The role of spinal neurons targeted by corticospinal neurons in central poststroke neuropathic pain.

BACKGROUND: Central poststroke pain (CPSP) is one of the primary sequelae following stroke, yet its underlying mechanisms are poorly understood. METHODS: By lesioning the lateral thalamic nuclei, we first established a CPSP model that exhibits mechanical and thermal hypersensitivity. Innocuous mechanical stimuli following the thalamic lesion evoked robust neural activation in somatosensory corticospinal neurons (CSNs), as well as in the deep dorsal horn, where low threshold mechanosensory afferents terminate. In this study, we used viral-based mapping and intersectional functional manipulations to decipher the role of somatosensory CSNs and their spinal targets in the CPSP pathophysiology. RESULTS: We first mapped the post-synaptic spinal targets of lumbar innervating CSNs using an anterograde trans-synaptic AAV1-based strategy and showed these spinal interneurons were activated by innocuous tactile stimuli post-thalamic lesion. Functionally, tetanus toxin-based chronic inactivation of spinal neurons targeted by CSNs prevented the development of CPSP. Consistently, transient chemogenetic silencing of these neurons alleviated established mechanical pain hypersensitivity and innocuous tactile stimuli evoked aversion linked to the CPSP. In contrast, chemogenetic activation of these neurons was insufficient to induce robust mechanical allodynia typically observed in the CPSP. CONCLUSION: The CSNs and their spinal targets are required but insufficient for the establishment of CPSP hypersensitivity. Our study provided novel insights into the neural mechanisms underlying CPSP and potential therapeutic interventions to treat refractory central neuropathic pain conditions.

Surgical treatment of small recurrent gliomas based on MR imaging examination.

Microrecurrent glioma is a common neurological tumor, and the key to its surgical treatment is to accurately evaluate the size, location and degree of recurrence of the lesion. The purpose of this study was to explore the surgical treatment of microrecurrent glioma based on MR Imaging, and to provide accurate and reliable basis for clinical decision-making. Before surgery, detailed MR Imaging tests were performed for each patient to accurately locate and evaluate the characteristics of the lesions. Multimodal imaging examination were arranged to accurate the pre-operation diagnosis. Neuro-navigation is necessary for the operation design and tumor confirmation. Function monitor and intraoperation MR were prepared when necessary.Mini was defined by the size, location and symptoms. In all 5 cases requiring reoperation, total resection was achieved. No systemic and local complications occurred. No permeant neurological dysfunction remained. The average stay time after the operation is days. All patients survived in the recent follow-up. Reoperation of mini recurrent glioma is a good treatment choice. We made little injury to patients, which wouldn't affect their conditions and next therapies. Through MR Imaging, the diagnosis and location of microrecurrent glioma, as well as the relationship with surrounding tissues and the degree of infiltration, provide important information for surgeons to evaluate the resectable lesion. By combining MR And functional imaging results, the blood supply and functional area of the lesion can be monitored in real time during surgery, thereby reducing surgical risk and maximizing the protection of surrounding healthy tissue.

Corticospinal-specific Shh overexpression in combination with rehabilitation promotes CST axonal sprouting and skilled motor functional recovery after ischemic stroke.

Ischemic stroke often leads to permanent neurological impairments, largely due to limited neuroplasticity in adult central nervous system. Here, we first showed that the expression of Sonic Hedgehog (Shh) in corticospinal neurons (CSNs) peaked at the 2nd postnatal week, when corticospinal synaptogenesis occurs. Overexpression of Shh in adult CSNs did not affect motor functions and had borderline effects on promoting the recovery of skilled locomotion following ischemic stroke. In contrast, CSNs-specific Shh overexpression significantly enhanced the efficacy of rehabilitative training, resulting in robust axonal sprouting and synaptogenesis of corticospinal axons into the denervated spinal cord, along with significantly improved behavioral outcomes. Mechanistically, combinatory treatment led to additional mTOR activation in CSNs when compared to that evoked by rehabilitative training alone. Taken together, our study unveiled a role of Shh, a morphogen involved in early development, in enhancing neuroplasticity, which significantly improved the outcomes of rehabilitative training. These results thus provide novel insights into the design of combinatory treatment for stroke and traumatic central nervous system injuries.

