Reactive astrocyte scar and axon regeneration:suppressor or facilitator?

Several major factors are known to contribute to CNS axon regenerative failure after injury, including reduced intrinsic growth capacity of developed neurons and extrinsic factors mediating axon outgrowth. For the latter, a non-permissive environment around the lesion and the lack of sufficient neurotrophic support within the adult CNS play important roles （Silver et al., 2015）. In addition to generation of various inhibitory substrates by oligodendrocytes, fibrotic tissues, inflammatory cells and other cell types, reactive astrocytes surrounding lesions are thought to highly suppress regeneration of injured CNS axons （Silver and Miller, 2004; Ohtake and Li, 2014）. A great number of studies suggest that reactive astrocytic scars form one of the major barriers preventing axon regeneration after CNS iniuries, including spinal cord injury （SCI）. However, reactive astrocytes were reported to provide a beneficial role by reducing infiltrating immunoreactive cells into adjacent domains, protecting bordering neural tissue from damage and generating numerous supportive extracellular matrix （ECM） components to promote cell survival and growth （Bush et al., 1999）. Previ- ous data showed that ablation of reactive astrocytes increased inflammation and secondary tissue damage, prevented blood- brain barrier formation and increased local neurite growth. Interestingly, a recent study by Anderson et al （2016） provides evidence that reactive astrocytes around the lesioned spinal cord support axon regeneration after SCI, rather than block regrowth （Anderson et al., 2016）.

Interleukin 4-induced neuroprotection and regulation of microglia activation as a therapeutic approach in the MPTP model of Parkinson's disease

Parkinson＇s disease （PD） has been described as one of the most common neurodegenerative diseases affecting up to 2% of the worldwide population over 60 years of age. The hallmarks of PD are progressive loss of midbrain dopaminergic （mDA） neurons and a decrease in striatal dopamine levels, which result in typ- ical clinical motor symptoms such as akinesia, resting tremor, rigidity, and gait impairments. Although the causes for PD are only partially understood and seem to be very heterogeneous, one of the common phenomenons observed in toxin-based an- imal models of PD as well as PD patients is a microglia-driven neuroinflammatory response,

Histological and Physiological Investigation of Channelrhodopsin-2 and Halorhodopsin in the Dorsal Cochlear Nucleus

We have delivered viral vectors containing either Chop2 fused with GFP, Channelrhodopsin-2 （ChR2）, or Halorhodopsin （HaloR） fused with mCherry （to form light gated cation channels or chloride pumps, respectively）, into the dorsal cochlear nucleus （DCN）. One to eighteen months later we examined the CN and inferior colliculus （IC） for evidence of virally transfected cells and processes. Production of ChR2 and HaloR was observed throughout the DCN. Rhodopsin localization within neurons was determined, with elongate, fusiform and giant cells identified based on morphology and location within the DCN. Production of ChR2 and HaloR was found at both the injection site as well as in regions projecting to and from the DCN. Light driven neuronal activity in the DCN was dependent upon the wavelength and intensity of the light, with only the appropriate wavelength resulting in activation and higher intensity light resulting in more neuronal activity. Transfecting cells via viral delivery of rhodopsins can be useful as a tract tracer and as a neuronal marker to delineate pathways. In the future rhodopsin delivery and activation may be developed as an alternative to electrical stimulation of neurons.

Cortical stimulation for treatment of neurological disorders of hyperexcitability: a role of homeostatic plasticity

Hyperexcitability of neural network is a key neurophysiological mechanism in several neurological disorders including epilepsy, neuropathic pain, and tinnitus. Although standard paradigm of pharmacological management of them is to suppress this hyperexcitability, such as having been exemplified by the use of certain antiepileptic drugs, their frequent refractoriness to drug treatment suggests likely different pathophysiological mechanism. Because the pathogenesis in these disorders exhibits a transition from an initial activity loss after injury or sensory deprivation to subsequent hyperexcitability and paroxysmal discharges, this process can be regarded as a process of functional compensation similar to homeostatic plasticity regulation, in which a set level of activity in neural network is maintained after injury-induced activity loss through enhanced network excitability. Enhancing brain activity, such as cortical stimulation that is found to be effective in relieving symptoms of these disorders, may reduce such hyperexcitability through homeostatic plasticity mechanism. Here we review current evidence of homeostatic plasticity in the mechanism of acquired epilepsy, neuropathic pain, and tinnitus and the effects and mechanism of cortical stimulation. Establishing a role of homeostatic plasticity in these disorders may provide a theoretical basis on their pathogenesis as well as guide the development and application of therapeutic approaches through electrically or pharmacologically stimulating brain activity for treating these disorders.

