Publication date: 1 November 2018 Source:Brain Research, Volume 1698 Author(s): Timothy J. Ness, Cary DeWitte, Jennifer J. DeBerry, Alan Randich There is increasing evidence that chronic pain may be associated with events that occur during critical periods of development. Recent studies have identified behavioral, spinal neurophysiological and spinal/peripheral neurochemical differences in rats that have experienced neonatal bladder inflammation (NBI): a putative model of the chronically painful bladder disorder, interstitial cystitis. Stress has been shown to exacerbate symptoms of interstitial cystitis and produces bladder hypersensitivity in animal models. We recently reported that Acute Footshock-induced bladder hypersensitivity was eliminated in otherwise normal rats by prior bilateral lesions of the central nucleus of the amygdala. Since the spinal and peripheral nervous systems of NBI-treated rats are known to differ from normal rats, the present experiments sought to determine whether a supraspinal nervous system structure, the central amygdala, is still necessary for the induction of Acute Footshock-induced hypersensitivity. The effect of bilateral amygdala electrolytic lesions on Acute Footshock-induced bladder hypersensitivity in adult female rats was tested in Control rats which underwent a control protocol as neonates and in experimental rats which experienced NBI. Consistent with our previous report, in Control rats, Acute Footshock-induced bladder hypersensitivity was eliminated by bilateral Amygdala Lesions. In contrast, Acute Footshock-induced bladder hypersensitivity in NBI-treated rats was unaffected by bilateral Amygdala Lesions. These findings provide evidence that NBI results in the recruitment of substrates of bladder hypersensitivity that may differ from those of normal rats. This, in turn, suggests that unique therapeutics may be needed for painful bladder disorders like interstitial cystitis.
Publication date: 1 November 2018 Source:Brain Research, Volume 1698 Author(s): Xinwei Wu, Xuemei Li, Yi Liu, Nannan Yuan, Chengwen Li, Zhimin Kang, Xinlei Zhang, Yuning Xia, Yimeng Hao, Yongxing Tan Cerebral ischemia/reperfusion injury (IRI) is a serious complication during the treatment of stroke patients with very few effective clinical treatment. Hydrogen (H2) can protect mitochondria function and have favorable therapeutic effects on cerebral IRI. Mitophagy plays an important role in eliminating damaged or dysfunctional mitochondria and maintaining mitochondria homeostasis. However, whether the protection of H2 on cerebral IRI is via regulating mitophagy is still unknown. In this study, OGD/R damaged hippocampal neurons were used to mimic cerebral IRI in vivo and we detected the effect of H2, Rap (autophagy activator) and 3-MA (autophagy inhibitor) on OGD/R neurons. The results of MTT indicated that H2 and RAP could increase cell viability after OGD/R treatment, while 3-MA further aggravated injury and inhibited the protection of H2 and RAP. Furthermore, the intracellular ROS and apoptosis ratio were determined, the results showed that ROS and apoptosis level significantly increased after OGD/R, H2 and RAP effectively restrained the increment of ROS level and apoptosis ratio but their protective effect can be weakened by 3-MA. Mitochondrial membrane potential (MMP) and mitophagy level were also determined, the data showed that H2 and RAP protected against the loss of MPP and increased the co-localization of mitochondria with GFP-LC3 while 3-MA exerted antagonistic effect. At last, the mitophagy-related factors LC3, PINK1 and Parkin expression were detected and analyzed. We found that the expression of LC3 was increased after OGD/R which can be further enhanced by H2 and RAP treatment, but treatment with 3-MA was opposite. The result revealed H2 and RAP could activate mitophagy while 3-MA inhibit mitophagy. In addition, the study found H2 and RAP could significantly induce the expression of PINK1 and Parkin in OGD/R neurons which was inhibited by 3-MA. Taken together, our findings demonstrated H2 had a neuroprotective effect on OGD/R damaged neurons by protecting mitochondrial function and the potential protection mechanism may closely related to enhancement of mitophagy mediated by PINK1/Parkin signaling pathway.
