The brain-derived neurotrophic factor in neuronal plasticity and neuroregeneration: new pharmacological concepts for old and new drugs

Neurotrophins：Neurotrophins are peptides or proteins that are known to regulate neuronal viability,development,and function Beyond synaptic plasticity,neurotrophins protect neurons from apoptosis and also promote neurogenesis to recover neuronal defici even in adulthood.

Cathepsins in neuronal plasticity

Proteases comprise a variety of enzymes defined by their ability to catalytically hydrolyze the peptide bonds of other proteins,resulting in protein lysis.Cathepsins,specifically,encompass a class of at least twenty proteases with potent endopeptidase activity.They are located subcellularly in lysosomes,organelles responsible for the cell’s degradative and autophagic processes,and are vital for normal lysosomal function.Although cathepsins are involved in a multitude of cell signaling activities,this chapter will focus on the role of cathepsins(with a special emphasis on Cathepsin B)in neuronal plasticity.We will broadly define what is known about regulation of cathepsins in the central nervous system and compare this with their dysregulation after injury or disease.Importantly,we will delineate what is currently known about the role of cathepsins in axon regeneration and plasticity after spinal cord injury.It is well established that normal cathepsin activity is integral to the function of lysosomes.Without normal lysosomal function,autophagy and other homeostatic cellular processes become dysregulated resulting in axon dystrophy.Furthermore,controlled activation of cathepsins at specialized neuronal structures such as axonal growth cones and dendritic spines have been positively implicated in their plasticity.This chapter will end with a perspective on the consequences of cathepsin dysregulation versus controlled,localized regulation to clarify how cathepsins can contribute to both neuronal plasticity and neurodegeneration.

Effects of respiratory syncytial virus infection on the airway neuronal plasticity and its relationship to the bronchial hyperresponsiveness in rats

Despite intense research efforts, the specific pathogenic mechanisms that underlie the link between respiratory syncytial virus （RSV） and childhood asthma remain unclear. Recent researches suggest that changes in the structure and function of the nerves themselves in response to changing conditions, a phenomenon known as neuronal plasticity, may also contribute to the pathophysiology of airway diseases. Therefore.

Mitochondrial membrane protein Bcl-xL, a regulator of adult neuronal growth and synaptic plasticity: multiple functions beyond apoptosis

The B-cell lymphoma 2 （Bcl2） family of proteins participates in cell death or survival through a mitochondrial pathway. The pro-apoptotic members of the Bcl2 family such as Bim, Bid, Bax and Bak trigger cell death by contributing to the enhancement of mitochondrial outer membrane permeabil- ity to pro-apoptotic factors such as cytochrome c, with the subsequent activation of caspases. The anti-apoptotic mem- bers, such as B-cell lymphoma-extra large （Bd-xL）, block the pro-apoptotic Bcl2 members and prevent cell death. Bcl-xL is abundantly expressed during development and in mature neurons, suggesting that it plays a role in protection from death from untoward events occurring in adult life such as ischemia, inflammation or trauma. When these neurotoxic in- sults occur, Bcl-xL translocates to mitochondria and prevents activation and homo-oligomerization of pro-apoptotic family members such Bax and Bak. Numerous studies have shown pro-survival roles for Bcl-xL in adult neurons using various models; nevertheless, the role of Bcl-xL outside of the field of neuronal death, i.e., in adult neuronal growth, excitability or synaptic plasticity, has not been studied in depth.

Chinese medicine active ingredients or monomers increase neuronal synaptic plasticity

Totally three articles focusing on Schisandra N-butanol extract effects on hippocampal CA1 synaptic morphology and plasticity in ovarectomized mice, as well as catalpol and GBE50 effects on neuronal synaptic plasticity in the motor cortex following cerebral ischemia were published in three issues. We hope that our readers find these papers useful to their research.