Circular smooth muscle contributes to esophageal shortening during peristalsis

AIM:To study the angle between the circular smooth muscle(CSM) and longitudinal smooth muscle(LSM) fibers in the distal esophagus.METHODS:In order to identify possible mechanisms for greater shortening in the distal compared to proximal esophagus during peristalsis,the angles between the LSM and CSM layers were measured in 9 cadavers.The outer longitudinal layer of the muscularis propria was exposed after stripping the outer serosa.The inner circular layer of the muscularis propria was then revealed after dissection of the esophageal mucosa and the underlying muscularis mucosa.Photographs of each specimen were taken with half of the open esophagus folded back showing both the outer longitudinal and inner circular muscle layers.Angles were measured every one cm for 10 cm proximal to the squamocolumnar junction(SCJ) by two independent investigators.Two human esophagi were obtained from organ transplant donors and the angles between the circular and longitudinal smooth muscle layers were measured using micro-computed tomography(micro CT) and Image J software.RESULTS:All data are presented as mean ± SE.The CSM to LSM angle at the SCJ and 1 cm proximal to SCJ on the autopsy specimens was 69.3 ± 4.62 degrees vs 74.9 ± 3.09 degrees,P = 0.32.The CSM to LSM angle at SCJ were statistically significantly lower than at 2,3,4 and 5 cm proximal to the SCJ,69.3 ± 4.62 degrees vs 82.58 ± 1.34 degrees,84.04 ± 1.64 degrees,84.87 ± 1.04 degrees and 83.72 ± 1.42 degrees,P = 0.013,P = 0.008,P = 0.004,P = 0.009 respectively.The CSM to LSM angle at SCJ was also statistically significantly lower than the angles at 6,7 and 8 cm proximal to the SCJ,69.3 ± 4.62 degrees vs 80.18 ± 2.09 degrees,81.81 ± 1.75 degrees and 80.96 ± 2.04 degrees,P = 0.05,P = 0.02,P = 0.03 respectively.The CSM to LSM angle at 1 cm proximal to SCJ was statistically significantly lower than at 3,4 and 5 cm proximal to the SCJ,74.94 ± 3.09 degrees vs 84.04 ± 1.64 degrees,84.87 ± 1.04 degrees and 83.72 ± 1.42 degrees,P = 0.019,P = 0.008,P = 0.02 respectively.At 10 cm above SCJ the angle was 80.06 ± 2.13 degrees which is close to being perpendicular but less than 90 degrees.The CSM to LSM angles measured on virtual dissection of the esophagus and the stomach on micro CT at the SCJ and 1 cm proximal to the SCJ were 48.39 ± 0.72 degrees and 50.81 ± 1.59 degrees.Rather than the angle of the CSM and LSM being perpendicular in the esophagus we found an acute angulation between these two muscle groups throughout the lower 10 cm of the esophagus.CONCLUSION:The oblique angulation of the CSM may contribute to the significantly greater shortening of distal esophagus when compared to the mid and proximal esophagus during peristalsis.

Transforming growth factor β1-mediated anti-inflammation slows progression of midbrain dopaminergic neurodegeneration in Parkinson's disease?

Parkinson’s disease（PD）is characterized by the progressive loss of midbrain dopaminergic（m DA）neurons and a subsequent decrease in striatal dopamine levels,which cause the typical clinical motor symptoms such as muscle rigidity,bradykinesia and tremor.

Differential expression of Bmp2,Bmp4 and Bmp3 in embryonic development of mouse anterior and posterior palate

Background The palate is differently regulated and developed along the anterior-posterior axis. The Bmp signal pathway plays a crucial role in palatogenesis. Conditioned-inactivation of Bmp type I receptor Alk2 or Alk3 in the neural crest or craniofacial region leads to palatal cleft in mice. However, how different Bmp members are involved in palatogenesis remains to be elucidated. In the present study, mRNA expression patterns of Bmp2, Bmp3 and Bmp4 in the developing anterior and posterior palates were examined and compared, focusing on the fusion stage.Methods To detect the expression of Bmp mRNA, antisense riboprobes were synthesized by in vitro transcription. Radioactive in situ hybridization was performed on sagital and coronal sections of mice head from E13 to E18.Results The expression of these Bmps were developmentally regulated in the anterior and posterior palates prior to, during and after palatal fusion. During palatal fusion, Bmp4 expression shifted from the anterior to the process, pattern whereas in their palates regulatingConclusions Bmp signalling is involved in palatogenesis in muhiple stages and has muhiple roles in regulating anterior and posterior palatal development. Disturbances of Bmp signalling during palatogenesis might be a possible mechanism of cleft palate.

Wuzi Yanzong Pill Plays A Neuroprotective Role in Parkinson’s Disease Mice via Regulating Unfolded Protein Response Mediated by Endoplasmic Reticulum Stress

Objective:To investigate the protective effects and its possible mechanism of Wuzi Yanzong Pill(WYP) on Parkinson’s disease(PD) model mice.Methods:Thirty-six C57BL/6 male mice were randomly assigned to 3 groups including normal,PD,and PD+WYP groups,12 mice in each group.One week of intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP) was used to establish the classical PD model in mice.Meanwhile,mice in the PD+WYP group were administrated with 16 g/kg WYP,twice daily by gavage.After 14 days of administration,gait test,open field test and pole test were measured to evaluate the movement function.Tyrosine hydroxylase(TH) neurons in substantia nigra of midbrain and binding immunoglobulin heavy chain protein(GRP78) in striatum and cortex were observed by immunohistochemistry.The levels of TH,GRP78,p-PERK,p-elF2α,ATF4,p-IRE1α,XBP1,ATF6,CHOP,ASK1,p-JNK,Caspase-12,-9 and-3 in brain were detected by Western blot.Results:Compared with the PD group,WYP treatment ameliorated gait balance ability in PD mice(P<0.05).Similarly,WYP increased the total distance and average speed(P<0.05or P<0.01),reduced rest time and pole time(P<0.05).Moreover,WYP significantly increased TH positive cells(P<0.01).Immunofluorescence showed WYP attenuated the levels of GRP78 in striatum and cortex.Meanwhile,WYP treatment significantly decreased the protein expressions of GRP78,p-PERK,p-elF2α,ATF4,p-IRE1α,XBP1,CHOP,Caspase-12 and Caspase-9(P<0.05or P<0.01).Conclusions:WYP ameliorated motor symptoms and pathological lesion of PD mice,which may be related to the regulation of unfolded protein response-mediated signaling pathway and inhibiting the endoplasmic reticulum stress-mediated neuronal apoptosis pathway.