Reshaping the Cortical Connectivity Gradient by Long-Term Cognitive Training During Development

The organization of the brain follows a topologi-cal hierarchy that changes dynamically during development.However,it remains unknown whether and how cognitive training administered over multiple years during develop-ment can modify this hierarchical topology.By measuring the brain and behavior of school children who had carried out abacus-based mental calculation(AMC)training for five years(starting from 7 years to 12 years old)in pre-training and post-training,we revealed the reshaping effect of long-term AMC intervention during development on the brain hierarchical topology.We observed the development-induced emergence of the default network,AMC training-promoted shifting,and regional changes in cortical gradi-ents.Moreover,the training-induced gradient changes were located in visual and somatomotor areas in association with the visuospatial/motor-imagery strategy.We found that gradient-based features can predict the math ability within groups.Our findings provide novel insights into the dynamic nature of network recruitment impacted by long-term cognitive training during development.

Dopaminergic Remodeling During a Critical Developmental Window:Linking Drug Use to Adult Aggression

Behaviors can be shaped and modulated by the dopamine system,which can be remodeled in adolescents due to environmental factors,including pharmacologic exposure,stress,and rewarding experiences,leading to various adolescentonset neuropsychiatric disorders[1-3].A deficiency of dopamine transporter(DAT),responsible for reuptaking extracellular DA.

Astrocyte-Mediated Myelin Phagocytosis in Ischemia

The myelin sheath-supporting cells,oligodendrocytes and Schwann cells,are susceptible toischemia.Therefore,ischemic stroke is usually characterized by evident demyelination^([l]).Although oligodendrocytes are the major player in myelination,glial cells,including microglia and astrocytes,also contribute to myelination and demyelination^([2]).In the early stages of ischemic stroke,microgliamediated myelin debris removal through phagocytosis has been widely studied^([3]).

The Structure and Function of Glial Networks:Beyond the Neuronal Connections

Glial cells,consisting of astrocytes,oligodendrocyte lineage cells,and microglia,account for>50% of the total number of cells in the mammalian brain.They play key roles in the modulation of various brain activities under physiological and pathological conditions.Although the typical morphological features and characteristic functions of these cells are well described,the organization of interconnections of the different glial cell populations and their impact on the healthy and diseased brain is not completely understood.Understanding these processes remains a profound challenge.Accumulating evidence suggests that glial cells can form highly complex interconnections with each other.The astroglial network has been well described.Oligodendrocytes and microglia may also contribute to the formation of glial networks under various circumstances.In this review,we discuss the structure and function of glial networks and their pathological relevance to central nervous system diseases.We also highlight opportunities for future research on the glial connectome.

Retraction Note to:Gray Matter-Based Age Prediction Characterizes Different Regional Patterns

The authors have retracted this article.After publication we found an error in the implementation code that resulted in data leakage in the age-prediction model training process.We have redesigned the prediction model and tested the mode with an extended dataset(around 2000 subjects,in contrast to the 600 subjects in this article).

Targeting Peripheral μ-opioid Receptors or μ-opioid Receptor-Expressing Neurons Does not Prevent Morphine-induced Mechanical Allodynia and Anti-allodynic Tolerance

The chronic use of morphine and other opioids is associated with opioid-induced hypersensitivity(OIH)and analgesic tolerance.Among the different forms of OIH and tolerance,the opioid receptors and cell types mediating opioid-induced mechanical allodynia and anti-allodynic tolerance remain unresolved.Here we demonstrated that the loss of peripheralμ-opioid receptors(MORs)or MOR-expressing neurons attenuated thermal tolerance,but did not affect the expression and maintenance of morphine-induced mechanical allodynia and anti-allodynic tolerance.To confirm this result,we made dorsal root ganglia-dorsal roots-sagittal spinal cord slice preparations and recorded low-threshold Aβ-fiber stimulation-evoked inputs and outputs in superficial dorsal horn neurons.Consistent with the behavioral results,peripheral MOR loss did not prevent the opening of Aβmechanical allodynia pathways in the spinal dorsal horn.Therefore,the peripheral MOR signaling pathway may not be an optimal target for preventing mechanical OIH and analgesic tolerance.Future studies should focus more on central mechanisms.