Efficacy of exercise rehabilitation for managing patients with Alzheimer's disease

Alzheimer's disease(AD) is a progressive and degenerative neurological disease characterized by the deterioration of cognitive functions. While a definitive cure and optimal medication to impede disease progression are currently unavailable, a plethora of studies have highlighted the potential advantages of exercise rehabilitation for managing this condition. Those studies show that exercise rehabilitation can enhance cognitive function and improve the quality of life for individuals affected by AD. Therefore, exercise rehabilitation has been regarded as one of the most important strategies for managing patients with AD. Herein, we provide a comprehensive analysis of the currently available findings on exercise rehabilitation in patients with AD, with a focus on the exercise types which have shown efficacy when implemented alone or combined with other treatment methods, as well as the potential mechanisms underlying these positive effects. Specifically, we explain how exercise may improve the brain microenvironment and neuronal plasticity. In conclusion, exercise is a cost-effective intervention to enhance cognitive performance and improve quality of life in patients with mild to moderate cognitive dysfunction. Therefore, it can potentially become both a physical activity and a tailored intervention. This review may aid the development of more effective and individualized treatment strategies to address the challenges imposed by this debilitating disease, especially in low-and middle-income countries.

Regulatory effects of inhibiting the activation of glial cells on retinal synaptic plasticity

Various retinal injuries induced by ocular hypertension have been shown to induce plastic changes in retinal synapses, but the potential regulatory mechanism of synaptic plasticity after retinal injury was still unclear. A rat model of acute ocular hypertension was established by injecting saline intravitreally for an hour, and elevating the intraocular pressure to 14.63 kPa （110 mmHg）. Western blot assay and immunofluorescence results showed that synaptophysin expression had a distinct spatiotemporal change that increased in the inner plexiform layer within 1 day and spread across the outer plexiform layer after 3 days. Glial fibrillary acidic protein expression in retinae was greatly increased after 3 days, and reached a peak at 7 days, which was also consistent with the peak time of synaptophysin expression in the outer plexiform layer following the increased intraocular pressure. Fluorocitrate, a glial metabolic inhibitor, was intravitreally injected to inhibit glial cell activation following high intraocular pressure. This significantly inhibited the enhanced glial fibrillary acidic protein expression induced by high intraocular pressure injury. Synaptophysin expression also decreased in the inner plexiform layer within a day and the widened distribution in the outer plexiform layer had disappeared by 3 days. The results suggested that retinal glial cell activation might play an important role in the process of retinal synaptic plasticity induced by acute high intraocular pressure through affecting the expression and distribution of synaptic functional proteins, such as synaptophysin.

Effect of vision loss on plasticity of the head and neck proprioception

AIM:To investigate whether head and neck proprioception and motor control could be compensatory enhanced by long-term vision loss or impairment.METHODS:Individuals who were blind,low vision or sighted were included in the study,which would undergo the head repositioning test(HRT).The constant error(CE),absolute error(AE),variable error(VE)and root mean square error(RMSE)of each subject were statistically analyzed.Data were analyzed using the SAS 9.4.Tukey-Kramer for one-way ANOVA was used for comparison of blind,low vision,and sighted subjects,as well as to compare subjects with balanced vision,strong vision in the left eye and strong vision in the right eye.Independent sample t-test was used to compare subjects with congenital blindness and acquired blindness,as well as left and right hand dominance subjects.RESULTS:A total of 90 individuals(25 blind subjects,31 low vision subjects,and 34 sighted subjects)were included in the study.Among the blind subjects,14 cases had congenital blindness and 11 cases had acquired blindness.Among the blind and low vision subjects,21 cases had balanced binocular vision,17 cases had strong vision in the left eye and 18 cases had strong vision in the right eye.Among all subjects,11 cases were left hand dominance,and 79 cases were right hand dominance.There were significant differences in AE,VE,and RMSE in head rotation between blind,low vision,and sighted subjects(P<0.01),in AE,VE,and RMSE between blind and sighted(P<0.01),and in VE and RMSE between low vision and sighted(P<0.05).No significant difference between blind and low vision(P>0.05).Significant differences in CE and AE of head right rotation and CE of general head rotation between congenital and acquired(P<0.05).No significant differences between left and right hand dominance and in balance or not of binocular vision(P>0.05).CONCLUSION:Long-term vision loss or impairment does not lead to compensatory enhancement of head and neck proprioception and motor control.Acquired experience contributes to HRT performance in the blind and has long-lasting effects on plasticity in the development of proprioception and sensorimotor control.

Ketamine enhances structural plasticity in human dopaminergic neurons:possible relevance for treatment-resistant depression

Depression refers to a series of mental health issues characterized by loss of interest and enjoyment in everyday life,low mood and selected emotional,cognitive,physical and behavioral symptoms.Depression is a common disorder,affecting 5–15%of the general population.When diagnosed as major depressive disorder（MDD）,patients are currentlytreated with pharmacological agents such as serotonin or noradren- aline uptake inhibitors （SSRI or SNRI） or tricyclics.

