Versatile strategies for adult neurogenesis:avenues to repair the injured brain

Brain injuries due to trauma or stroke are major causes of adult death and disability.Unfortunately,few interventions are effective for post-injury repair of brain tissue.After a long debate on whether endogenous neurogenesis actually happens in the adult human brain,there is now substantial evidence to support its occurrence.Although neurogenesis is usually significantly stimulated by injury,the reparative potential of endogenous differentiation from neural stem/progenitor cells is usually insufficient.Alternatively,exogenous stem cell transplantation has shown promising results in animal models,but limitations such as poor long-term survival and inefficient neuronal differentiation make it still challenging for clinical use.Recently,a high focus was placed on glia-to-neuron conversion under single-factor regulation.Despite some inspiring results,the validity of this strategy is still controversial.In this review,we summarize historical findings and recent advances on neurogenesis strategies for neurorepair after brain injury.We also discuss their advantages and drawbacks,as to provide a comprehensive account of their potentials for further studies.

Brain-wide N2cG compensation permits glycoprotein-deleted rabies virus to trace neural circuits across multiple synapses

Rabies-viruses-based retrograde tracers can spread across multiple synapses in a retrograde direction in the nervous system of rodents and primates,making them powerful tools for determining the structure and function of the complicated neural circuits of the brain.However,they have some limitations,such as posing high risks to human health and the inability to retrograde trans-synaptic label inputs from genetically-de¯ned starter neurons.Here,we established a new retrograde trans-multi-synaptic tracing method through brain-wide rabies virus glycoprotein(RVG)compensation,followed by glycoprotein-deleted rabies virus(RV-△G)infection in specific brain regions.Furthermore,in combination with the avian tumor virus receptor A(TVA)controlled by a cell-type-specific promoter,we found that EnvA-pseudotyped RV-△G can mediate e±cient retrograde trans-multi-synaptic transduction from cell-type-specific starter neurons.This study provides new alternative methods for neuroscience researchers to analyze the input neural networks of rodents and nonhuman primates.

Next-generation regenerative therapy for ischemic stroke using peripheral blood mononuclear cells

Stroke is the second leading cause of death and the third leading cause of disability worldwide after heart disease.Researchers predict that stroke deaths and permanent disabilities will increase worldwide by the year 2050.Single-target therapies may be insufficient,because ischemic cerebral injury involves several mechanisms.Cell-mediated therapies are ideal,because they target multiple cell types to enhance protection and recovery.

Soluble alpha-synuclein post-translational modifications:unexpected regulators of pathological alpha-synuclein amplification

The build-up of misfoldedα-synuclein(α-syn)in the central nervous system is the pathological hallmark of a number of neurodegenerative diseases that are known asα-synucleinopathies.These include Parkinson’s disease(PD),Parkinson’s disease with dementia(PDD),dementia with Lewy body(LB),multiple system atrophy(MSA),and a subset of Alzheimer’s disease.Growing evidence underscores that the intercellular transmission and amplification of pathologicalα-syn are critical processes underlying the progression ofα-synucleinopathies(Peng et al.,2020),and as such,the study of these processes could lead to the identification of promising therapeutics to mitigate disease progression.Most previous studies have focused solely on pathological seeds in relation to disease progression.

Recent advances and future therapy development for Alzheimer’s disease and related disorders

Over 55 million people globally live with Alzheimer’s disease(AD)or related dementias(ADRD)and the number is expected to double every twenty years.Unt i l recent l y,onl y symptomatic treatments were available to patients with AD,including acetylcholine esterase inhibitors,of which the last one,galantamine,was approved by the US Food and Drug Administration(FDA)in 2001.