Deep Transcranial Magnetic Stimulation as a Potential Approach for Digital Pain Management in Patients with Psychotic Disorder

Dear Editor,Pain is a common and complex clinical problem which affects 28%-50%of the general population and is responsible for large health-related costs.People with chronic pain often develop nociceptive sensitization,having mood and anxiety disorders as comorbidities.Sustained pain may alter the processing of affective information in the brain,thereby inducing anxio-depressive disorders.

Reading-related Brain Function Restored to Normal After Articulation Training in Patients with Cleft Lip and Palate:An fMRI Study

Cleft lip and/or palate(CLP)are the most common craniofacial malformations in humans.Speech problems often persist even after cleft repair,such that follow-up articulation training is usually required.However,the neural mechanism behind effective articulation training remains largely unknown.We used fMRI to investigate the differences in brain activation,functional connectivity,and effective connectivity across CLP patients with and without articulation training and matched normal participants.We found that training promoted task-related brain activation among the articulation-related brain networks,as well as the global attributes and nodal efficiency in the functional-connectivity-based graph of the network.Our results reveal the neural correlates of effective articulation training in CLP patients,and this could contribute to the future improvement of the post-repair articulation training program.

CRISPR-Based Genome-Editing Tools for Huntington’s Disease Research and Therapy

Huntington’s disease(HD)is an autosomal dominantly-inherited neurodegenerative disease,which is caused by CAG trinucleotide expansion in exon 1 of the Huntingtin(HTT)gene.Although HD is a rare disease,its monogenic nature makes it an ideal model in which to understand pathogenic mechanisms and to develop therapeutic strategies for neurodegenerative diseases.Clustered regularly-interspaced short palindromic repeats(CRISPR)is the latest technology for genome editing.Being simple to use and highly efficient,CRISPR-based genome-editing tools are rapidly gaining popularity in biomedical research and opening up new avenues for disease treatment.Here,we review the development of CRISPR-based genome-editing tools and their applications in HD research to offer a translational perspective on advancing the genome-editing technology to HD treatment.

cPKCγ Deficiency Exacerbates Autophagy Impairment and Hyperphosphorylated Tau Buildup through the AMPK/mTOR Pathway in Mice with Type 1 Diabetes Mellitus

Type 1 diabetes mellitus(T1DM)-induced cognitive dysfunction is common,but its underlying mechanisms are still poorly understood.In this study,we found that knockout of conventional protein kinase C(cPKC)γsignificantly increased the phosphorylation of Tau at Ser214 and neurofibrillary tangles,but did not affect the activities of GSK-3βand PP2A in the hippocampal neurons of T1DM mice.cPKCγdeficiency significantly decreased the level of autophagy in the hippocampal neurons of T1DM mice.Activation of autophagy greatly alleviated the cognitive impairment induced by cPKCγdeficiency in T1DM mice.Moreover,cPKCγdeficiency reduced the AMPK phosphorylation levels and increased the phosphorylation levels of mTOR in vivo and in vitro.The high glucose-induced Tau phosphorylation at Ser214 was further increased by the autophagy inhibitor and was significantly decreased by an mTOR inhibitor.In conclusion,these results indicated that cPKCγpromotes autophagy through the AMPK/mTOR signaling pathway,thus reducing the level of phosphorylated Tau at Ser214 and neurofibrillary tangles.

RhoGEF Trio Regulates Radial Migration of Projection Neurons via Its Distinct Domains

