Hippocampal ripples down-regulate synapses Norimoto, Hiroaki; Makino, Kenichi; Gao, Mengxuan ...
Science (American Association for the Advancement of Science),
03/2018, Volume:
359, Issue:
6383
Journal Article
Peer reviewed
The specific effects of sleep on synaptic plasticity remain unclear. We report that mouse hippocampal sharp-wave ripple oscillations serve as intrinsic events that trigger long-lasting synaptic ...depression. Silencing of sharp-wave ripples during slow-wave states prevented the spontaneous down-regulation of net synaptic weights and impaired the learning of new memories. The synaptic down-regulation was dependent on the
-methyl-d-aspartate receptor and selective for a specific input pathway. Thus, our findings are consistent with the role of slow-wave states in refining memory engrams by reducing recent memory-irrelevant neuronal activity and suggest a previously unrecognized function for sharp-wave ripples.
Bioluminescence is a natural light source based on luciferase catalysis of its substrate luciferin. We performed directed evolution on firefly luciferase using a red-shifted and highly deliverable ...luciferin analog to establish AkaBLI, an all-engineered bioluminescence in vivo imaging system. AkaBLI produced emissions in vivo that were brighter by a factor of 100 to 1000 than conventional systems, allowing noninvasive visualization of single cells deep inside freely moving animals. Single tumorigenic cells trapped in the mouse lung vasculature could be visualized. In the mouse brain, genetic labeling with neural activity sensors allowed tracking of small clusters of hippocampal neurons activated by novel environments. In a marmoset, we recorded video-rate bioluminescence from neurons in the striatum, a deep brain area, for more than 1 year. AkaBLI is therefore a bioengineered light source to spur unprecedented scientific, medical, and industrial applications.
Optical clearing methods facilitate deep biological imaging by mitigating light scattering in situ. Multi-scale high-resolution imaging requires preservation of tissue integrity for accurate signal ...reconstruction. However, existing clearing reagents contain chemical components that could compromise tissue structure, preventing reproducible anatomical and fluorescence signal stability. We developed ScaleS, a sorbitol-based optical clearing method that provides stable tissue preservation for immunochemical labeling and three-dimensional (3D) signal rendering. ScaleS permitted optical reconstructions of aged and diseased brain in Alzheimer's disease models, including mapping of 3D networks of amyloid plaques, neurons and microglia, and multi-scale tracking of single plaques by successive fluorescence and electron microscopy. Human clinical samples from Alzheimer's disease patients analyzed via reversible optical re-sectioning illuminated plaque pathogenesis in the z axis. Comparative benchmarking of contemporary clearing agents showed superior signal and structure preservation by ScaleS. These findings suggest that ScaleS is a simple and reproducible method for accurate visualization of biological tissue.
Dysfunctional mitochondria accumulate in many human diseases. Accordingly, mitophagy, which removes these mitochondria through lysosomal degradation, is attracting broad attention. Due to ...uncertainties in the operational principles of conventional mitophagy probes, however, the specificity and quantitativeness of their readouts are disputable. Thorough investigation of the behaviors and fates of fluorescent proteins inside and outside lysosomes enabled us to develop an indicator for mitophagy, mito-SRAI. Through strict control of its mitochondrial targeting, we were able to monitor mitophagy in fixed biological samples more reproducibly than before. Large-scale image-based high-throughput screening led to the discovery of a hit compound that induces selective mitophagy of damaged mitochondria. In a mouse model of Parkinsons disease, we found that dopaminergic neurons selectively failed to execute mitophagy that promoted their survival within lesions. These results show that mito-SRAI is an essential tool for quantitative studies of mitochondrial quality control.
