Current view of neurotransmitter changes underlying tinnitus

<正>Tinnitus is the perception of a monotonous sound not present in the environment.Nearly 20%of the U.S.population suffers from tinnitus,and tinnitus has been reported to be the most prevalent service-connected disability of all U.S.veterans(Henry et al.,2005;Eggermont,2012;Veterans Benefits Administration,2014).Many types of peripheral injury have been understood to induce tinnitus,including damage to the cochlea by intense     

Perspectives on disrupted-in-schizophrenia 1 signaling in neurogenesis

<正>New neurons are generated and integrate into existing circuitry within the hippocampal dentate gyrus and the olfactory bulb of most mammals(Gage and Temple,2013).Neurogenesis in the hippocampus persists through adulthood,and while its function and importance remains unclear,it appears to be required in the formation of specific types of     

Role of the caudate-putamen nucleus in sensory gating in induced tinnitus in rats

Tinnitus can be described as the conscious perception of sound without external stimulation,and it is often accompanied by anxiety,depression,and insomnia.Current clinical treatments for tinnitus are ineffective.Although recent studies have indicated that the caudateputamen nucleus may be a sensory gating area involved in noise elimination in tinnitus,the underlying mechanisms of this disorder are yet to be determined.To investigate the potential role of the caudate-putamen nucleus in experimentally induced tinnitus,we created a rat model of tinnitus induced by intraperitoneal administration of 350 mg/kg sodium salicylate.Our results revealed that the mean spontaneous firing rate of the caudate-putamen nucleus was increased by sodium salicylate treatment,while dopamine levels were decreased.In addition,electrical stimulation of the caudate-putamen nucleus markedly reduced the spontaneous firing rate of neurons in the primary auditory cortex.These findings suggest that the caudate-putamen nucleus plays a sensory gating role in sodium salicylate-induced tinnitus.This study was approved by the Institutional Animal Care and Use Committee of Peking University Health Science Center(approval No.A2010031)on December 6,2017.     

Economic “Activity-Silent” Synaptic Mechanisms of Working Memory

正Working memory(WM)allows humans to hold necessary information in temporary storage and manipulate such information online for higher-order cognitive functions,such as language understanding,decision making,and problem solving.Since its first appearance in the science of psychology in the 1960s,many theories have sought to elucidate the nature of WM.The most accepted model is     

“Standby” EMT and “immune cell trapping” structure as novel mechanisms for limiting neuronal damage after CNS injury

<正>The central nervous system(CNS)contains the two most important organs,the brain and spinal cord,for the orchestration of the mental and physical activities of life.Because of its importance,the human body has evolved barrier systems to protect CNS tissue from the external environment.This barrier is a membrane composed of tightly apposed cells and is selectively permeable to specific molecules by way of membrane transporters.The major barriers in the brain and their corresponding cellular constituents are the bloodbrain barrier(BBB)composed of endothelial cells in brain     

Cadmium-induced neurotoxicity: still much ado

Cadmium(Cd) is a highly toxic heavy metal that accumulates in living system and as such is currently one of the most important occupational and environmental pollutants. Cd reaches into the environment by anthropogenic mobilization and it is absorbed from tobacco consumption or ingestion of contaminated substances. Its extremely long biological half-life(approximately 20–30 years in humans) and low rate of excretion from the body cause cadmium storage predominantly in soft tissues(primarily, liver and kidneys) with a diversity of toxic effects such as nephrotoxicity, hepatotoxicity, endocrine and reproductive toxicities. Moreover, a Cd-dependent neurotoxicity has been also related to neurodegenerative diseases such as Alzheimer's and Parkinson's diseases, amyotrophic lateral sclerosis, and multiple sclerosis. At the cellular level, Cd affects cell proliferation, differentiation, apoptosis and other cellular activities. Among all these mechanisms, the Cd-dependent interference in DNA repair mechanisms as well as the generation of reactive oxygen species, seem to be the most important causes of its cellular toxicity. Nevertheless, there is still much to find out about its mechanisms of action and ways to reduce health risks. This article gives a brief review of the relevant mechanisms that it would be worth investigating in order to deep inside cadmium toxicity.     

Therapeutic potential of glial cell line-derived neurotrophic factor and cell reprogramming for hippocampal-related neurological disorders

Hippocampus serves as a pivotal role in cognitive and emotional processes,as well as in the regulation of the hypothalamus-pituitary axis.It is known to undergo mild neurodegenerative changes during normal aging and severe atrophy in Alzheimer's disease.Furthermore,dysregulation in the hippocampal function leads to epilepsy and mood disorders.In the first section,we summarized the most salient knowledge on the role of glial cell-line-derived neurotrophic factor and its receptors focused on aging,cognition and neurodegenerative and hippocampal-related neurological diseases mentioned above.In the second section,we reviewed the therapeutic approaches,particularly gene therapy,using glial cell-line-derived neurotrophic factor or its gene,as a key molecule in the development of neurological disorders.In the third section,we pointed at the potential of regenerative medicine,as an emerging and less explored strategy for the treatment of hippocampal disorders.We briefly reviewed the use of partial reprogramming to restore brain functions,non-neuronal cell reprogramming to generate neural stem cells,and neural progenitor cells as source-specific neuronal types to be implanted in animal models of specific neurodegenerative disorders.     

