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  • The Prefrontal Cortex and the Caudate Nucleus Respond Conjointly to Methylphenidate (Ritalin). Concomitant Behavioral and Neuronal Recording Study
    Brain Res. Bull. (IF 3.103) Pub Date : 2020-01-24
    Sidish S. Venkataraman; Catherine M. Claussen; Natasha Kharas; Nachum Dafny

    Methylphenidate (MPD) is commonly used to treat attention-deficit hyperactivity disorder (ADHD). Recently, it is being abused for cognitive enhancement and recreation leading to concerns regarding its addictive potential. The prefrontal cortex (PFC) and caudate nucleus (CN) are two of the brain structures involved in the motive/reward circuit most affected by MPD and are also thought to be responsible for ADHD phenomena. This study is unique in that it investigated acute and chronic, dose-response MPD exposure on animals’ behavior activity concomitantly with PFC and CN neuronal circuitry in freely behaving adult animals without the interference of anesthesia. Further, it compared acute and chronic MPD action on over 1,000 subcortical and cortical neurons simultaneously, allowing for a more accurate interpretation of drug action on corticostriatal neuronal circuitry. For this experiment, four groups of animals were used: saline (control), 0.6, 2.5, and 10.0 mg/kg MPD following acute and repetitive exposure. The data shows that the same MPD dose elicits behavioral sensitization in some animals and tolerance in others and that the PFC and CN neuronal activity correlates with the animals' behavioral responses to MPD. The expression of sensitization and tolerance are experimental biomarkers indicating that a drug has addictive potential. In general, a greater percentage of CN units responded to both acute and chronic MPD exposure as compared to PFC units. Dose response differences between the PFC and the CN units were observed. The dichotomy that some PFC and CN units responded to the same MPD dose by excitation and other units by attenuation in neuronal firing rate is discussed. In conclusion, to understand the mechanism of action of the drug, it is essential to study, simultaneously, on more than one brain site, the electrophysiological and behavioral effects of acute and chronic drug exposure, as sensitization and tolerance are experimental biomarkers indicating that a drug has addictive potential. The behavioral and neuronal data obtained from this study indicates that chronic MPD exposure results in behavioral and biochemical changes consistent with a substance abuse disorder.

  • Xenon modulates the GABA and glutamate responses at genuine synaptic levels in rat spinal neurons
    Brain Res. Bull. (IF 3.103) Pub Date : 2020-01-24
    Hisahiko Kubota; Hironari Akaike; Nobuharu Okamitsu; Il-Sung Jang; Kiku Nonaka; Naoki Kotani; Norio Akaike

    Effects of xenon (Xe) on whole-cell currents induced by glutamate (Glu), its three ionotropic subtypes, and GABA, as well as on the fast synaptic glutamatergic and GABAergic transmissions, were studied in the mechanically dissociated “synapse bouton preparation” of rat spinal sacral dorsal commissural nucleus (SDCN) neurons. This technique evaluates pure single or multi-synapse responses from native functional nerve endings and enables us to quantify how Xe influences pre- and postsynaptic transmissions accurately. Effects of Xe on glutamate (Glu)-, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-, kainate (KA)- and N-methyl-d-aspartate (NMDA)- and GABAA receptor-mediated whole-cell currents were investigated by the conventional whole-cell patch configuration. Excitatory and inhibitory postsynaptic currents (EPSCs and IPSCs) were measured as spontaneous (s) and evoked (e) EPSCs and IPSCs. Evoked synaptic currents were elicited by paired-pulse focal electric stimulation. Xe decreased Glu, AMPA, KA, and NMDA receptor-mediated whole-cell currents but did not change GABAA receptor-mediated whole-cell currents. Xe decreased the frequency and amplitude but did not affect the 1/e decay time of the glutamatergic sEPSCs. Xe decreased the frequency without affecting the amplitude and 1/e decay time of GABAergic sIPSCs. Xe decreased the amplitude and increased the failure rate (Rf) and paired-pulse ratio (PPR) without altering the 1/e decay time of both eEPSC and eIPSC, suggesting that Xe acts on the presynaptic side of the synapse. The presynaptic inhibition was greater in eEPSCs than in eIPSCs. We conclude that Xe decreases glutamatergic and GABAergic spontaneous and evoked transmissions at the presynaptic level. The glutamatergic presynaptic responses are the main target of anesthesia-induced neuronal responses. In contrast, GABAergic responses minimally contribute to Xe anesthesia.

