolae-mediated pathway in aECs is a major contributor to neurovascular coupling. Our findings indicate that vasodilation is largely mediated by endothelial cells that actively relay signals from the central nervous system to SMCs via a caveolae-dependent pathway.
Topics: Animals; Arterioles; Caveolae; Central Nervous System; Cerebral Cortex; Endothelial Cells; Female; Male; Mice; Microscopy, Fluorescence, Multiphoton; Neurovascular Coupling; Nitric Oxide Synthase Type III; Vasodilation; Vibrissae
PubMed: 32076269
DOI: 10.1038/s41586-020-2026-1 -
Nature Reviews. Neuroscience Sep 2019Tactile sensory information from facial whiskers provides nocturnal tunnel-dwelling rodents, including mice and rats, with important spatial and textural information... (Review)
Review
Tactile sensory information from facial whiskers provides nocturnal tunnel-dwelling rodents, including mice and rats, with important spatial and textural information about their immediate surroundings. Whiskers are moved back and forth to scan the environment (whisking), and touch signals from each whisker evoke sparse patterns of neuronal activity in whisker-related primary somatosensory cortex (wS1; barrel cortex). Whisking is accompanied by desynchronized brain states and cell-type-specific changes in spontaneous and evoked neuronal activity. Tactile information, including object texture and location, appears to be computed in wS1 through integration of motor and sensory signals. wS1 also directly controls whisker movements and contributes to learned, whisker-dependent, goal-directed behaviours. The cell-type-specific neuronal circuitry in wS1 that contributes to whisker sensory perception is beginning to be defined.
Topics: Animals; Mice; Nerve Net; Rats; Rodentia; Sensorimotor Cortex; Signal Transduction; Somatosensory Cortex; Touch; Vibrissae
PubMed: 31367018
DOI: 10.1038/s41583-019-0200-y