Skeletal muscle activity and CNS neuro-plasticity

The systemic health benefits of regular skeletal muscle activity are well documented.Increased skeletal muscle activity is associated with an improved systemic metabolic state,reduced incidence of diabetes and obesity,and improved function with age.Despite these known systemic benefits,many healthy people do not meet the recommended daily dose of skeletal muscle activity（exercise）needed to prevent systemic metabolic disease,leading to an in-creased prevalence of obesity.

Mismatch negativity,social cognition,and functional outcomes in patients after traumatic brain injury

Mismatch negativity is generated automatically, and is an early monitoring indicator of neuronal integrity impairment and functional abnormality in patients with brain injury, leading to decline of cognitive function. Antipsychotic medication cannot affect mismatch negativity. The present study aimed to explore the relationships of mismatch negativity with neurocognition, daily life and social functional outcomes in patients after brain injury. Twelve patients with traumatic brain injury and 12 healthy controls were recruited in this study. We examined neurocogni-tion with the Wechsler Adult Intelligence Scale-Revised China, and daily and social functional outcomes with the Activity of Daily Living Scale and Social Disability Screening Schedule, re-spectively. Mismatch negativity was analyzed from electroencephalogram recording. The results showed that mismatch negativity amplitudes decreased in patients with traumatic brain injury compared with healthy controls. Mismatch negativity amplitude was negatively correlated with measurements of neurocognition and positively correlated with functional outcomes in patients after traumatic brain injury. Further, the most signiifcant positive correlations were found be-tween mismatch negativity in the fronto-central region and measures of functional outcomes. The most signiifcant positive correlations were also found between mismatch negativity at the FCz electrode and daily living function. Mismatch negativity amplitudes were extremely positive-ly associated with Social Disability Screening Schedule scores at the Fz electrode in brain injury patients. These experimental ifndings suggest that mismatch negativity might efifciently relfect functional outcomes in patients after traumatic brain injury.

Effects of cortical intermittent theta burst stimulation combined with precise root stimulation on motor function after spinal cord injury: a case series study

Activation and reconstruction of the spinal cord circuitry is important for improving motor function following spinal cord injury.We conducted a case series study to investigate motor function improvement in 14 patients with chronic spinal cord injury treated with 4 weeks of unilateral(right only)cortical intermittent theta burst stimulation combined with bilateral magnetic stimulation of L3-L4 nerve roots,five times a week.Bilateral resting motor evoked potential amplitude was increased,central motor conduction time on the side receiving cortical stimulation was significantly decreased,and lower extremity motor score,Berg balance score,spinal cord independence measure-III score,and 10 m-walking speed were all increased after treatment.Right resting motor evoked potential amplitude was positively correlated with lower extremity motor score after 4 weeks of treatment.These findings suggest that cortical intermittent theta burst stimulation combined with precise root stimulation can improve nerve conduction of the corticospinal tract and lower limb motor function recovery in patients with chronic spinal cord injury.

Role of the hippocampus on learning and memory functioning and pain modulation

The hippocampus, an important part of the limbic system, is considered to be an important region of the brain for learning and memory functioning. Recent studies have demonstrated that synaptic plasticity is thought to be the basis of learning and memory functioning. A series of studies report that similar synaptic plasticity also exists in the spinal cord in the conduction pathway of pain sensation, which may contribute to hyperalgesia, abnormal pain, and analgesia. The synaptic plasticity of learning and memory functioning and that of the pain conduction pathway have similar mechanisms, which are related to the N-methyl-D-aspartic acid receptor. The hippocampus also has a role in pain modulation. As pain signals can reach the hippocampus, the precise correlation between synaptic plasticity of the pain pathway and that of learning and memory functioning deserves further investigation. The role of the hippocampus in processing pain information requires to be identified.