Publication date: 1 November 2018 Source:Brain Research, Volume 1698 Author(s): Mari Kaneko, Satoshi Fujita, Noriyoshi Shimizu, Mitsuru Motoyoshi, Masayuki Kobayashi During orthodontic treatment, binding teeth, may change the topographically organized representation of teeth in the cerebral cortex. To test the hypothesis that experimental tooth movement (ETM) changes the somatotopy of an individual tooth arrangement in the somatosensory cortex, we examined the spatiotemporal features of cortical excitatory propagation in response to mechanical stimulation of the maxillary incisor or molar using optical imaging in late adolescent rats without or with ETM. The ETM models consisted of 1d, 3d, and 7d ETM in which a closed-coil spring was ligated between the maxillary first molar and incisors. In controls, incisor and molar mechanical stimulation evoked excitation in the rostral and dorsocaudal regions of the primary somatosensory cortex (S1), respectively. In addition, the secondary somatosensory cortex and insular oral region (S2/IOR) were also activated. Incisor stimulation-induced excitatory regions in S1 of 3d and 7d ETM shifted without changing the maximum excitatory area or peak amplitude; the incisor stimulation-responding region moved toward the dorsocaudal region, which responded to molar stimulation in the control. This shift in excitatory region was not observed in 1d ETM. One day after removal of the coil spring that was attached for 6 days, the excitatory region shift in S1 was recovered to the control region. On the other hand, 1d ETM exhibited facilitation of the excitatory area and peak amplitude upon molar stimulation, and the facilitation of excitatory propagation disappeared in 3d and 7d ETM. These results may explain the clinical finding that abnormal sensation temporally occurs during orthodontic treatment.
Publication date: 1 November 2018 Source:Brain Research, Volume 1698 Author(s): S. Gasparini, M.R. Melo, G.M.F. Andrade-Franzé, J.C. Geerling, J.V. Menani, E. Colombari Aldosterone infusion into the 4th ventricle (4th V), upstream the nucleus of the solitary tract (NTS), produces strong 0.3 M NaCl intake. In the present study, we investigated whether aldosterone infusion into the 4th V activates HSD2 neurons, changes renal excretion, or alters blood pressure and cardiovascular reflexes. Chronic infusion of aldosterone (100 ng/h) into the 4th V increased daily 0.3 M NaCl intake (up to 44 ± 10, vs. vehicle: 5.6 ± 3.4 ml/24 h) and also c-Fos expression in HSD2 neurons in the NTS and in non-HSD2 neurons in the NTS. Natriuresis, diuresis and positive sodium balance were present in rats that ingested 0.3 M NaCl, however, renal excretion was not modified by 4th V aldosterone in rats that had no access to NaCl. 4th V aldosterone also reduced baroreflex sensitivity (−2.8 ± 0.5, vs. vehicle: −5.1 ± 0.9 bpm/mmHg) in animals that had sodium available, without changing blood pressure. The results suggest that sodium intake induced by aldosterone infused into the 4th V is associated with activation of NTS neurons, among them the HSD2 neurons. Aldosterone infused into the 4th V in association with sodium intake also impairs baroreflex sensitivity, without changing arterial pressure.
