摘要：Generationof genetically uniform non-human primates may help to establish animal modelsfor primate biology and biomedical research. In this study, we havesuccessfully cloned cynomolgus monkeys (Macaca fascicularis) by somatic cell nucleartransfer (SCNT). We found that injection of H3K9me3 demethylase Kdm4d mRNA andtreatment with histone deacetylase inhibitor trichostatin A at one-cell stagefollowing SCNT greatly improved blastocyst development and pregnancy rate oftransplanted SCNT embryos in surrogate monkeys. For SCNT using fetal monkeyfibroblasts, 6 pregnancies were confirmed in 21 surrogates and yielded2 healthy babies. For SCNT using adult monkey cumulus cells, 22pregnancies were confirmed in 42 surrogates and yielded 2 babies that wereshort-lived. In both cases, genetic analyses confirmed that the nuclear DNA andmitochondria DNA of the monkey offspring originated from the nucleus donor cell andthe oocyte donor monkey, respectively. Thus, cloning macaque monkeys by SCNT isfeasible using fetal fibroblasts.
参考文献：Cloningof Macaque Monkeys by Somatic Cell Nuclear Transfer. Cell. 2018 Feb8;172(4):881-887.e7.
摘要：Spinalcord injury leads to severe locomotor deficits or even complete leg paralysis.Here we introduce targeted spinal cord stimulation neurotechnologies thatenabled voluntary control of walking in individuals who had sustained a spinalcord injury more than four years ago and presented with permanent motordeficits or complete paralysis despite extensive rehabilitation. Using animplanted pulse generator with real-time triggering capabilities, we deliveredtrains of spatially selective stimulation to the lumbosacral spinal cord withtiming that coincided with the intended movement. Within one week, thisspatiotemporal stimulation had re-established adaptive control of paralysedmuscles during overground walking. Locomotor performance improved duringrehabilitation. After a few months, participants regained voluntary controlover previously paralysed muscles without stimulation and could walk or cyclein ecological settings during spatiotemporal stimulation. These resultsestablish a technological framework for improving neurological recovery andsupporting the activities of daily living after spinal cord injury.
参考文献：Targetedneurotechnology restores walking in humans with spinal cord injury. Nature.2018 Nov;563(7729):65-71.
摘要：Althoughgenetic factors contribute to almost half of all cases of deafness, treatmentoptions for genetic deafness are limited. We developed a genome-editingapproach to target a dominantly inherited form of genetic deafness. Here weshow that cationic lipid-mediated in vivo delivery of Cas9-guide RNA complexescan ameliorate hearing loss in a mouse model of human genetic deafness. Wedesigned and validated, both in vitro and in primary fibroblasts, genomeediting agents that preferentially disrupt the dominant deafness-associatedallele in the Tmc1 (transmembrane channel-like gene family 1) Beethoven (Bth)mouse model, even though the mutant Tmc1Bth allele differs from the wild-typeallele at only a single base pair. Injection of Cas9-guide RNA-lipid complexestargeting the Tmc1Bth allele into the cochlea of neonatal Tmc1Bth/+ micesubstantially reduced progressive hearing loss. We observed higher hair cellsurvival rates and lower auditory brainstem response thresholds in injectedears than in uninjected ears or ears injected with control complexes thattargeted an unrelated gene. Enhanced acoustic startle responses were observedamong injected compared to uninjected Tmc1Bth/+ mice. These findings suggestthat protein-RNA complex delivery of target gene-disrupting agents in vivo is apotential strategy for the treatment of some types of autosomal-dominanthearing loss.
参考文献：Treatmentof autosomal dominant hearing loss by in vivo delivery of genome editingagents. Nature. 2018 Jan 11;553(7687):217-221.