Nematodes feel a craving - Using Caenorhabditis elegans as a model to study alcohol addiction

Alcohol is the most frequently-used addictive drug. However, the mechanism by which its consumption leads to addiction remains largely elusive. Given the conservation of behavioral reactions to alcohol, Caenorhabitis elegans （C. elegans） has been effectively used as a model system to investigate the relevant molecular targets and pathways mediating these responses. In this article, we review the roles of BK channels （also called SLO-1）, the lipid microenvironment, receptors, the synaptic machinery, and neurotransmitters in both the acute and chronic effects of alcohol. We provide an overview of the genes and mechanisms involved in alcoholism- related behaviors in C. elegans.     

Neurotrophic fragments as therapeutic alternatives to ameliorate brain aging

Aging is a global phenomenon and a complex biological process of all living beings that introduces various changes. During this physiological process, the brain is the most affected organ due to changes in its structural and chemical functions, such as changes in plasticity and decrease in the number, diameter, length, and branching of dendrites and dendritic spines. Likewise, it presents a great reduction in volume resulting from the contraction of the gray matter. Consequently, aging can affec...     

Natural stilbenes effects in animal models of Alzheimer's disease

Alzheimer’s disease is one of the most frequent neurodegenerative diseases.This pathology is characterized by protein aggregates,mainly constituted by amyloid peptide and tau,leading to neuronal death and cognitive impairments.Drugs currently proposed to treat this pathology do not prevent neurodegenerative processes and are mainly symptomatic therapies.However,stilbenes presenting multiple pharmacological effects could be good potential therapeutic candidates.The aim of this review is to gather the more significant papers among the broad literature on this topic,concerning the beneficial effects of stilbenes (resveratrol derivatives) in animal models of Alzheimer’s disease.Indeed,numerous studies focus on cellular models,but an in vivo approach remains of primary importance since in animals (mice or rats,generally),bioavailability and metabolism are taken into account,which is not the case in in vitro studies.Furthermore,examination of memory ability is feasible in animal models,which strengthens the relevance of a compound with a view to future therapy in humans.This paper is addressed to any researcher who needs to study untested natural stilbenes or who wants to experiment the most effective natural stilbenes in largest animals or in humans.This review shows that resveratrol,the reference polyphenol,is largely studied and seems to have interesting properties on amyloid plaques,and cognitive impairment.However,some resveratrol derivatives such as gnetin C,trans-piceid,or astringin have never been tested on animals.Furthermore,pterostilbene is of particular interest,by its improvement of cognitive disorders and its neuroprotective role.It could be relevant to evaluate this molecule in clinical trials.     

Differences in individual susceptibility affect the development of trigeminal neuralgia

Trigeminal neuralgia is a syndrome due to dysfunctional hyperactivity of the trigeminal nerve,and is characterized by a sudden,usually unilateral,recurrent lancinating pain arising from one or more divisions of the nerve.The most accepted pathogenetic mechanism for trigeminal neuralgia is compression of the nerve at its dorsal root entry zone or in its distal course.In this paper,we report four cases with trigeminal neuralgia due to an unknown mechanism after an intracranial intervention.The onset of trigeminal neuralgia after surgical interventions that are unrelated to the trigeminal nerve suggests that in patients with greater individual susceptibility,nerve contact with the vascular structure due to postoperative pressure and changes in cerebrospinal fluid flow may cause the onset of pain.     

Dantrolene enhances the protective effect of hypothermia on cerebral cortex neurons

Therapeutic hypothermia is the most promising non-pharmacological neuroprotective strategy against ischemic injury. However, shivering is the most common adverse reaction. Many studies have shown that dantrolene is neuroprotective in in vitro and in vivo ischemic injury models. In addition to its neuroprotective effect, dantrolene neutralizes the adverse reaction of hypothermia. Dantrolene may be an effective adjunctive therapy to enhance the neuroprotection of hypothermia in treating ischemic stroke. Cortical neurons isolated from rat fetuses were exposed to 90 minutes of oxygen-glucose deprivation followed by reoxygenation. Neurons were treated with 40 μM dantrolene, hypothermia(at 33°C), or the combination of both for 12 hours. Results revealed that the combination of dantrolene and hypothermia increased neuronal survival and the mitochondrial membrane potential, and reduced intracellular active oxygen cytoplasmic histone-associated DNA fragmentation, and apoptosis. Furthermore, improvements in cell morphology were observed. The combined treatment enhanced these responses compared with either treatment alone. These findings indicate that dantrolene may be used as an effective adjunctive therapy to enhance the neuroprotective effects of hypothermia in ischemic stroke.     