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•mito-SRAI provides reliable mitophagy readouts under both live and fixed conditions•mito-SRAI uses a fluorescent protein that is resistant to lysosomal environments•High-throughput screening led to the discovery of mitophagy-inducing compounds•Evidence was given for loss of nigral dopaminergic neurons due to mitophagy failure
Through investigation of the behaviors and fates of fluorescent proteins inside and outside of lysosomes, Katayama et al. developed a signal-retaining autophagy indicator, which they localize to mitochondria (mito-SRAI) to quantitatively measure mitophagy. They apply their new tool in a high-throughput in vitro screen for chemical inducers of mitophagy and in a mouse model of Parkinsons disease.
The axonal arbors of single nigrostriatal dopaminergic neurons were visualized with a viral vector expressing membrane-targeted green fluorescent protein in rat brain. All eight reconstructed ...tyrosine hydroxylase-positive dopaminergic neurons possessed widely spread and highly dense axonal arborizations in the neostriatum. All of them emitted very little axon collateral arborization outside of the striatum except for tiny arborization in the external pallidum. The striatal axonal bush of each reconstructed dopaminergic neuron covered 0.45-5.7% (mean +/- SD = 2.7 +/- 1.5%) of the total volume of the neostriatum. Furthermore, all the dopaminergic neurons innervated both striosome and matrix compartments of the neostriatum, although each neuron's arborization tended to favor one of these compartments. Our findings demonstrate that individual dopaminergic neurons of the substantia nigra can broadcast a dopamine signal and exert strong influence over a large number of striatal neurons. This divergent signaling should be a key to the function of the nigrostriatal system in dopamine-based learning and suggests that neurodegeneration of individual nigral neurons can affect multiple neurons in the striatum. Thus, these results would also contribute to understanding the clinicopathology of Parkinson's disease and related syndromes.
Fast and wide field-of-view imaging with single-cell resolution, high signal-to-noise ratio, and no optical aberrations have the potential to inspire new avenues of investigations in biology. ...However, such imaging is challenging because of the inevitable tradeoffs among these parameters. Here, we overcome these tradeoffs by combining a resonant scanning system, a large objective with low magnification and high numerical aperture, and highly sensitive large-aperture photodetectors. The result is a practically aberration-free, fast-scanning high optical invariant two-photon microscopy (FASHIO-2PM) that enables calcium imaging from a large network composed of ∼16,000 neurons at 7.5 Hz from a 9 mm2 contiguous image plane, including more than 10 sensory-motor and higher-order areas of the cerebral cortex in awake mice. Network analysis based on single-cell activities revealed that the brain exhibits small-world rather than scale-free behavior. The FASHIO-2PM is expected to enable studies on biological dynamics by simultaneously monitoring macroscopic activities and their compositional elements.
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•High optical invariant was achieved with resonant-based two-photon microscopy•A 3 mm square of the mouse cortex can be scanned at 7.5 Hz for calcium imaging•Activity of over 16,000 neurons across multiple areas was observed•Network analysis revealed small-world properties: cost-effective cortical dynamics
Ota et al. present fast and wide field-of-view two-photon microscopy with practically no optical aberrations. Combining high-performance large lenses and devices and a fast laser-scanning engine enables the recording of >16,000 neurons in awake mice. Functional network analysis with single-cell resolution reveals the small-world connectivity of the cortex.
Persistent mechanical hypersensitivity that occurs in the setting of injury or disease remains a major clinical problem largely because the underlying neural circuitry is still not known. Here we ...report the functional identification of key components of the elusive dorsal horn circuit for mechanical allodynia. We show that the transient expression of VGLUT3 by a discrete population of neurons in the deep dorsal horn is required for mechanical pain and that activation of the cells in the adult conveys mechanical hypersensitivity. The cells, which receive direct low threshold input, point to a novel location for circuit initiation. Subsequent analysis of c-Fos reveals the circuit extends dorsally to nociceptive lamina I projection neurons, and includes lamina II calretinin neurons, which we show also convey mechanical allodynia. Lastly, using inflammatory and neuropathic pain models, we show that multiple microcircuits in the dorsal horn encode this form of pain.