四. 《Nature medicine》和《Cell》：C9orf72致病新机制被揭示—多聚GR二肽重复扩增损害蛋白翻译和应激颗粒动力学，而应激颗粒还具有破坏核质运输过程的负面作用。最后，神经元形成的多聚GA异常聚集体可以募集蛋白酶体。
摘要：The major genetic cause of frontotemporaldementia (FTD) and amyotrophic lateral sclerosis (ALS) is a C9orf72 G4C2 repeat expansion1,2.Proposed mechanisms by which the expansion causes c9FTD/ALS include toxicityfrom repeat-containing RNA and from dipeptide repeat proteins translated fromthese transcripts. To investigate the contribution of poly(GR) dipeptide repeatproteins to c9FTD/ALS pathogenesis in a mammalian in vivo model, we generatedmice that expressed GFP-(GR)100 inthe brain.GFP-(GR)100 micedeveloped age-dependent neurodegeneration, brain atrophy,and motor and memory deficits through the accumulation of diffuse, cytoplasmicpoly(GR). Poly(GR) co-localized with ribosomal subunits and the translationinitiation factor eIF3η in GFP-(GR)100 mice and, of importance, in c9FTD/ALSpatients. Combined with the differential expression of ribosome-associatedgenes in GFP-(GR)100 mice,these findings demonstrate poly(GR)-mediated ribosomal distress. Indeed,poly(GR) inhibited canonical and non-canonical protein translation in HEK293Tcells, and also induced the formation of stress granules and delayed theirdisassembly. These data suggest that poly(GR) contributes to c9FTD/ALS byimpairing protein translation and stress granule dynamics, consequently causingchronic cellular stress and preventing cells from mounting an effective stressresponse. Decreasing poly(GR) and/or interrupting interactions between poly(GR)and ribosomal and stress granule-associated proteins may thus representpotential therapeutic strategies to restore homeostasis.
1.Poly(GR) impairs protein translation and stress granule dynamics inC9orf72-associated frontotemporal dementia and amyotrophic lateral sclerosis.Nat Med. 2018 Aug;24(8):1136-1142.
2.Stress Granule Assembly Disrupts Nucleocytoplasmic Transport. Cell. 2018 May3;173(4):958-971.e17.
3.In Situ Structure of Neuronal C9orf72 Poly-GA Aggregates Reveals ProteasomeRecruitment. Cell. 2018 Feb 8;172(4):696-705.e12.
4.Context-Dependent and Disease-Specific Diversity in Protein Interactions withinStress Granules. Cell. 2018 Jan 25;172(3):590-604.
摘要：TheN-methyl-d-aspartate receptor (NMDAR) antagonist ketamine has attractedenormous interest in mental health research owing to its rapid antidepressantactions, but its mechanism of action has remained elusive. Here we show thatblockade of NMDAR-dependent bursting activity in the 'anti-reward center', thelateral habenula (LHb), mediates the rapid antidepressant actions of ketaminein rat and mouse models of depression. LHb neurons show a significant increasein burst activity and theta-band synchronization in depressive-like animals,which is reversed by ketamine. Burst-evoking photostimulation of LHb drivesbehavioural despair and anhedonia. Pharmacology and modelling experimentsreveal that LHb bursting requires both NMDARs and low-voltage-sensitive T-typecalcium channels (T-VSCCs). Furthermore, local blockade of NMDAR or T-VSCCs inthe LHb is sufficient to induce rapid antidepressant effects. Our resultssuggest a simple model whereby ketamine quickly elevates mood by blockingNMDAR-dependent bursting activity of LHb neurons to disinhibit downstreammonoaminergic reward centres, and provide a framework for developing newrapid-acting antidepressants.
1.Ketamine blocks bursting in the lateral habenula to rapidly relieve depression.Nature. 2018 Feb 14;554(7692):317-322.
2.Astroglial Kir4.1 in the lateral habenula drives neuronal bursts in depression.Nature. 2018 Feb 14;554(7692):323-327.
摘要：It haslong been hypothesized that aging and neurodegeneration are associated withsomatic mutation in neurons; however, methodological hurdles have preventedtesting this hypothesis directly. We used single-cell whole-genome sequencingto perform genome-wide somatic single-nucleotide variant (sSNV) identificationon DNA from 161 single neurons from the prefrontal cortex and hippocampus of 15normal individuals (aged 4 months to 82 years), as well as 9 individualsaffected by early-onset neurodegeneration due to genetic disorders of DNA repair(Cockayne syndrome and xeroderma pigmentosum). sSNVs increased approximatelylinearly with age in both areas (with a higher rate in hippocampus) and weremore abundant in neurodegenerative disease. The accumulation of somaticmutations with age-which we term genosenium-shows age-related, region-related,and disease-related molecular signatures and may be important in other humanage-associated conditions.