  • Bisphenol A exposure inhibits contrast sensitivity in cats involving increased response noise and inhibitory synaptic transmission
    Brain Res. Bull. (IF 3.103) Pub Date : 2020-01-23
    Fan Hu; Jiachen Liu; Guangwei Xu; Huan Wang; Jiawei Shen; Yifeng Zhou

    Contrast sensitivity (CS) is one of the primary fundamental factors determining how well we can see, and it directly influences object recognition. Whether bisphenol-A (BPA, an environmental xenoestrogen) can perturb contrast detection in the visual system has yet to be elucidated. In the present study, we analyzed CS of single neurons in the primary visual cortex (area 17, A17) of cats before and after BPA exposure using a multiple-channel recording technique. The results showed that CS of A17 neurons was markedly depressed with an increased contrast threshold after two hour of intravenous BPA administration, which had a positive correlation with decreased firing rates of A17 neurons. Additionally, responses of these neurons presented an overt increase in the trial-to-trail response variability (a kind of neuronal noise), which could disturb the information-filtering function of single neurons. We also found that neuronal CS in the visual relay station was not disturbed after BPA administration, which rules out the contribution of CS alteration in the optical pathway. Importantly, acute BPA treatment obviously increased the inhibitory innervation to the visual pyramidal neurons. This implies that alteration of intracortical inhibitory regulation contributes to the compromised contrast detection in the visual system after BPA treatment.

  • Effects of Acute versus Recurrent Insulin-Induced Hypoglycemia on Ventromedial Hypothalamic Nucleus Metabolic-Sensory Neuron AMPK Activity: Impact of Alpha1-Adrenergic Receptor Signaling
    Brain Res. Bull. (IF 3.103) Pub Date : 2020-01-22
    Karen P. Briski; Santosh K. Mandal; Khaggeswar Bheemanapally; Mostafa M.H. Ibrahim

    Mechanisms that underlie metabolic sensor acclimation to recurring insulin-induced hypoglycemia (RIIH) are unclear. Norepinephrine (NE) regulates ventromedial hypothalamic nucleus (VMN) gluco-stimulatory nitric oxide (NO) and gluco-inhibitory γ-aminobutryic acid (GABA) neuron signaling. Current research addressed the hypothesis that during RIIH, NE suppresses 5’-AMP-activated protein kinase (AMPK) reactivity in both populations and impedes counter-regulation. The brain is postulated to utilize non-glucose substrates, e.g. amino acids glutamine (Gln), glutamate (Gln), and aspartate (Asp), to produce energy during hypoglycemia. A correlated aim investigated whether NE controls pyruvate recycling pathway marker protein (glutaminase, GLT; malic enzyme, ME-1) expression in either metabolic-sensory cell population. Male rats were injected subcutaneously with vehicle or insulin on days 1-3, then pretreated on day 4 by intracerebroventricular delivery of the alpha1-adrenergic receptor (α1-AR) reverse-agonist prazocin (PRZ) or vehicle before final insulin therapy. PRZ prevented acute hypoglycemic augmentation of AMPK activation in each cell group. Antecedent hypoglycemic repression of sensor activity was reversed by PRZ in GABA neurons. During RIIH, nitrergic neurons exhibited α1-AR – dependent up-regulated GLT and α2-AR profiles, while GABA cells showed down-regulated α1-AR. UHPLC-MS/ESI analysis documented a decline in VMN Glu, Gln, and Asp concentrations during acute hypoglycemia, and habituation of former two profiles to RIIH. PRZ attenuated glucagon and corticosterone secretion during acute hypoglycemia, but reversed decrements in output of both hormones during RIIH. Results implicate adjustments in impact of α1-AR signaling in repressed VMN metabolic-sensory AMPK activation and counter-regulatory dysfunction during RIIH. Antecedent hypoglycemia may up-regulate NO neuron energy yield via α1-AR – mediated up-regulated pyruvate recycling.