Effects of progesterone on T-type-Ca^(2+)-channel expression in Purkinje cells

Plasticity of cerebellar Purkinje cells(PC)is influenced by progeste rone via the classical progeste rone receptors PR-A and PR-B by stimulating dendritogenesis,spinogenesis,and synaptogenesis in these cells.Dissociated PC cultures were used to analyze progeste rone effects at a molecular level on the voltage-gated T-type-Ca^(2+)-channels Ca_(v)3.1,Ca_(v)3.2,and Ca_(v)3.3 as they helped determine neuronal plasticity by regulating Ca^(2+)-influx in neuronal cells.The results showed direct effects of progesterone on the mRNA expression of T-type-Ca^(2+)-channels,as well as on the protein kinases A and C being involved in downstream signaling pathways that play an important role in neuronal plasticity.For the mRNA expression studies of T-type-Ca^(2+)-channels and protein kinases of the signaling cascade,laser microdissection and purified PC cultures of diffe rent maturation stages were used.Immunohistochemical staining was also performed to characte rize the localization of T-type-Ca^(2+)-channels in PC.Expe rimental progesterone treatment was performed on the purified PC culture for 24 and 48 hours.Our results show that progesterone increases the expression of Ca_(v)3.1 and Ca_(v)3.3 and associated protein kinases A and Cin PC at the mRNA level within 48 hours after treatment at latest.These effects extend the current knowledge of the function of progesterone in the central nervous system and provide an explanatory approach for its influence on neuronal plasticity.

Magnetic resonance imaging and cell-based neurorestorative therapy after brain injury

Restorative cell-based therapies for experimental brain injury, such as stroke and traumatic brain injury,substantially improve functional outcome. We discuss and review state of the art magnetic resonance imaging methodologies and their applications related to cell-based treatment after brain injury. We focus on the potential of magnetic resonance imaging technique and its associated challenges to obtain useful new information related to cell migration, distribution, and quantitation, as well as vascular and neuronal remodeling in response to cell-based therapy after brain injury. The noninvasive nature of imaging might more readily help with translation of cell-based therapy from the laboratory to the clinic.

Neurological rehabilitation of stroke patients via motor imaginary-based brain-computer interface technology

The present study utilized motor imaginary-based brain-computer interface technology combined with rehabilitation training in 20 stroke patients. Results from the Berg Balance Scale and the Holden Walking Classification were significantly greater at 4 weeks after treatment （P 〈 0.01）, which suggested that motor imaginary-based brain-computer interface technology improved balance and walking in stroke patients.

Pre-attentive auditory discrimination skill in Indian classical vocal musicians and non-musicians

Objective:To test for pre-attentive auditory discrimination skills in Indian classical vocal musicians and non-musicians.Design:Mismatch negativity(MMN) was recorded to test for pre-attentive auditory discrimination skills with a pair of stimuli of /1000 Hz/ and/1100 Hz/,with /1000 Hz/ as the frequent stimulus and /1100 Hz/ as the infrequent stimulus.Onset,offset and peak latencies were the considered latency parameters,whereas peak amplitude and area under the curve were considered for amplitude analysis.Study sample:Exactly 50 participants,out of which the experimental group had 25 adult Indian classical vocal musicians and 25 age-matched non-musicians served as the control group,were included in the study.Experimental group participants had a minimum professional music experience in Indian classic vocal music of 10 years.However,control group participants did not have any formal training in music.Results:Descriptive statistics showed better waveform morphology in the experimental group as compared to the control.MANOVA showed significantly better onset latency,peak amplitude and area under the curve in the experimental group but no significant difference in the offset and peak latencies between the two groups.Conclusion:The present study probably points towards the enhancement of pre-attentive auditory discrimination skills in Indian classical vocal musicians compared to non-musicians.It indicates that Indian classical musical training enhances pre-attentive auditory discrimination skills in musicians,leading to higher peak amplitude and a greater area under the curve compared to non-musicians.

Psilocybin facilitates fear extinction in mice by promoting hippocampal neuroplasticity