Publication date: 1 November 2018 Source:Brain Research, Volume 1698 Author(s): Xiaoxia Huang, Jinyuan Li, Jin Xie, Yang Li, Yan Gao, Xiaohui Li, Xueqin Xu, Ruoshi Shi, Wanjun Yao, Changbin Ke Activation of spinal cord microglia is crucial for the development of bone cancer pain (BCP). The essential signal between neuronal excitability and microglial activation is not fully understood. In the present study, carcinoma implantation into tibia was used to induce BCP and RNAi-lentivirus was injected into spinal cord to knock down C1, C2 or C3 of complement cascade. We showed that C1, C2 and C3 co-localized in the same neurons and increased in cancer-bearing rats along with microglial activation. Knocked down of C1, C2 or C3 inhibited microglial activation and prevented the development of cancer-induced bone pain. Intrathecal administration of either minocycline (an inhibitor of microglial activity) to inhibit the activation of microglia or compstatin (a C3-targeted complement inhibitor) to block the complement cascade reversed cancer induced bone pain. Further study indicated that neuronal complement promoted the activation of microglia via complement 3 receptor (C3R). In the in vitro experiments, the proliferation of microglia was enhanced by the activation product of C3 (iC3b), but was inhibited by compstatin. These results indicated that neuronal complement pathway promoted the activation of microglia via C3R and contributed to the development of BCP.
Publication date: 1 November 2018 Source:Brain Research, Volume 1698 Author(s): Maycon I.O. Milanez, Érika E. Nishi, Alex Y.S. Sato, Henrique A. Futuro Neto, Cássia T. Bergamaschi, Ruy R. Campos The role of spinal cord neurons in renal sympathoexcitation remains unclear in renovascular hypertension, represented by the 2-kidney, 1-clip (2K1C) model. Thus, we aimed to assess the influence of spinal glutamatergic and AT1 angiotensin II receptors on renal sympathetic nerve activity (rSNA) in 2K1C Wistar rats. Hypertension was induced by clipping the renal artery with a silver clip. After six weeks, a catheter (PE-10) was inserted into the subarachnoid space and advanced to the T10-11 vertebral level in urethane-anaesthetized rats. The effects of intrathecally (i.t.) injected kynurenic acid (KYN) or losartan (Los) on blood pressure (BP) and rSNA were analysed over 2 consecutive hours. KYN induced a significantly larger drop in rSNA among 2K1C rats than among control (CTL) rats (CTL vs. 2K1C: −8 ± 3 vs. −52 ± 9 spikes/s after 120′). Los also evoked a significantly larger drop in rSNA among 2K1C rats than among CTL rats starting at 80′ after administration (CTL vs. 2K1C – 80 min: −10 ± 2 vs. –32 ± 6∗; 100 min: −15 ± 4 vs. −37 ± 9∗; 120 min: −12 ± 5 vs. −37 ± 8∗ spikes/s). KYN decreased BP similarly in the CTL and 2K1C groups; however, Los significantly decreased BP in the 2K1C group only. We found upregulation of AT1 gene expression in the T11-12 spinal segments in the 2K1C group but no change in gene expression for AT2 or ionotropic glutamate (NMDA, kainate and AMPA) receptors. Thus, our data show that spinal ionotropic glutamatergic and AT1 receptors contribute to increased rSNA in the 2K1C model, leading to the maintenance of hypertension; however, the participation of spinal AT1 receptors seems to be especially important in the establishment of sympathoexcitation in this model. The origins of those projections, i.e., the brain areas involved in establishing the activity of spinal glutamatergic and angiotensinergic pathways, remain unclear.
Publication date: 1 November 2018 Source:Brain Research, Volume 1698 Author(s): Anderson V. Catarina, Carolina Luft, Samuel Greggio, Gianina T. Venturin, Fernanda Ferreira, Eduardo P. Marques, Letícia Rodrigues, Krista Wartchow, Marina C. Leite, Carlos A. Gonçalves, Angela T.S. Wyse, Jaderson C. Da Costa, Jarbas R. De Oliveira, Gisele Branchini, Fernanda B. Nunes Sepsis is one of the main causes of hospitalization and mortality in Intensive Care Units. One of the first manifestations of sepsis is encephalopathy, reported in up to 70% of patients, being associated with higher mortality and morbidity. The factors that cause sepsis-associated encephalopathy (SAE) are still not well known, and may be multifactorial, as perfusion changes, neuroinflammation, oxidative stress and glycolytic metabolism alterations. Fructose-1,6-bisphosphate (FBP), a metabolite of the glycolytic route, has been reported as neuroprotective agent. The present study used an experimental sepsis model in C57BL/6 mice. We used in vivo brain imaging to evaluate glycolytic metabolism through microPET scans and the radiopharmaceutical 18F-fluoro-2-deoxy-D-glucose (18F-FDG). Brain images were obtained before and 12 h after the induction of sepsis in animals with and without FBP treatment. We also evaluated the treatment effects in the brain oxidative stress by measuring the production of reactive oxygen species (ROS), the activity of catalase (CAT) and glutathione peroxidase (GPx), and the levels of fluorescent marker 2′7′-dichlorofluorescein diacetate (DCF). There was a significant decrease in brain glucose metabolism due to experimental sepsis. A significant protective effect of FBP treatment was observed in the cerebral metabolic outcomes. FBP also modulated the production of ROS, evidenced by reduced CAT activity and lower levels of DCF. Our results suggest that FBP may be a possible candidate in the treatment of SAE.