  • GABA-cannabinoid interplays in the dorsal hippocampus and basolateral amygdala mediate morphine-induced amnesia
    Brain Res. Bull. (IF 3.103) Pub Date : 2020-01-22
    Khadijeh Alsadat Sharifi; Ameneh Rezayof; Sakineh Alijanpour; Mohammad-Reza Zarrindast

    The aim of the current study was to investigate the involvement of GABA neurotransmission in the CA1 region and endocannabinoid system in the basolateral amygdala (BLA) on morphine-induced memory impairment. We hypothesized that possible functional interaction between the GABAergic and cannabinoid systems in these brain regions would modulate morphine response in memory processing. Step-through type inhibitory avoidance paradigm was used for evaluating memory consolidation in adult male Wistar rats. Our results indicated that post-training systemic injection of morphine (3 and 5 mg/kg, i.p.) impaired memory retrieval. The microinjection of a GABA-A receptor agonist, muscimol (0.01-0.03 µg/rat) into the CA1 region increased the response of an ineffective dose of morphine (0.5 mg/kg, i.p.) and induced memory impairment, suggesting a synergistic interaction between morphine and muscimol. Interestingly, the activation of the BLA CB1 receptors by the microinjection of WIN55,212-2 (0.05-0.1 µg/rat) increased the effect of ineffective doses of muscimol (0.01 µg/rat; intra-CA1) and morphine (0.5 mg/kg, i.p.), inducing amnesia. The obtained results also showed that microinjection of AM251, a cannabinoid CB1 receptor antagonist, (1-2 μg/rat) into the BLA reversed the synergistic effect of muscimol and morphine, improving memory consolidation. It should be noted that the intra-CA1 microinjection of muscimol, intra-BLA microinjection of WIN55,212-2 or AM251 alone could not affect memory consolidation. Accordingly, it can be concluded that there may be a synergistic interaction between the CA1 GABAergic system and the BLA endocannabinoid neurotransmission with respect to the modulation of morphine-induced memory impairment.

  • Effect of morphine exposure on novel object memory of the offspring: the role of histone H3 and ΔFosB
    Brain Res. Bull. (IF 3.103) Pub Date : 2020-01-17
    Mitra-Sadat Sadat-Shirazi; Pardis Asgari; Sarah Mahboubi; Setareh Nouri Zadeh-Tehrani; Ghorbangol Ashabi; Kiyana Rohbani; Saba Sabzevari; Haniyeh Soltani; Solmaz Khalifeh; Mohammad-Reza Zarrindast

    It has been demonstrated that alteration in histone acetylation in the regions of the brain involved in the reward which may have an important role in morphine addiction. It is well established that epigenetic changes prior to birth influence the function and development of the brain. The current study was designed to evaluate changes in novel object memory, histone acetylation and ΔFosB in the brain of the offspring of morphine-withdrawn parents. Male and female Wistar rats received morphine orally for 21 following days. After ten days of abstinent, they were prepared for mating. The male offspring of the first parturition were euthanized on postnatal days 5, 21, 30 and 60. The novel object recognition (NOR) test was performed on adult male offspring. The amount of acetylated histone H3 and ΔFosB were evaluated in the prefrontal cortex (PFC) and hippocampus using western blotting. Obtained results indicated that the discrimination index in the NOR test was decreased in the offspring of morphine-withdrawn parents as compared with morphine-naïve offspring. In addition, the level of acetylated histone H3 was decreased in the PFC and hippocampus in the offspring of morphine-withdrawn parents during lifetime (postnatal days 5,21,30 and 60). In the case of ΔFosB, it also decreased in these regions in the morphine-withdrawn offspring. These results demonstrated that parental morphine exposure affects NOR memory, and decreased the level of histone H3 acetylation and ΔFosB in the PFC and hippocampus. Taken together, the effect of morphine might be transmitted to the next generation even after stop consuming morphine.