Unveiling the Threat: Case Reports of Extra-Pulmonary Tuberculosis among Sanctuary Chimpanzees

Primate sanctuaries across Africa play a pivotal role in the rescue and rehabilitation of confiscated and rescued wild primates, many of whom have had extensive contact with humans prior to their arrival and throughout the rehabilitation process, heightening the risk of disease transmission. While tuberculosis is not naturally occurring in free-living chimpanzees, it has been extensively observed in captive primates that have been in close proximity to humans or other captive primates infected with Mycobacterium tuberculosis. This case report delves into an outbreak of extra-pulmonary tuberculosis among juvenile chimpanzees within a sanctuary, detailing the associated diagnostic challenges and treatment approaches. The five cases had close contact with a caregiver infected with tuberculosis, subsequently transmitting the infection to other in-contact chimpanzees. Prolonged treatment, employing the human protocol of quadri-therapy (rifampicin, isoniazid, pyrazinamide, and ethambutol), followed by bi-therapy (rifampicin and isoniazid), resulted in complete resolution for all five cases. These cases underscore the critical importance of maintaining high levels of biosecurity, implementing effective quarantine measures, and adhering to strict hygiene practices when working with non-human primates.

Morphological disruption and visual tuning alterations in the primary visual cortex in glaucoma(DBA/2J)mice

Glaucoma is a leading cause of irreve rsible blindness wo rldwide,and previous studies have shown that,in addition to affecting the eyes,it also causes abnormalities in the brain.However,it is not yet clear how the primary visual cortex(V1)is altered in glaucoma.This study used DBA/2J mice as a model for spontaneous secondary glaucoma.The aim of the study was to compare the electrophysiological and histomorphological chara cteristics of neurons in the V1between 9-month-old DBA/2J mice and age-matched C57BL/6J mice.We conducted single-unit recordings in the V1 of light-anesthetized mice to measure the visually induced responses,including single-unit spiking and gamma band oscillations.The morphology of layerⅡ/Ⅲneurons was determined by neuronal nuclear antigen staining and Nissl staining of brain tissue sections.Eighty-seven neurons from eight DBA/2J mice and eighty-one neurons from eight C57BL/6J mice were examined.Compared with the C57BL/6J group,V1 neurons in the DBA/2J group exhibited weaker visual tuning and impaired spatial summation.Moreove r,fewer neuro ns were observed in the V1 of DBA/2J mice compared with C57BL/6J mice.These findings suggest that DBA/2J mice have fewer neurons in the VI compared with C57BL/6J mice,and that these neurons have impaired visual tuning.Our findings provide a better understanding of the pathological changes that occur in V1 neuron function and morphology in the DBA/2J mouse model.This study might offer some innovative perspectives regarding the treatment of glaucoma.

The impact of vitamin D deficiency on neurogenesis in the adult brain

There is increasing evidence from epidemiological studies indicating that vitamin D deficiency during adulthood is associated with adverse brain outcomes in humans(Ginde et al.,2009)and rodents(Groves et al.,2014),however,a causal relationship has not yet been established.We have previously shown in a mouse model that vitamin D deficiency during adulthood impacts on a range of brain functions(Groves et al.,2013)and should therefore be con-

Focus on the gut-brain axis: multiple sclerosis, the intestinal barrier and the microbiome

The brain-gut axis serves as the bidirectional connection between the gut microbiome, the intestinal barrier and the immune system that might be relevant for the pathophysiology of inflammatory demyelinating diseases. People with multiple sclerosis have been shown to have an altered microbiome, increased intestinal permeability and changes in bile acid metabolism. Experimental evidence suggests that these changes can lead to profound alterations of peripheral and central nervous system immune regulation. Besides being of pathophysiological interest, the brain-gut axis could also open new avenues of therapeutic targets. Modification of the microbiome, the use of probiotics, fecal microbiota transplantation, supplementation with bile acids and intestinal barrier enhancers are all promising candidates. Hopefully, pre-clinical studies and clinical trials will soon yield significant results.