The radial migration of cortical pyramidal neurons(PNs)during corticogenesis is necessary for establishing a multilayered cerebral cortex.Neuronal migration defects are considered a critical etiology of neurodevelopmental disorders,including autism spectrum disorders(ASDs),schizophrenia,epilepsy,and intellectual disability(ID).TRIO is a high-risk candidate gene for ASDs and ID.However,its role in embryonic radial migration and the etiology of ASDs and ID are not fully understood.In this study,we found that the in vivo conditional knockout or in utero knockout of Trio in excitatory precursors in the neocortex caused aberrant polarity and halted the migration of late-born PNs.Further investigation of the underlying mechanism revealed that the interaction of the Trio N-terminal SH3 domain with Myosin X mediated the adherence of migrating neurons to radial glial fibers through regulating the membrane location of neuronal cadherin(N-cadherin).Also,independent or synergistic overexpression of RAC1 and RHOA showed different phenotypic recoveries of the abnormal neuronal migration by affecting the morphological transition and/or the glial fiber-dependent locomotion.Taken together,our findings clarify a novel mechanism of Trio in regulating N-cadherin cell surface expression via the interaction of Myosin X with its N-terminal SH3 domain.These results suggest the vital roles of the guanine nucleotide exchange factor 1(GEF1)and GEF2 domains in regulating radial migration by activating their Rho GTPase effectors in both distinct and cooperative manners,which might be associated with the abnormal phenotypes in neurodevelopmental disorders.

Neuroscience Bulletin Copyright Transfer Statement and Submission Form

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Co-editing PINK1 and DJ-1 Genes Via Adeno-Associated Virus-Delivered CRISPR/Cas9 System in Adult Monkey Brain Elicits Classical Parkinsonian Phenotype

Whether direct manipulation of Parkinson’s disease(PD)risk genes in the adult monkey brain can elicit a Parkinsonian phenotype remains an unsolved issue.Here,we used an adeno-associated virus serotype 9(AAV9)-delivered CRISPR/Cas9 system to directly co-edit PINK1 and DJ-1 genes in the substantia nigras(SNs)of two monkey groups:an old group and a middle-aged group.After the operation,the old group exhibited all the classic PD symptoms,including bradykinesia,tremor,and postural instability,accompanied by key pathological hallmarks of PD,such as severe nigral dopaminergic neuron loss(>64%)and evidentα-synuclein pathology in the gene-edited SN.In contrast,the phenotype of their middle-aged counterparts,which also showed clear PD symptoms and pathological hallmarks,were less severe.In addition to the higher final total PD scores and more severe pathological changes,the old group were also more susceptible to gene editing by showing a faster process of PD progression.These results suggested that both genetic and aging factors played important roles in the development of PD in the monkeys.Taken together,this system can effectively develop a large number of genetically-edited PD monkeys in a short time(6–10 months),and thus provides a practical transgenic monkey model for future PD studies.

Tau Accumulation and Defective Autophagy:A Common Pathological Mechanism Underlying Repeat-Expansion-Induced Neurodegenerative Diseases?

Repetitive DNA tracts(microsatellites)occur thousands of times throughout the human genome,and their expansion is known to cause many diseases.Expansion of CAG repeats encoding poly glutamine(polyQ)tracts is a pathological cause of nine neurodegenerative diseases:spinal and bulbar muscular atrophy,Huntington’s disease,dentatorubropallidoluysian atrophy,and six autosomal dominant forms of spinocerebellar ataxia(SCA1,2,3,6,7,and 17)[1].

“Transient”or“Persistent”Coding for Working Memory

Working memory(WM)maintains information temporarily for subsequent goal-directed behaviors,such as remembering a telephone number to dial.WM serves as a supporting mental workspace for many cognitive functions such as mental calculation,reading,and learning new skills.The critical role of persistent activity in the prefrontal cortex in WM,originally proposed to bridge sensory information and motor responses[1],has been severely debated recently[2,3].

Purines:From Diagnostic Biomarkers to Therapeutic Agents in Brain Injury

The purines constitute a family of inter-related compounds that serve a broad range of important intracellular and extracellular biological functions.In particular,adenosine triphosphate(ATP)and its metabolite and precursor,adenosine,regulate a wide variety of cellular and systems-level physiological processes extending from ATP acting as the cellular energy currency,to the adenosine arising from the depletion of cellular ATP and responding to reduce energy demand and hence to preserve ATP during times of metabolic stress.This inter-relationship provides opportunities for both the diagnosis of energy depletion during conditions such as stroke,and the replenishment of ATP after such events.In this review we address these opportunities and the broad potential of purines as diagnostics and restorative agents.