  • Facilitation of microglial motility by thyroid hormones requires the presence of neurons in cell culture: a distinctive feature of the brainstem versus the cortex
    Brain Res. Bull. (IF 3.103) Pub Date : 2020-01-16
    Jean-Philippe Rousseau; Mami Noda; Richard Kinkead

    Microglia are critical for the refinement of neural networks that takes place during the perinatal period. Their phenotype and actions are guided by the signals produced by neighbouring cells and hormones present in their surrounding milieu. Cell populations and the signals they produce differ between regions. The fact that thyroid hormones (THs) promote the growth and morphological differentiation of microglia within the cortex contributes to the TH’s powerful actions on the developing brain. The brainstem is especially active during early life owing to its role in generation of the rhythmic respiratory motor command. Despite evidences indicating that THs are necessary to proper development of the neural networks regulating this vital homeostatic function, their actions on microglia originating from the brainstem remain unknown. Using primary cultured microglia from newborn mice (C57BL/6 J), we first report that regulation of microglial motility by THs is different between cortex and brainstem. Microglial motility (µm traveled over 3 hours) was monitored with or without triiodothyronine (T3, 1µM). Exposure to T3 did not stimulate microglial motility from brainstem, but significantly stimulated (316%) when they were co-cultured with neurons. Motility of cortex microglia was stimulated to the similar extent either with or without neurons. These data suggest that the microglial function in different regions of the brain is determined by the surrounding environment.

  • MicroRNAs expressed in neuronal differentiation and their associated pathways: systematic review and bioinformatics analysis
    Brain Res. Bull. (IF 3.103) Pub Date : 2020-01-13
    Roberta Giorgi Silveira; Camila Perelló Ferrúa; Cainá Corrêa do Amaral; Tiago Fernandez Garcia; Karoline Brizola de Souza; Fernanda Nedel
  • Neuroprotective effects of leptin on cerebral ischemia through JAK2/STAT3/PGC-1-mediated mitochondrial function modulation
    Brain Res. Bull. (IF 3.103) Pub Date : 2020-01-11
    Wenfang Zhang; Yinchuan Jin; Dong Wang; Jingjing Cui

    Neuroprotective effects of leptin have been shown in mouse model of cerebral ischemia/reperfusion injury and primary cortical neuronal culture with oxygen-glucose deprivation (OGD), while the underlying mechanisms are less understood. In the present study, we investigated whether leptin modulated mitochondrial function through JAK2/STAT3 in vivo mouse model of transient middle cerebral artery occlusion (MCAO) and in OGD-challenged primary neuronal cultures. JAK2/STAT3; mitochondrial biogenesis markers (PGC-1α); and apoptosis-associated proteins (caspase-3, BCL-2, BCL-XL, and cytochrome c) were detected by western blotting and reverse transcription-polymerase chain reaction at 1 h before and after ischemia/reperfusion. P-STAT3 and PGC-1α in neurons and astrocytes were detected. Moreover, mitochondrial morphology of the ischemic ipsilateral penumbra is examined using transmission electron microscopy. Primary cerebral cortical neurons were evaluated for viability, mitochondrial membrane potential (MMP), and apoptosis to assess whether dose-dependent neuroprotective effects of leptin during OGD were mitigated by the JAK2/STAT3 inhibitor AG490. Leptin activated JAK2/STAT3 signaling in neurons and astrocytes distributed in the ischemic ipsilateral penumbra, with peak p-STAT3 levels observed at 1 h after reperfusion. Leptin increased PGC-1α, BCL-2, and BCL-XL protein levels, cell viability, and MMP and decreased apoptosis both in vitro and in vivo; these effects were reversed by AG490 treatment. Our findings suggest that leptin-mediated neuroprotective effects in tMCAO may peak at 1 h to induce the transcription of its target gene PGC-1α, stabilization of MMP, inhibition of mitochondrial permeability transition pore opening, release of cytochrome c, and apoptosis.

  • Multiple inflammatory profiles of microglia and altered neuroimages in APP/PS1 transgenic AD mice
    Brain Res. Bull. (IF 3.103) Pub Date : 2020-01-10
    Lifen Liu; Yutong Liu; Nana Li; Runzhi Huang; Ximing Zheng; Liang Huang; Shuangxin Hou; Qionglan Yuan