Rehabilitative training paired with peripheral stimulation promotes motor recovery after ischemic cerebral stroke.

Spontaneous recovery of ischemic stroke is very limited and often results in the loss of motor and sensory function. Till now, rehabilitative training is the most widely accepted therapy to improve long-term outcome. However, its effectiveness is often suboptimal, largely due to a sharp decline of neuroplasticity in adults. In this study, we hypothesized that a combination of proprioceptive stimulation and rehabilitative training will promote neuroplasticity and functional recovery post injury. To test this hypothesis, we first established a photothrombotic stroke model that lesions the hindlimb sensorimotor cortex. Next, we demonstrated that injecting Cre-dependent AAV-retro viruses into the dorsal column of PV-Cre mice achieves specific and efficient targeting of proprioceptors. With chemogenetics, this method enables chronic activation of proprioceptors. We then assessed effects of combinatorial treatment on motor and sensory functional recovery. Our results showed that pairing proprioceptive stimulation with rehabilitative training significantly promoted skilled motor, but not tactile sensory functional recovery. This further led to significant improvement when compared to rehabilitation training or proprioceptor stimulation alone. Mechanistically, combinatorial treatment promoted cortical layer V neuronal mTOR activity and sprouting of corticospinal axon into the area where proprioceptive afferents terminate in the denervated side of the spinal cord. Serving as a proof of principle, our study thus provided novel insights into the application of combining proprioceptive stimulation and rehabilitative training to improve functional recovery of ischemic stroke and other traumatic brain or spinal cord injuries.

Overexpression of DSPP promotes the proliferation and migration of astrocytes.

Astrocytes are activated after central nervous system (CNS) injury, such as spinal cord injury (SCI). Activated astrocytes can form glial scar to block nerve regeneration. Dentin sialophosphoprotein (DSPP), a member of the SIBLING (Small integrin-binding ligand N-linked glycoproteins) family, has been reported to contribute to the proliferation and migration of different types of tumor cells, including glioma. However, the functions of DSPP in reactive astrocytes after CNS injury remain unknown. In this study, starvation-serum stimulation model in astrocytes was conducted to explore this issue. Our results showed that DSPP expression was increased in reactive astrocytes comparing to normal ones. Meanwhile, up-regulation of DSPP was accompanied with PCNA and GFAP. To explore the role of DSPP in astrocytes, we overexpressed DSPP with recombinant GFP-DSPP plasmid and the results showed that overexpression of DSPP could promote the proliferation and migration of the cells, the important characteristics of reactive astrocytes. In addition, overexpression of DSPP obviously increased the activation of Akt/mTOR pathway in astrocytes. Taken together, we demonstrated that DSPP may play a key role in the proliferation and migration of astrocytes, suggesting that targeting DSPP might be a promising therapeutic strategy for treating CNS injury which characterized by glia scar formation.

Long term follow-up and outcomes in adult patients with thalamic gliomas.

OBJECTIVES: To investigate the optimal treatment and prognosis of thalamic glioma in adult patients. PATIENTS AND METHODS: We retrospectively analyzed the adult patients with thalamic glioma admitted to our hospital from May 2005 to September 2016. Patients were divided into two groups according to their treatment: surgery-based combined treatment and intensity modulated radiation therapy (IMRT)-based treatment. Univariate chi-square test and multivariate logistic regression were used to identify independent factors for the treatment modality. A log-rank test, adjusting for propensity score, was used to compare the overall survival (OS) and progression-free survival (PFS) of patients between the two groups. RESULTS: Fifty-eight adult patients with thalamic gliomas were included in the analysis. Of them, 31 were treated with surgery-based treatment, and 27 were treated with IMRT-based treatment. The overall survival (OS) and progression-free survival (PFS) of patients between the two groups were not significantly different (median OS 16.0 (range 1.0-163.0) months vs. 10.0 (range 1.0-118.0) months, p = 0.344 and median PFS 10.0 (range 1.0-163.0) months vs. 6.0 (range 1.0-118.0) months, p = 0.464, respectively) even after adjusting for potential confounding factors. CONCLUSIONS: The OS and PFS of adult patients with thalamic glioma were not significantly different between patients in the surgical group and in the IMRT group. IMRT might be an acceptable alternative to surgery for adult patients with unresectable thalamic glioma.