Mild closed head traumatic brain injury-induced changes in monoamine neurotransmitters in the trigeminal subnuclei of a rat model:mechanisms underlying orofacial allodynias and headache

Our recent findings have demonstrated that rodent models of closed head traumatic brain injury exhibit comprehensive evidence of progressive and enduring orofacial allodynias, a hypersensitive pain response induced by non-painful stimulation. These allodynias, tested using thermal hyperalgesia, correlated with changes in several known pain signaling receptors and molecules along the trigeminal pain pathway, especially in the trigeminal nucleus caudalis. This study focused to extend our previous work to investigate the changes in monoamine neurotransmitter immunoreactivity changes in spinal trigeminal nucleus oralis, pars interpolaris and nucleus tractus solitaries following mild to moderate closed head traumatic brain injury, which are related to tactile allodynia, touch-pressure sensitivity, and visceral pain. Our results exhibited significant alterations in the excitatory monoamine, serotonin, in spinal trigeminal nucleus oralis and pars interpolaris which usually modulate tactile and mechanical sensitivity in addition to the thermal sensitivity. Moreover, we also detected a robust alteration in the expression of serotonin, and inhibitory molecule norepinephrine in the nucleus tractus solitaries, which might indicate the possibility of an alteration in visceral pain, and existence of other morbidities related to solitary nucleus dysfunction in this rodent model of mild to moderate closed head traumatic brain injury. Collectively, widespread changes in monoamine neurotransmitter may be related to orofacial allodynhias and headache after traumatic brain injury.

Biliverdin Reductase-A correlates with inducible nitric oxide synthasein in atorvastatin treated aged canine brain

Alzheimer's disease is a neurodegenerative disorder characterized by progressive cognitive impairment and neuropathology. Recent preclinical and epidemiological studies proposed statins as a possible therapeutic drug for Alzheimer's disease, but the exact mechanisms of action are still unknown. Biliverdin reductase-A is a pleiotropic enzyme involved in cellular stress responses. It not only transforms biliverdin-IX alpha into the antioxidant bilirubin-IX alpha but its serine/threonine/ tyrosine kinase activity is able to modulate cell signaling networks. We previously reported the beneficial effects of atorvastatin treatment on biliverdin reductase-A and heme oxygenase-1 in the brains of a well characterized pre-clinical model of Alzheimer's disease, aged beagles, together with observed improvement in cognition. Here we extend our knowledge of the effects of atorvastatin on inducible nitric oxide synthase in parietal cortex, cerebellum and liver of the same animals. We demonstrated that atorvastatin treatment (80 mg/day for 14.5 months) to aged beagles selectively increased inducible nitric oxide synthase in the parietal cortex but not in the cerebellum. In contrast, inducible nitric oxide synthase protein levels were significantly decreased in the liver. Significant positive correlations were found between biliverdin reductase-A and inducible nitric oxide synthase as well as heme oxygenase-1 protein levels in the parietal cortex. The opposite was observed in the liver. Inducible nitric oxide synthase up-regulation in the parietal cortex was positively associated with improved biliverdin reductase-A functions, whereas the oxidative-induced impairment of biliverdin reductase-A in the liver negatively affected inducible nitric oxide synthase expression, thus suggesting a role for biliverdin reductase-A in atorvastatin-dependent inducible nitric oxide synthase changes. Interestingly, increased inducible nitric oxide synthase levels in the parietal cortex were not associated with higher oxidative/nitrosative stress levels. We hypothesize that biliverdin reductase-A-dependent inducible nitric oxide synthase regulation strongly contributes to the cognitive improvement observed following atorvastatin treatment.

Military traumatic brain injury:a challenge straddling neurology and psychiatry

Military psychiatry, a new subcategory of psychiatry, has become an invaluable, intangible effect of the war. In this review, we begin by examining related military research, summarizing the related epidemiological data, neuropathology, and the research achievements of diagnosis and treatment technology, and discussing its comorbidity and sequelae. To date, advances in neuroimaging and molecular biology have greatly boosted the studies on military traumatic brain injury(TBI). In particular, in terms of pathophysiological mechanisms, several preclinical studies have identified abnormal protein accumulation, blood–brain barrier damage, and brain metabolism abnormalities involved in the development of TBI. As an important concept in the field of psychiatry, TBI is based on organic injury, which is largely different from many other mental disorders. Therefore, military TBI is both neuropathic and psychopathic, and is an emerging challenge at the intersection of neurology and psychiatry.