    Aβ plaques of Alzheimer’s disease (AD) are believed to precede cognitive deficits or clinical manifestation by decades. However, validated biomarkers for early diagnosis of the AD disease are still not available. In this present study, we combined MRI-based neuroimages and histological assessment of the glial response and altered cytokines, neurogenesis during the early course of Aβ deposits in TgAPP/PS1 mice to find potential early biomarkers for AD. We found that microglia and astrocytes were initially activated and clustered around Aβ plaques at the age of 6 months and significantly increased with age from 6 to 12 months of age. Confocal microscope analysis revealed that microglia not astrocytes began to phagocytose Aβ in 6-month-old TgAPP/PS1 mice, evidenced by the intracellular Aβ in Iba1 positive microglia not in GFAP positive astrocytes. In parallel with these observations, we found that mainly clustered microglia significantly upregulated the production of proinflammatory factors including TNF-α, iNOS and IL-1β, and anti-inflammatory cytokines including IL-4, TGF-β and extracellular protecting matrix YM-1 and enzyme arginase 1 (Arg1) at 6 to 12 months of age. Interestingly, reactive astrocyte did not express these cytokines and YM-1 and Arg1. These results may suggest that microglia rather than astrocytes play crucial roles in clearing Aβ and neuroinflammation in early stage of AD. In addition, the number of neural stem cells labeled by BrdU and immature neurons labeled by doublecortin was significantly decreased in 3-month-old TgAPP/PS1 mice ahead of Aβ deposits. Finally, DTI conforms that reduced fractional anisotropy (FA) in dentate gyrus of hippocampus and rs-MRI shows an increased connectivity in the networks of somatosensory cortex-caudoputamen and insula in TgAPP/PS1 mice at 6 months. These findings provide a clue to early biomarkers for diagnosis of the AD disease.

  • Gonadotropin-releasing hormone-Cu complex (Cu-GnRH) transcriptional activity in vivo in the female rat anterior pituitary gland
    Brain Res. Bull. (IF 3.103) Pub Date : 2020-01-10
    Grzegorz Kotarba; Marlena Zielinska-Gorska; Katarzyna Biernacka; Alina Gajewska

    Unlike gonadotropin-releasing hormone (GnRH) analogues characterized by amino acid replacement in decapeptide primary structure, Cu-GnRH molecule preserves the native sequence but contains a Cu2+ ion stably bound to the nitrogen atoms including that of the imidazole ring of His2. Cu-GnRH can operate via cAMP/PKA signalling in anterior pituitary cells, suggesting that it may affect selected gonadotropic network gene transcription in vivo. We analysed pituitary mRNA expression of Egr-1, Nr5a1, and Lhb based on their role in luteinizing hormone (LH) synthesis; and Nos1, Adcyap1, and Prkaca due to their dependence on cAMP/PKA activity. In two independent experiments, ovariectomized rats received intracerebroventricular pulsatile (one pulse/h or two pulses/h over 5 h) microinjections of 2 nM Cu-GnRH; 2 nM antide (GnRH antagonist) + 2 nM Cu-GnRH; 100 nM PACAP6-38 (PACAP receptor antagonist) + 2 nM Cu-GnRH. Relative expression of selected mRNAs was determined by qRT-PCR. LH serum concentration was examined according to RIA. All examined genes responded to Cu-GnRH stimulation with increased transcriptional activity in a manner dependent on pulse frequency pattern. Increased expression of Nr5a1, Lhb, Nos1, Adcyap1, and Prkaca mRNA was observed solely in rats receiving the complex with frequency of two pulses/h over 5 h. Egr-1 transcription was up-regulated for both applied Cu-GnRH pulsatile patterns. The stimulatory effect of Cu-GnRH on gene transcription was dependent on both GnRH receptor and PAC-1 activation. In conclusion, obtained results indicate that Cu-GnRH complex is a GnRH analogue able to induce both IP3/PKC and cAMP/PKA-dependent gonadotrope network gene transcription in vivo.

  • Chronic hyperglycemia induces tau hyperphosphorylation by downregulating OGT-involved O-GlcNAcylation in vivo and in vitro
    Brain Res. Bull. (IF 3.103) Pub Date : 2020-01-10
    Rong Huang; Sai Tian; Haoqiang Zhang; Wenwen Zhu; Shaohua Wang