Knock down of lncRNA H19 promotes axon sprouting and functional recovery after cerebral ischemic stroke.

Ischemic stroke is a leading cause of irreversible brain damages and disabilities. In the past decade, much attention has been focused on exploring effective strategies to promote circuit reorganization and functional recovery post injury. Here, we showed that the expression level of a long non-coding RNA (lncRNA H19) is bilaterally increased in the sensorimotor cortex after a cerebral ischemia induced by middle cerebral artery occlusion (MCAO). Knock down of contralaterally elevated H19 robustly enhanced the midline-crossing sprouting of the intact corticospinal axons in the spinal cord. Furthermore, H19 knockdown mice showed significant improvement on the performance of the food pellet retrieval assay, a skilled, cortical dependent motor task. Mechanistically, lncRNA H19 inhibition increased IGF1R expression and activated IGF1 mediated mTOR pathway. Our research thereby provided novel insights into identifying therapeutic targets for ischemic stroke.

Astrocytic thrombin-evoked VEGF release is dependent on p44/42 MAPKs and PAR1.

Intracerebral haemorrhage (ICH) often causes severe neurological deficits in survived patients, although its underlying mechanisms remain elusive. A common feature of ICH is the accumulation of thrombin around the lesion site. Previous studies showed that thrombin promotes VEGF release and angiogenesis at a late stage post ICH [1]. In current study, we explored the source for thrombin-induced VEGF release by adding thrombin or its receptor agonist peptide to the neuronal or astrocytic primarily cultures. We identified that astrocytes specifically respond to thrombin by up-regulating and releasing VEGF. Furthermore, such release is dependent on p44/42 MAPKs and PAR1, a thrombin specific receptor. Our study therefore helps clarifying the underlying mechanisms of thrombin-induced VEGF release in ICH, which will further provide novel insights into the designing principles for treating ICH and traumatic brain injuries.

High-grade thalamic gliomas: Microsurgical treatment and prognosis analysis.

This retrospective study is aimed to investigate the efficacy of microsurgical treatment for high-grade thalamic gliomas, and to analyze the relevant prognosis. From May 2011 to Aug 2015, 49 patients with thalamic gliomas underwent microsurgical resection, and received chemotherapy and radiotherapy postoperatively. The postoperative symptoms and complications were documented, and the overall survival (OS) and the progression-free survival (PFS) data were collected. The prognostic factors were evaluated by univariate and multivariate analyses. Finally, there was no perioperative death. Twenty cases, 24 cases and 5 cases were achieved subtotal resection (>90%), partial resection (70-90%) and less than partial resection (<70%) respectively. All patients' pathological diagnosis was confirmed. The symptoms were improved in 32 cases, unchanged in 11 cases, and worsen in 6 cases. Postoperative complications were absent in 9 cases. The 6-month, 12-month, and 24-month OS were 71.4%, 38.9%, and 12.1% respectively; corresponding PFS were 66.6%, 27.1%, and 10.2% respectively. The median OS time and PFS time were 9.0 months (95% CI 6.9-11.1) and 9.0 months (95% CI 6.6-11.4) respectively. Multivariate analysis revealed extent of resection were independent prognostic factors for OS (p < .05), patients with postoperative adjuvant chemotherapy and radiotherapy had a significant prolonged OS (p < .001) and PFS (p < .001). The study shows that the short-term efficacy of microsurgery for high-grade thalamic gliomas is satisfactory. Microsurgery can effectively alleviate patients' symptoms and improve life quality. Postoperative adjuvant chemotherapy and radiotherapy are helpful for prolonging the survival time.

Thrombin preferentially induces autophagy in glia cells in the rat central nervous system.