Distribution pattern of axonal cytoskeleton proteins in the human optic nerve head

<正>Glaucoma is one of the leading causes of blindness in the developed world.It is a progressive optic neuropathy where structural loss of retinal ganglion cell(RGC)axons corresponds with functional visual field defect.Glaucoma is distinguished from other optic neuropathies by its selective loss of RGC axons.Superior and inferior peripheral nerve sectors are found to be most vulnerable to pressure induced injury whereas the inner temporal sector is most resilient(Quigley et al.,1988).Patho-     

Potential utility of aldose reductase-deficient Schwann cells IKARS1 for the study of axonal degeneration and regeneration

正Diabetic peripheral neuropathy(DPN)is one of the most common and intractable complications of diabetes mellitus.Its irritating symptoms,such as paresthesia,hyperalgesia and allodynia,can be causes of insomnia and depression;whereas its progression to more advanced stages can result in serious consequences,such as lower limb amputations and lethal arrhythmias.The pathogenesis     

Gene therapy in Parkinson’s disease:targeting the endplasmic reticulum proteostasis network

<正>Parkinson’s disease(PD)is the second most common neurodegenerative disease affecting 1%of the population over 60 years of age.The progressive degeneration of dopaminergic neurons at the substantia nigra pars compacta(SNpc)results in a severe and gradual depletion of dopamine content in the striatum,a phenomena that is responsible for the characteristic motor symptoms of this disease.There is no cure for PD and available treatments only aim to restore dopamine deficits.Administration of the dopamine precursor Levodopa(L-DOPA)is the main temporal palliative treatment that increases overall dopamine levels.However,its chronic use limits its effectiveness and generates a number of adverse effects such as debilitating dyskinesia.     

Harnessing neural activity to promote repair of the damaged corticospinal system after spinal cord injury

As most spinal cord injuries(SCIs) are incomplete,an important target for promoting neural repair and recovery of lost motor function is to promote the connections of spared descending spinal pathways with spinal motor circuits.Among the pathways,the corticospinal tract(CST) is most associated with skilled voluntary functions in humans and many animals.CST loss,whether at its origin in the motor cortex or in the white matter tracts subcortically and in the spinal cord,leads to movement impairments and paralysis.To restore motor function after injury will require repair of the damaged CST.In this review,I discuss how knowledge of activity-dependent development of the CST—which establishes connectional specificity through axon pruning,axon outgrowth,and synaptic competition among CST terminals—informed a novel activity-based therapy for promoting sprouting of spared CST axons after injur in mature animals.This therapy,which comprises motor cortex electrical stimulation with and without concurrent trans-spinal direct current stimulation,leads to an increase in the gray matter axon length of spared CST axons in the rat spinal cord and,after a pyramidal tract lesion,restoration of skilled locomotor movements.I discuss how this approach is now being applied to a C4 contusion rat model.     

Gut microbiome:a balancing act between degeneration and regeneration

In a symbiotic and mutualistic manner,the gut microbiota strongly influences many vital aspects of host physiology,biology,repair,and regeneration.The role of microbiota in many areas of regenerative medicine is just beginning to emerge,but it is under-recognized because of its complexity.As we remove the barriers that impede our understanding of this complex entity,we will uncover some of the most vital facets of our microbiome that make us who we are,its intrinsic connection with not only our wellbeing,but also with regeneration within.This will subsequently define its utility in regenerative medicine.     

Mutation inε-Sarcoglycan Induces a Myoclonus-Dystonia Syndrome-Like Movement Disorder in Mice

Myoclonus dystonia syndrome(MDS)is an inherited movement disorder,and most MDS-related mutations have so far been found in theε-sarcoglycan(SGCE)coding gene.By generating SGCE-knockout(KO)and human 237 C>T mutation knock-in(KI)mice,we showed here that both KO and KI mice exerted typical movement defects similar to those of MDS patients.SGCE promoted filopodia development in vitro and inhibited excitatory synapse formation both in vivo and in vitro.Loss of function of SGCE leading to excessive excitatory synapses that may ultimately contribute to MDS pathology.Indeed,using a zebrafish MDS model,we found that among 1700 screened chemical compounds,Vigabatrin was the most potent in readily reversing MDS symptoms of mouse disease models.Our study strengthens the notion that mutations of SGCE lead to MDS and most likely,SGCE functions to brake synaptogenesis in the CNS.