Publication date: 1 September 2018 Source:Brain Research, Volume 1694 Author(s): Toshiki Nozaki, Hiroyuki Ura, Ichiro Takumi, Shiro Kobayashi, Eiichi Maru, Akio Morita Blood–brain barrier (BBB) breakdown and the subsequent exposure of the cerebral cortex to serum albumin are known to activate transforming growth factor β (TGF-β) signaling in astrocytes and to play key roles in epileptogenesis after brain injury. It was recently reported that the angiotensin II type I receptor antagonist losartan suppresses activation of TGF-β signaling and prevents epileptogenesis in a rat vascular injury model. Here, we investigated the effects of losartan on epileptogenesis following amygdala kindling in rats. Systemic or intracerebroventricular (i.c.v.) administration of losartan significantly delayed the development of severe behavioral seizures and stimulus-induced seizures on EEG (afterdischarge) in the early stage of amygdala kindling, as assessed by electroencephalography. Losartan also significantly increased the number of stimulations required to reach the fully kindled state. However, losartan had no effects on the threshold for afterdischarge induction, the afterdischarge duration, or seizure severity in fully kindled rats. Evaluation of BBB permeability by Evans blue staining did not indicate BBB breakdown (extravasation of serum albumin) in any region of the brain in the fully kindled animals. Thus, losartan may be useful in preventing epileptogenesis, even in post brain-insult epilepsy, in the absence of BBB breakdown.
Publication date: 1 September 2018 Source:Brain Research, Volume 1694 Author(s): Yongqi Rong, Parmil K. Bansal, Peng Wei, Hong Guo, Kristen Correia, Jennifer Parris, James I. Morgan Cbln1 is the prototype of a family (Cbln1-Cbln4) of secreted glycoproteins and is essential for normal synapse structure and function in cerebellum by bridging presynaptic Nrxn to postsynaptic Grid2. Here we report the effects of glycosylation on the in vitro receptor binding properties of Cblns. Cbln1, 2 and 4 harbor two N-linked glycosylation sites, one at the N-terminus is in a region implicated in Nrxn binding and the second is in the C1q domain, a region involved in Grid2 binding. Mutation (asparagine to glutamine) of the N-terminal site, increased neurexin binding whereas mutation of the C1q site markedly increased Grid2 binding. These mutations did not influence subunit composition of Cbln trimeric complexes (mediated through the C1q domain) nor their assembly into hexamers (mediated by the N-terminal region). Therefore, glycosylation likely masks the receptor binding interfaces of Cblns. As Cbln4 has undetectable Grid2 binding in vitro we assessed whether transgenic expression of wild type Cbln4 or its glycosylation mutants rescued the Cbln1-null phenotype in vivo. Cbln4 partially rescued and both glycosylation mutants completely rescued ataxia in cbln1-null mice. Thus Cbln4 has intrinsic Grid2 binding that is attenuated by glycosylation, and glycosylation mutants exhibit gain of function in vivo. Graphical abstract