1.Aging and neurodegeneration are associated with increased mutations in singlehuman neurons. Science. 2018 Feb 2;359(6375):555-559.
2.Somatic APP gene recombination in Alzheimer's disease and normal neurons.Nature. 2018 Nov;563(7733):639-645.
摘要：We previously reported1 thepresence of amyloid-β protein (Aβ) deposits in individuals withCreutzfeldt-Jakob disease (CJD)who had been treated during childhood with human cadaveric pituitary-derivedgrowth hormone (c-hGH) contaminated with prions. The marked deposition of parenchymal and vascular Aβ in theserelatively young individuals with treatment-induced (iatrogenic) CJD (iCJD), incontrast to other prion-disease patients and population controls,allied with the ability of Alzheimer's disease brain homogenatesto seed Aβ deposition in laboratory animals, led us to argue that theimplicated c-hGH batches might have been contaminated with Aβ seeds as well aswith prions. However, this was necessarily an association, and not anexperimental, study in humans and causality could not be concluded. Given thepublic health importance of our hypothesis, we proceeded to identify andbiochemically analyse archived vials of c-hGH. Here we show that certain c-hGHbatches to which patients with iCJD and Aβ pathology were exposed havesubstantial levels of Aβ40, Aβ42 and tau proteins, and that thismaterial can seed the formation of Aβ plaques and cerebral Aβ-amyloidangiopathy in intracerebrally inoculated mice expressing a mutant, humanizedamyloid precursor protein. These results confirm the presence of Aβ seeds inarchived c-hGH vials and are consistent with the hypothesized iatrogenic humantransmission of Aβ pathology. This experimental confirmation has implicationsfor both the prevention and the treatment of Alzheimer's disease, and should prompt a review of therisk of iatrogenic transmission of Aβ seeds by medical and surgical procedureslong recognized to pose a risk of accidental prion transmission2,3.
参考文献：Transmission of amyloid-β protein pathologyfrom cadaveric pituitary growth hormone. Nature. 2018 Dec;564(7736):415-419.
摘要：Clinicalobservations indicate that the paramedian region of the thalamus is a criticalnode for controlling wakefulness. However, the specific nucleus and neuralcircuitry for this function remain unknown. Using in vivo fiber photometry ormultichannel electrophysiological recordings in mice, we found thatglutamatergic neurons of the paraventricular thalamus (PVT) exhibited highactivities during wakefulness. Suppression of PVT neuronal activity caused areduction in wakefulness, whereas activation of PVT neurons induced atransition from sleep to wakefulness and an acceleration of emergence fromgeneral anesthesia. Moreover, our findings indicate that the PVT-nucleus accumbensprojections and hypocretin neurons in the lateral hypothalamus to PVTglutamatergic neurons' projections are the effector pathways for wakefulnesscontrol. These results demonstrate that the PVT is a keywakefulness-controlling nucleus in the thalamus.
1.The paraventricular thalamus is a critical thalamic area for wakefulness.Science.2018 Oct 26;362(6413):429-434.
2.Dynamic salience processing in paraventricular thalamus gates associativelearning. Science. 2018 Oct 26;362(6413):423-429.
摘要：Why aresome visual stimuli consciously detected, whereas others remain subliminal? Weinvestigated the fate of weak visual stimuli in the visual and frontal cortexof awake monkeys trained to report stimulus presence. Reported stimuli wereassociated with strong sustained activity in the frontal cortex, and frontalactivity was weaker and quickly decayed for unreported stimuli. Informationabout weak stimuli could be lost at successive stages en route from the visualto the frontal cortex, and these propagation failures were confirmed throughmicrostimulation of area V1. Fluctuations in response bias and sensitivityduring perception of identical stimuli were traced back to prestimulusbrain-state markers. A model in which stimuli become consciously reportablewhen they elicit a nonlinear ignition process in higher cortical areasexplained our results.
参考文献：Thethreshold for conscious report: Signal loss and response bias in visual andfrontal cortex. Science. 2018 May 4;360(6388):537-542.