Biological characteristics of brain natriuretic peptide and its association with central nervous system diseases

OBJECTIVE: To explain the mechanisms of tuhe synthesis, secretion and regulation of brain natriuretic peptide (BNP), and analyze its role in central nervous system diseases. DATA SOURCES: An online search of Pubmed was undertaken to identify articles related to BNP published in English from January 1990 to February 2007 by using the of "brain natriuretic peptide (BNP), central nervous system, subarachnoid hemorrhage (SAH), brain edema, epilepsy". Other articles were searched in China Hospital Knowledge Database (CHKD) by concrete name of journals and title of articles. STUDY SELECTION: The collected articles were primarily screened, those about BNP and its association with central nervous system diseases were selected, whereas the obviously irrelative ones excluded, and the full-texts of the other literatures were searched manually. DATA EXTRACTION: Totally 96 articles were collected, 40 of them were enrolled, and the other 56 were excluded due to repetitive studies or reviews. DATA SYNTHESIS: At present, there are penetrating studies on BNP in the preclinical medicine and clinical medicine of cerebrovascular and cardiovascular diseases, and the investigative outcomes have been gradually applied in clinical practice, and satisfactory results have been obtained. However, the application of BNP in diagnosing and treating central nervous system diseases is still at the experimental phase without - outstanding outcomes, thus the preclinical and clinical studies should be enhanced. CONCLUSION: As a kind of central medium or modulator, BNP plays a certain role in the occurrence, development and termination of central nervous system diseases, the BNP level in serum has certain changing law in SAH, brain edema, epilepsy, etc., but the specific mechanisms are unclear.

An orbitofrontal cortex to midbrain projection modulates neuropathic pain

Neuropathic pain is a long term and common pain disorder in clinics that is refractory to treatment,however,the neural substrates and underlying mechanisms are poorly understood.Using the com bination of neuronal mapping,optogenetics,chemogenetics,eletrophysiological recording,in vivo fiber photometry and behavioral testing,we previously identified a new neural circuit of BLA-mPFC-vIPAG and its key role in encoding and modulation of the spared nerve injury(SNI)-induced neuropathic pain..Here we report that the V M-vlOFC-vIPAG circuit modulates neuropathic pain and dissects the underlying mechanisms at cellular and circuitry level.

Emerging roles of NRBF2/PI3KC3 axis in maintaining homeostasis of brain and guts

NRBF2 has been identified as the fifth component of PI3KC3 complex and is required for maintaining the kinase activity to promote autophagy.However,the physiological and pathological roles of NRBF2are largely unknown.

Post-Concussion Syndrome after a Mild Traumatic Brain Injury: A Minefield for Clinical Practice

In this clinical practice review, the controversies and difficulties managing post concussion symptoms following mild traumatic brain injury are discussed. Based on considerable clinical experience in a designated Concussion Clinic, the authors (a neuropsychologist, a psychiatrist, and a neurologist) review relevant literature and issues for clinical practice, particularly with respect to understanding risk factors for and vulnerability to, development of chronic post-concussion symptoms. We contend it is not just the kind of head that matters but also the kind of complications, the kind of outcomes and the kind of management that can influence injury recovery. Given these complexities, a bio-psychosocial conceptualization of chronic post-concussion syndrome is appropriate. Though understanding is still elusive, management should not be biased by physiogenic or psychogenic aetiological theories for management needs to address patient reported outcomes regardless of underpinning aetiology.

Mapping big brains at subcellular resolution in the era of big data in zoology

Connectome-scale structural mapping is fundamental for understanding the underlying mechanisms of brain cognition and brain disease pathogenesis.By combining rapidly developing three-dimensional(3D)imaging techniques and big data analysis methods,researchers are working on mesoscale mapping of mammalian brains at an accelerated pace.Here,we briefly describe existing brain-wide imaging strategies,especially our recently established primateoptimized pipeline capable of pan-brain neuronal connectivity mapping at subcellular resolution,and further discuss their vast application prospects in the big data era of zoology.