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•Deep dorsal horn neurons transiently express VGLUT3 and convey mechanical allodynia•They receive innocuous input and reside at the interface between touch and pain•Their local activation reveals a dorsally directed pathway for mechanical allodynia•Different microcircuits encode mechanical allodynia depending on the injury
Peirs et al. identified deep dorsal horn neurons that transiently express VGLUT3 and are required for mechanical allodynia. The neurons transmit innocuous input to dorsally directed pain microcircuits that are differentially engaged depending on the type of injury.
Abstract
Type 2 diabetes mellitus (T2DM) has long been considered a risk factor for Alzheimer’s disease (AD). However, the molecular links between T2DM and AD remain obscure. Here, we reported that ...serum-/glucocorticoid-regulated kinase 1 (SGK1) is activated by administering a chronic high-fat diet (HFD), which increases the risk of T2DM, and thus promotes Tau pathology via the phosphorylation of tau at Ser214 and the activation of a key tau kinase, namely, GSK-3ß, forming SGK1-GSK-3ß-tau complex. SGK1 was activated under conditions of elevated glucocorticoid and hyperglycemia associated with HFD, but not of fatty acid–mediated insulin resistance. Elevated expression of SGK1 in the mouse hippocampus led to neurodegeneration and impairments in learning and memory. Upregulation and activation of SGK1, SGK1-GSK-3ß-tau complex were also observed in the hippocampi of AD cases. Our results suggest that SGK1 is a key modifier of tau pathology in AD, linking AD to corticosteroid effects and T2DM.
Parvalbumin (PV)-positive fast-spiking cells in the neocortex are known to generate gamma oscillations by mutual chemical and electrical connections. Recent findings suggest that this rhythm might be ...responsible for higher-order brain functions, and related to psychiatric disorders. To elucidate the precise structural rules of the connections of PV neurons, we first produced genetic tools. Using a lentiviral expression system, we developed neuron-specific promoters and a new reporter protein that labels the somatodendritic membrane of neurons. We applied the reporter protein to the generation of transgenic mice, and succeeded in visualizing the dendrites and cell bodies of PV neurons efficiently. Then we analyzed excitatory and inhibitory inputs to PV neurons in the primary somatosensory cortex using the mice. Corticocortical glutamatergic inputs were more frequently found on the distal dendrites than on the soma, whereas thalamocortical inputs did not differ between the proximal and distal portions. Corticocortical inhibitory inputs were more densely distributed on the soma than on the dendrites. We further investigated which types of neocortical GABAergic neurons preferred the PV soma over their dendrites. We revealed that the somatic and dendritic compartments principally received GABAergic inputs from vasoactive intestinal polypeptide (VIP)-positive and PV neurons, respectively. This compartmental organization suggests that PV neurons communicate with each other mainly via the dendrites, and that their activity is effectively controlled by the somatic inputs of VIP neurons. These findings provide new insights into the neuronal circuits involving PV neurons, and contribute to a better understanding of brain functions and mental disorders.
Social deficits are one of the major symptoms of psychiatric disorders, including autism spectrum disorders (ASDs) and schizophrenia. However, the underlying mechanism remains ill-defined. Here, we ...focused on the anterior cingulate cortex (ACC), a brain region that is related to social behaviors, of mice that received poly(I:C)-induced maternal immune activation. Offspring born from poly(I:C)-treated dams exhibited social deficits in a three-chamber task at juvenile stages. Using whole-cell patch clamp recordings, we found that layer 2/3 pyramidal cells were hyperactive in acute ACC slices prepared from poly(I:C)-treated mice compared to those from saline-treated mice. The hyperexcitation was associated with a reduction in inhibitory synapse activity. Local injection of the GABAA receptor enhancer clonazepam into the ACC of poly(I:C)-treated mice restored the social behaviors of the mice. These results suggest that the balanced excitability of ACC neurons is essential for social ability.
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•Maternal immune activation (MIA) is a risk factor of developmental social deficits.•The neuronal activity in the anterior cingulate cortex is hyperactive in MIA-model mice.•Pharmacological suppression of anterior cingulate cortex restored social ability.
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