Background:Posttraumatic stress disorder(PTSD)and depression are highly comorbid.Psilocybin exerts substantial therapeutic effects on depression by promoting neuroplasticity.Fear extinction is a key process in the mechanism of first-line exposure-based therapies for PTSD.We hypothesized that psilocybin would facilitate fear extinction by promoting hippocampal neuroplasticity.Methods:First,we assessed the effects of psilocybin on percentage of freezing time in an auditory cued fear conditioning(FC)and fear extinction paradigm in mice.Psilocybin was administered 30 min before extinction training.Fear extinction testing was performed on the first day;fear extinction retrieval and fear renewal were tested on the sixth and seventh days,respectively.Furthermore,we verified the effect of psilocybin on hippocampal neuroplasticity using Golgi staining for the dendritic complexity and spine density,Western blotting for the protein levels of brain derived neurotrophic factor(BDNF)and mechanistic target of rapamycin(mTOR),and immunofluorescence staining for the numbers of doublecortin(DCX)-and bromodeoxyuridine(BrdU)-positive cells.Results:A single dose of psilocybin(2.5 mg/kg,i.p.)reduced the increase in the percentage of freezing time induced by FC at 24 h,6th day and 7th day after administration.In terms of structural neuroplasticity,psilocybin rescued the decrease in hippocampal dendritic complexity and spine density induced by FC;in terms of neuroplasticity related proteins,psilocybin rescued the decrease in the protein levels of hippocampal BDNF and mTOR induced by FC;in terms of neurogenesis,psilocybin rescued the decrease in the numbers of DCX-and BrdU-positive cells in the hippocampal dentate gyrus induced by FC.Conclusions:A single dose of psilocybin facilitated rapid and sustained fear extinction;this effect might be partially mediated by the promotion of hippocampal neuroplasticity.This study indicates that psilocybin may be a useful adjunct to exposure-based therapies for PTSD and other mental disorders characterized by failure of fear extinction.

Chinese herbal compound Jinsiwei(金思维)improves synaptic plasticity in mice with sporadic Alzheimer’s disease induced by streptozotocin

OBJECTIVE:To investigate the efficacy of Jinsiwei(a patented Chinese herbal compound)on learning and memory impairment,the number of synapses and synaptic plasticity-related structural and functional protein expression in mice with sporadic Alzheimer’s disease(SAD)induced by streptozotocin.METHODS:Seventy-five C57/BL6J male mice were intracerebroventricularly injected with streptozotocin to establish the animal model of SAD.Mice were randomly divided into the model group(MG),donepezil group(DG),and the Jinsiwei high,medium,and low-dose groups(JH,JM,JL).Another fifteen C57/BL6J male mice were injected with artificial cerebrospinal fluid as the control group(CG).The intervention groups were intragastrically administrated with corresponding medicine,while the CG and MG were given 0.5%carboxymethyl cellulose by gavage.After 3 months,the Morris Water Maze test and step-down passive avoidance test were used to assess the learning and memory ability of mice.Synapses in hippocampal CA1 were observed by transmission electron microscope.Immunohistochemistry and western blotting were used to assess the distribution and expression levels of synaptic plasticity-related structural and functional proteins involving drebrin,cofilin,synapsin(syn),and N-methyl D-aspartate receptor subtype 2B(NR2B).RESULTS:The Morris Water Maze results showed that the escape latency in the Jinsiwei intervention groups was significantly shorter than that of the MG.Results of the step-down passive-avoidance test showed that the error times in the Jinsiwei intervention groups were significantly reduced compared with the MG.Transmission electron microscope results showed that the number of synapses in hippocampal CA1 was obviously increased in the Jinsiwei intervention groups compared with the MG.Immunohistochemical and western blotting results revealed that the positive cells and expression levels of drebrin,syn,and NR2B were significantly decreased in the MG and meanwhile cofilin significantly increased,while these changes were reversed after the Jinsiwei treatment.CONCLUSIONS:Jinsiwei can alleviate learning and memory impairments in a mouse model of SAD,increase the number of synapses and enhance synaptic plasticity via rescuing the expression of drebrin,syn,and NR2B and inhibiting cofilin expression.

Supplementary motor area deactivation impacts the recovery of hand function from severe peripheral nerve injury

Although some patients have successful peripheral nerve regeneration,a poor recovery of hand function often occurs after peripheral nerve injury.It is believed that the capability of brain plasticity is crucial for the recovery of hand function.The supplementary motor area may play a key role in brain remodeling after peripheral nerve injury.In this study,we explored the activation mode of the supplementary motor area during a motor imagery task.We investigated the plasticity of the central nervous system after brachial plexus injury,using the motor imagery task.Results from functional magnetic resonance imaging showed that after brachial plexus injury,the motor imagery task for the affected limbs of the patients triggered no obvious activation of bilateral supplementary motor areas.This result indicates that it is difficult to excite the supplementary motor areas of brachial plexus injury patients during a motor imagery task,thereby impacting brain remodeling.Deactivation of the supplementary motor area is likely to be a serious problem for brachial plexus injury patients in terms of preparing,initiating and executing certain movements,which may be partly responsible for the unsatisfactory clinical recovery of hand function.