Anatomical Evidence for the Neural Connection from the Emotional Brain to Autonomic Innervation in the Anterior Chamber Structures of the Eye

Objective Previous studies have shown that the autonomic nervous system(ANS),which can be affected by emotions,is important in the occurrence or progression of glaucoma.The autonomic innervation distributed in the anterior chamber(AC)structures might play an efferent role in the neural regulation of intraocular pressure(IOP).This study aimed to investigate the anatomic neural connection from the emotional brain to autonomic innervation in the AC.Methods A retrograde trans-multisynaptic pseudorabies virus encoded with an enhanced green fluorescent protein(PRV531)and non-trans-synaptic tracer FAST Dil were injected into the right eye of mice,respectively.Fluorescent localization in the emotional brain and preganglionic nuclei was studied.Five and a half days after PRV531 injection into the right AC,fluorescent signals were observed in several emotional brain regions,including the amygdala,agranular insular cortex,lateral septal nuclei,periaqueductal gray,and hypothalamus.Autonomic preganglionic nuclei,including Edinger-Westphal nucleus,superior salivatory nucleus,and intermediolateral nucleus,were labeled using PRV531.Results The sensory trigeminal nuclei were not labeled using PRV531.The fluorescence signals in the nuclei mentioned above showed bilateral distribution,primarily on the ipsilateral side.Seven days after injecting FAST Dil into the AC,we observed no FAST Dil-labeled neurons in the central nervous system.Conclusion Our results indicate a neural connection from the emotional brain to autonomic innervation in the AC,which provides anatomical support for the emotional influence of IOP via the ANS.

Nature can still be the strongest help against aging and neurodegeneration:the sirtuins way

Unfortunately,ag ing is not a reversible phenomenon and the processes of senescence are unavoidable.However,the biological effects of aging may be turned back,and with those,it can be reduced risk of all age-related illnesses,such as cardiovascular diseases,cancer,diabetes,and neurodegenerative diseases,including Alzheimer’s disease(AD),and Parkinson’s diseases(PD).In the latest decades,scientists worldwide therefore have developed several strategies,either natural or pharmacological,to counteract aging phenomena,with the final goal to improve human life expectancy.The main scientific rationale beyond these strategies focuses on the opportunity to reduce chronic low-grade inflammation(inflammaging),the increase in oxidative stress damage,and the impairment in the immune system,all typical mechanisms of senescence(Verdaguer et al.,2012).

A novel phenotype of B cells associated with enhanced phagocytic capability and chemotactic function after ischemic stroke

Accumulating evidence has demonstrated the involvement of B cells in neuroinflammation and neuroregeneration.However,the role of B cells in ischemic stroke remains unclear.In this study,we identified a novel phenotype of macrophage-like B cells in brain-infiltrating immune cells expressing a high level of CD45.Macrophage-like B cells chara cterized by co-expression of B-cell and macrophage markers,showed stronger phagocytic and chemotactic functions compared with other B cells and showed upregulated expression of phagocytosis-related genes.Gene Ontology analysis found that the expression of genes associated with phagocytosis,including phagosome-and lysosome-related genes,was upregulated in macrophage-like B cells.The phagocytic activity of macrophage-like B cells was ve rified by immunostaining and three-dimensional reconstruction,in which TREM2-labeled macrophage-like B cells enwrapped and internalized myelin debris after cerebral ischemia.Cell-cell interaction analysis revealed that macrophage-like B cells released multiple chemokines to recruit peripheral immune cells mainly via CCL pathways.Single-cell RNA sequencing showed that the transdiffe rentiation to macrophage-like B cells may be induced by specific upregulation of the transcription factor CEBP fa mily to the myeloid lineage and/or by downregulation of the transcription factor Pax5 to the lymphoid lineage.Furthermore,this distinct B cell phenotype was detected in brain tissues from mice or patients with traumatic brain injury,Alzheimer’s disease,and glioblastoma.Overall,these results provide a new perspective on the phagocytic capability and chemotactic function of B cells in the ischemic brain.These cells may serve as an immunotherapeutic target for regulating the immune response of ischemic stroke.