Paraventricular Thalamus as A Major Thalamic Structure for Wake Control

The thalamus is the gate of the cerebral cortex, the ultimate target for the neural networks controlling behavioral states and cognitive functions. According to the reticular theory initially proposed by Moruzzi and Magoun, excitatory inputs from large reticular zones of the brainstem via widespread intra- and extra-thalamocortical systems finally activate the cerebral cortex to cause generalized cortical activation and wakefulness [1]. This theory proposes a central relay role to the thalamus for cortical activation as supported by early studies using neurodegeneration techniques and by the elegant work of Steriade’s group and other investigators illustrating the electrophysiological mechanisms of the thalamocortical system at the cellular level during wakefulness, rapid eye-movement sleep (REMs) and non-REM sleep (NREMs)[2].

Legal and Ethical Issues in Brain Banking

The legal and ethical issues in brain banking are numerous.The post-mortem removal and retention of organs as well as research with human tissue and genetic information,have posed various dilemmas in the fields of law and ethics.Due to the relative novelty of these issues,the law is often lacking in clear instructions and unambiguous guidelines.The ethical problems specifically involving post-mortem cell and tissue banking for research purposes are not always specifically taken into account.This means that a brain bank frequently does not qualify for a certain well-defined legal regime.Because of this and the fact that the existing regimes differ significantly throughout the world,many uncertainties arise for the initiation and management of brain banks.Guidelines on informed consent,confidentiality,financial sustainability,accountability,and transparency are conditions sine qua non for the good conduct of a professional brain bank and are briefly highlighted.

Cortical Organization of Centrifugal Afferents to the Olfactory Bulb: Mono-and Trans-synaptic Tracing with Recombinant Neurotropic Viral Tracers

Sensory processing is strongly modulated by different brain and behavioral states,and this is based on the top-down modulation.In the olfactory system,local neural circuits in the olfactory bulb(OB)are innervated by centrifugal afferents in order to regulate the processing of olfactory information in the OB under different behavioral states.The purpose of the present study was to explore the organization of neural networks in olfactory-related cortices and modulatory nuclei that give rise to direct and indirect innervations to the glomerular layer(GL)of the OB at the whole-brain scale.Injection of different recombinant attenuated neurotropic viruses into the GL showed that it received direct inputs from each layer in the OB,centrifugal inputs from the ipsilateralanterior olfactory nucleus(AON),anterior piriform cortex(Pir),and horizontal limb of diagonal band of Broca(HDB),and various indirect inputs from bilateral cortical neurons in the AON,Pir,amygdala,entorhinal cortex,hippocampus,HDB,dorsal raphe,median raphe and locus coeruleus.These results provide a circuitry basis that will help further understand the mechanism by which olfactory informationprocessing in the OB is regulated.

Blockade of Endogenous Angiotensin-(1–7) in Hypothalamic Paraventricular Nucleus Attenuates High Salt-Induced Sympathoexcitation and Hypertension

Angiotensin(Ang)-(1–7) is an important biologically-active peptide of the renin-angiotensin system. This study was designed to determine whether inhibition of Ang-(1–7) in the hypothalamic paraventricular nucleus(PVN) attenuates sympathetic activity and elevates blood pressure by modulating pro-inflammatory cytokines(PICs)and oxidative stress in the PVN in salt-induced hypertension. Rats were fed either a high-salt(8% NaCl) or a normal salt diet(0.3% NaCl) for 10 weeks, followed by bilateral microinjections of the Ang-(1–7) antagonist A-779 or vehicle into the PVN. We found that the mean arterial pressure(MAP), renal sympathetic nerve activity(RSNA), and plasma norepinephrine(NE) were significantly increased in salt-induced hypertensive rats. The high-salt diet also resulted in higher levels of the PICs interleukin-6, interleukin-1 beta, tumor necrosis factor alpha, and monocyte chemotactic protein-1, as well as higher gp91 phoxexpression and superoxide production in the PVN. Microinjection of A-779(3 nmol/50 nL) into the bilateral PVN of hypertensive rats not only attenuated MAP, RSNA, and NE, but also decreased the PICs and oxidative stress in the PVN. These results suggest that the increased MAP and sympathetic activity in salt-induced hypertension can be suppressed by blockade of endogenous Ang-(1–7) in the PVN, through modulation of PICs and oxidative stress.