摘要：Thesensory cells that are responsible for hearing include the cochlear inner haircells (IHCs) and outer hair cells (OHCs), with the OHCs being necessary forsound sensitivity and tuning1. Both cell types are thought to arise from commonprogenitors; however, our understanding of the factors that control the fate ofIHCs and OHCs remains limited. Here we identify Ikzf2 (which encodes Helios) asan essential transcription factor in mice that is required for OHC functionalmaturation and hearing. Helios is expressed in postnatal mouse OHCs, and in thecello mouse model a point mutation in Ikzf2 causes early-onset sensorineuralhearing loss. Ikzf2cello/cello OHCs have greatly reduced prestin-dependentelectromotile activity, a hallmark of OHC functional maturation, and showreduced levels of crucial OHC-expressed genes such as Slc26a5 (which encodesprestin) and Ocm. Moreover, we show that ectopic expression of Ikzf2 in IHCs:induces the expression of OHC-specific genes; reduces the expression ofcanonical IHC genes; and confers electromotility to IHCs, demonstrating thatIkzf2 can partially shift the IHC transcriptome towards an OHC-like identity.
1. Helios is a key transcriptionalregulator of outer hair cell maturation.Nature. 2018 Nov;563(7733):696-700.
2.Trans-differentiation of outer hair cells into inner hair cells in the absenceof INSM1. Nature. 2018 Nov;563(7733):691-695.
摘要：Ageing is a major risk factor for many neurologicalpathologies, but its mechanisms remain unclear. Unlike other tissues, theparenchyma of the central nervous system (CNS) lacks lymphatic vasculature andwaste products are removed partly through a paravascular route. (Re)discoveryand characterization of meningeal lymphatic vessels has prompted an assessmentof their role in waste clearance from the CNS. Here we show that meningeallymphatic vessels drain macromolecules from the CNS (cerebrospinal andinterstitial fluids) into the cervical lymph nodes in mice. Impairment ofmeningeal lymphatic function slows paravascular influx of macromolecules intothe brain and efflux of macromolecules from the interstitial fluid, and inducescognitive impairment in mice. Treatment of aged mice with vascular endothelialgrowth factor C enhances meningeal lymphatic drainage of macromolecules fromthe cerebrospinal fluid, improving brain perfusion and learning and memoryperformance. Disruption of meningeallymphatic vessels in transgenic mouse models of Alzheimer's disease promotesamyloid-β deposition in the meninges, which resembles human meningealpathology, and aggravates parenchymal amyloid-β accumulation. Meningeallymphatic dysfunction may be an aggravating factor in Alzheimer's diseasepathology and in age-associated cognitive decline. Thus, augmentation ofmeningeal lymphatic function might be a promising therapeutic target forpreventing or delaying age-associated neurological diseases.
参考文献：Functional aspects of meningeal lymphaticsin ageing and Alzheimer's disease. Nature. 2018 Aug;560(7717):185-191.
摘要：The pathologic accumulation andaggregation of α-synuclein (α-syn) underlies Parkinson's disease (PD).The molecular mechanisms by which pathologic α-syn causes neurodegeneration inPD are not known. Here, we found that pathologic α-syn activates poly(adenosine5'-diphosphate-ribose) (PAR) polymerase-1 (PARP-1), and PAR generationaccelerates the formation of pathologic α-syn, resulting in celldeathvia parthanatos. PARP inhibitors or genetic deletion of PARP-1 preventedpathologic α-syn toxicity. In a feed-forward loop, PAR converted pathologicα-syn to a more toxic strain. PAR levels were increased in the cerebrospinal fluidand brains of patients with PD, suggesting that PARP activation plays a role inPD pathogenesis. Thus, strategies aimed at inhibiting PARP-1 activation couldhold promise as a disease-modifying therapy to prevent the loss ofdopamine neurons in PD.
参考文献：Poly(ADP-ribose) drives pathologicα-synuclein neurodegeneration in Parkinson's disease. Science. 2018 Nov2;362(6414). pii: eaat8407.
摘要：Models of systems memory consolidation postulatea fast-learning hippocampal store and a slowly developing, stable neocorticalstore. Accordingly, early neocortical contributions to memory are deemed toreflect a hippocampus-driven online reinstatement of encoding activity. Incontrast, we found that learning rapidly engenders an enduring memory engram inthe human posterior parietal cortex. We assessed microstructural plasticity viadiffusion-weighted magnetic resonance imaging as well as functional brain activity in an object-location learning task. Wedetected neocortical plasticity as early as 1 hour after learning and foundthat it was learning specific, enabled correct recall, and overlapped withmemory-related functional activity. These microstructural changes persistedover 12 hours. Our results suggest that new traces can be rapidly encoded intothe parietal cortex, challenging views of a slow-learning neocortex.