Autophagy widely occurs after intracerebral hemorrhage (ICH). In our previous study, we demonstrated that thrombin, a serine protease produced after hematoma, contributes to ICH-induced autophagy. However, whether thrombin plays a neuronal and/or astrocytic role in autophagy induction is largely unknown. Here, we examined the autophagic role of thrombin on neurons and glia cells, respectively. In vivo, we found that intracaudate injection of thrombin specifically elevated the astrocytic expression of beclin-1 and LC3, two autophagic markers, and promoted the formation of autophagic vacuoles within astrocytes rather than neurons in the ipsilateral basal ganglia. Consistent with this, thrombin enhanced the LC3-II level and increased the number of MDC-labeled autophagic vacuoles in cultured astrocytes. These results indicated that thrombin preferentially activated astrocytic autophagy after ICH, and therefore provided novel insights into the pathophysiological mechanisms and therapeutic targets for hemorrhage stroke and brain trauma.

The role of miR-182 in regulating pineal CLOCK expression after hypoxia-ischemia brain injury in neonatal rats.

Circadian rhythm disorder is a common neurological deficit caused by neonatal hypoxic-ischemic brain damage (HIBD). However, little is known about its underlying mechanisms. Our previous studies revealed a significant elevation of clock genes at the protein, but not mRNA, levels in the pineal gland after neonatal HIBD. To investigate the mechanisms of post-transcriptional regulation on clock genes, we screened changes of miRNA levels in the pineal gland after neonatal HIBD using high-throughput arrays. Within the miRNAs whose expression was significantly down-regulated, we identified one miRNA (miR182) that targeted the 3'-untranslated region (3'-UTR) of Clock, a key component of clock genes, and played a crucial role in regulating CLOCK expression after oxygen-glucose deprivation in primarily cultured pinealocytes. Our findings therefore provide new insight on studies of therapeutic targets for circadian rhythm disturbance after neonatal HIBD.

T2 and T2* magnetic resonance imaging sequences predict brain injury after intracerebral hemorrhage in rats.

Magnetic resonance imaging (MRI) has been widely used in intracerebral hemorrhage (ICH) animal models and patients. In the current study, we examined whether MRI can predict at-risk brain tissue during the acute phase and long-term brain tissue loss after ICH. Male Sprague-Dawley rats had an intracaudate injection of autologous whole blood (10, 50 or 100 µL). MRI (T2 and T2*) sequences were performed at days 1, 3, 7, 14, and 28. The volume of brain tissue at risk was calculated as the difference between T2 and T2* lesion volumes. Dopamine- and cAMP-regulated phosphoprotein, Mr 32 kDa (DARPP-32) was used as a neuronal marker in the basal ganglia. Brain swelling at day 3 and brain tissue loss at day 28 after ICH were also measured. We found that the difference in lesion volumes between T2 and T2* measured by MRI coincided well with the difference between the volume of the DARPP-32-negative area and that of the hematoma measured in brain sections. Volumes of brain tissue at risk at day 3 correlated with the brain swelling at day 3 (p < 0.01) as well as the final brain tissue loss at day 28 (n = 9, p < 0.05). The results suggest that the difference between T2 lesions and T2* lesions could be an indicator of at-risk brain tissue and it could be used as a predictor of neuronal loss in ICH patients.

Thrombin-induced autophagy: a potential role in intracerebral hemorrhage.

Autophagy occurs in the brain after intracerebral hemorrhage (ICH) and thrombin contributes to ICH-induced brain injury and cell death. In this study, we investigated whether thrombin may activate autophagy (in vivo and in cultured astrocytes) and its potential role in ICH. Autophagy was examined using electron microscopy, conversion of light chain 3(LC3) from the LC3-I form to LC3-II, cathepsin D Western blotting and monodansylcadaverine (MDC) staining to detect autophagic vacuoles. 3-Methyladenine (3-MA) was used as an autophagy inhibitor. In vivo, we found that intracaudate injection of thrombin increased conversion of LC3-I to LC3-II, cathepsin D levels, and formation of autophagic vacuoles in the ipsilateral basal ganglia. ICH-induced upregulation of LC3-I to LC3-II conversion and cathepsin D levels was reduced by a thrombin inhibitor, hirudin. In cultured astrocytes, thrombin enhanced the conversion of LC3-I to LC3-II and increased MDC-labeled autophagic vacuoles. 3-MA inhibited thrombin-induced autophagic vacuole formation and exacerbated thrombin-induced cell death. These results indicate that thrombin activates autophagy in the brain and that thrombin has a role in ICH-induced autophagy.