参考文献：Fasttrack to the neocortex: A memory engram in the posterior parietal cortex. Science.2018 Nov 30;362(6418):1045-1048.
摘要：Episodicmemory, the conscious recollection of past events, is typically experiencedfrom a first-person (egocentric) perspective. The hippocampus plays anessential role in episodic memory and spatial cognition. Although theallocentric nature of hippocampal spatial coding is well understood, little isknown about whether the hippocampus receives egocentric information aboutexternal items. We recorded in rats the activity of single neurons from thelateral entorhinal cortex (LEC) and medial entorhinal cortex (MEC), the two majorinputs to the hippocampus. Many LEC neurons showed tuning for egocentricbearing of external items, whereas MEC cells tended to represent allocentricbearing. These results demonstrate a fundamental dissociation between thereference frames of LEC and MEC neural representations.
参考文献：Egocentriccoding of external items in the lateral entorhinal cortex. Science. 2018 Nov23;362(6417):945-949.
摘要：The gutis now recognized as a major regulator of motivational and emotional states.However, the relevant gut-brain neuronal circuitry remains unknown. We showthat optical activation of gut-innervating vagal sensory neurons recapitulatesthe hallmark effects of stimulating brain reward neurons. Specifically, right,but not left, vagal sensory ganglion activation sustained self-stimulationbehavior, conditioned both flavor and place preferences, and induced dopaminerelease from Substantia nigra. Cell-specific transneuronal tracing revealedasymmetric ascending pathways of vagal origin throughout the CNS. Inparticular, transneuronal labeling identified the glutamatergic neurons of thedorsolateral parabrachial region as the obligatory relay linking the rightvagal sensory ganglion to dopamine cells in Substantia nigra. Consistently,optical activation of parabrachio-nigral projections replicated the rewardingeffects of right vagus excitation. Our findings establish the vagalgut-to-brain axis as an integral component of the neuronal reward pathway. Theyalso suggest novel vagal stimulation approaches to affective disorders.
参考文献：ANeural Circuit for Gut-Induced Reward. Cell. 2018 Oct 18;175(3):665-678.e23.
摘要：Thehuman cerebral cortex is distinguished by its large size and abundantgyrification, or folding. However, the evolutionary mechanisms that drivecortical size and structure are unknown. Although genes that are essential forcortical developmental expansion have been identified from the genetics ofhuman primary microcephaly (a disorder associated with reduced brain size andintellectual disability) 1 , studies of these genes in mice, which have asmooth cortex that is one thousand times smaller than the cortex of humans,have provided limited insight. Mutations in abnormal spindle-likemicrocephaly-associated (ASPM), the most common recessive microcephaly gene,reduce cortical volume by at least 50% in humans2-4, but have little effect onthe brains of mice5-9; this probably reflects evolutionarily divergentfunctions of ASPM10,11. Here we used genome editing to create a germlineknockout of Aspm in the ferret (Mustela putorius furo), a species with alarger, gyrified cortex and greater neural progenitor cell diversity12-14 thanmice, and closer protein sequence homology to the human ASPM protein. Aspm knockoutferrets exhibit severe microcephaly (25-40% decreases in brain weight),reflecting reduced cortical surface area without significant change in corticalthickness, as has been found in human patients3,4, suggesting that loss of'cortical units' has occurred. The cortex of fetal Aspm knockout ferretsdisplays a very large premature displacement of ventricular radial glial cellsto the outer subventricular zone, where many resemble outer radial glia, asubtype of neural progenitor cells that are essentially absent in mice and havebeen implicated in cerebral cortical expansion in primates12-16. These datasuggest an evolutionary mechanism by which ASPM regulates cortical expansion bycontrolling the affinity of ventricular radial glial cells for the ventricularsurface, thus modulating the ratio of ventricular radial glial cells, the mostundifferentiated cell type, to outer radial glia, a more differentiatedprogenitor.
参考文献：Aspmknockout ferret reveals an evolutionary mechanism governing cerebral corticalsize. Nature. 2018 Apr;556(7701):370-375.
摘要：Thespecific effects of sleep on synaptic plasticity remain unclear. We report thatmouse hippocampal sharp-wave ripple oscillations serve as intrinsic events thattrigger long-lasting synaptic depression. Silencing of sharp-wave ripplesduring slow-wave states prevented the spontaneous down-regulation of netsynaptic weights and impaired the learning of new memories. The synapticdown-regulation was dependent on the N-methyl-d-aspartate receptor andselective for a specific input pathway. Thus, our findings are consistent withthe role of slow-wave states in refining memory engrams by reducing recentmemory-irrelevant neuronal activity and suggest a previously unrecognizedfunction for sharp-wave ripples.
参考文献：Hippocampalripples down-regulate synapses. Science. 2018 Mar 30;359(6383):1524-1527.
摘要：Walkingis the predominant locomotor behavior expressed by land-dwelling vertebrates,but it is unknown when the neural circuits that are essential for limb controlfirst appeared. Certain fish species display walking-like behaviors, raisingthe possibility that the underlying circuitry originated in primitive marinevertebrates. We show that the neural substrates of bipedalism are present inthe little skate Leucoraja erinacea, whose common ancestor with tetrapodsexisted ∼420 million years ago. Leucorajaexhibits core features of tetrapod locomotor gaits, including left-rightalternation and reciprocal extension-flexion of the pelvic fins. Leucoraja alsodeploys a remarkably conserved Hox transcription factor-dependent program thatis essential for selective innervation of fin/limb muscle. This network encodesperipheral connectivity modules that are distinct from those used in axialmuscle-based swimming and has apparently been diminished in most modern fish.These findings indicate that the circuits that are essential for walkingevolved through adaptation of a genetic regulatory network shared by all vertebrateswith paired appendages. VIDEO ABSTRACT.
参考文献：TheAncient Origins of Neural Substrates for Land Walking. Cell. 2018 Feb8;172(4):667-682.e15.
摘要：Neuronalsynapse formation and remodeling are essential to central nervous system (CNS)development and are dysfunctional in neurodevelopmental diseases. Innate immunesignals regulate tissue remodeling in the periphery, but how this affects CNSsynapses is largely unknown. Here, we show that the interleukin-1 familycytokine interleukin-33 (IL-33) is produced by developing astrocytes and isdevelopmentally required for normal synapse numbers and neural circuit functionin the spinal cord and thalamus. We find that IL-33 signals primarily tomicroglia under physiologic conditions, that it promotes microglial synapseengulfment, and that it can drive microglial-dependent synapse depletion invivo. These data reveal a cytokine-mediated mechanism required to maintainsynapse homeostasis during CNS development.
参考文献：Astrocyte-derivedinterleukin-33 promotes microglial synapse engulfment and neural circuitdevelopment. Science. 2018 Mar 16;359(6381):1269-1273.
摘要：Decidingwhen and whether to move is critical for survival. Loss of dopamine neurons(DANs) of the substantia nigra pars compacta (SNc) in patients with Parkinson'sdisease causes deficits in movement initiation and slowness of movement. Therole of DANs in self-paced movement has mostly been attributed to their tonicactivity, whereas phasic changes in DAN activity have been linked to rewardprediction. This model has recently been challenged by studies showingtransient changes in DAN activity before or during self-paced movementinitiation. Nevertheless, the necessity of this activity for spontaneousmovement initiation has not been demonstrated, nor has its relation toinitiation versus ongoing movement been described. Here we show that a largeproportion of SNc DANs, which did not overlap with reward-responsive DANs,transiently increased their activity before self-paced movement initiation inmice. This activity was not action-specific, and was related to the vigour offuture movements. Inhibition of DANs when mice were immobile reduced theprobability and vigour of future movements. Conversely, brief activation ofDANs when mice were immobile increased the probability and vigour of futuremovements. Manipulations of dopamine activity after movement initiation did notaffect ongoing movements. Similar findings were observed for the initiation andexecution of learned action sequences. These findings causally implicate DANactivity before movement initiation in the probability and vigour of futuremovements.
参考文献：Dopamineneuron activity before action initiation gates and invigorates futuremovements. Nature. 2018 Feb 8;554(7691):244-248.
27、神经科学临床和基础Learning & Memory亚群；