    Objective Diabetes mellitus (DM) can increase the risk of cognitive dysfunction, but its exact mechanisms remain unclear. The involvement of aberrant O-GlcNAcylation has been identified in hyperglycemia and DM, as well as the pathogenesis of Alzheimer’s disease via competition with tau phosphorylation. This study was designed to investigate the role of O-GlcNAcylation in diabetes-associated cognitive dysfunction (DACD). Methods Fifteen-week old male KK-Ay mice were used as DACD models, and advanced glycation end product (AGE)-treated HT22 cells were used as a model of high glucose toxicity. Morris water maze tests, histological staining, real-time quantitative PCR, and Western blot were also applied. Results Mice with DACD exhibited evident obesity, hyperinsulinemia, hyperglycemia, and impaired learning and memory function. O-GlcNAcylation levels decreased and tau phosphorylation levels at Ser396, Ser404, Thr212, and Thr231 increased in the hippocampus of mice with DACD, as well as in AGE-treated HT22 cells. Hypoglycemic therapy improved these anomalies and elevated O-GlcNAc transferase (OGT) levels in mice with DACD. OGT plasmid transfection in HT22 cells partially reversed AGE-induced decreases in O-GlcNAcylation levels and increased tau phosphorylation levels. Conclusions Chronic hyperglycemia can induce tau hyperphosphorylation by downregulating OGT-involved O-GlcNAcylation in vivo and in vitro, which mediates DACD.

  • Aquaporin 4 knockout increases complete Freund's adjuvant-induced spinal central sensitization
    Brain Res. Bull. (IF 3.103) Pub Date : 2020-01-09
    Cong Wang; Qi Wu; Ze Wang; Liang Hu; Charles Marshall; Ming Xiao

    Growing evidence suggests a critical role of astrocytes for pain regulation. The water channel protein aquaporin 4 (AQP4), a functional regulator of astrocytes, is involved in various neurological disorders. However, the pathophysiological roles of AQP4 in pain conditions remain unclear. In the present study, we investigated the effect of AQP4 gene knockout in central sensitization induced by complete Freund's adjuvant (CFA). The behavioral analysis revealed that mechanical allodynia and thermal hyperalgesia were more severe in AQP4 null mice than those of wild-type controls over the course of 11 days following CFA intraplantar injection. CFA caused activation of astrocytes with upregulated expression levels of AQP4 and glutamate transporter 1 (GLT1) in the dorsal horn of the spinal cord. AQP4 deficiency reduced GLT1 up-regulation, causing persistent expression of the neuronal activation marker Fos within superficial dorsal horn neurons, including glutamatergic neurons. However, AQP4 deletion did not affect CFA-evoked proinflammatory cytokine expression in the spinal cord. Together, these results have shown that AQP4 absence intensifies CFA-induced spinal central sensitization, which is associated with reduced compensatory up-regulation of GLT1, subsequently increasing glutamatergic overexcitation. Therefore, targeting spinal cord AQP4 may serve as a potential strategy for treatment of peripheral inflammation-evoked hyperalgesia.

  • Saikosaponin d downregulates microRNA-155 and upregulates FGF2 to improve depression-like behaviors in rats induced by unpredictable chronic mild stress by negatively regulating NF-κB
    Brain Res. Bull. (IF 3.103) Pub Date : 2020-01-08
    Bin Chao; Shijing Huang; Juhua Pan; Ying Zhang; Yanyun Wang

    Saikosaponin d (SSd) is a traditional Chinese medicine that has been widely used in depression treatment. Given the lack of studies demonstrating the underlying mechanism of action of SSd in depression, the presented study was conducted with aims of investigating the effect of SSd on rats with depression-like behaviors induced by unpredicted chronic mild stress (UCMS) and its underlying molecular mechanism. To investigate the effect of SSd on depression, rat models with depression-like behaviors were established through 3-week exposure to UCMS, followed by administration of 10 mg/kg fluoxetine, 0.75 mg/kg SSd, 1.50 mg/kg SSd, or 10 mg/kg caffeic acid phenethyl ester (CAPE). The depression-like behaviors of rats were evaluated by sucrose preference test, open field test, forced swimming test, and tail suspension test. Afterwards, the regulatory relationship among nuclear factor-κB (NF-κB), microRNA (miR)-155 and fibroblast growth factor 2 (FGF2) were detected by dual-luciferase reporter gene assay and ChIP. RT-qPCR and Western blot analysis was conducted to determine the expression of genes and proteins. Finally, hippocampal neurons were extracted from modeled rats and transfected with miR-155 mimic, miR-155 inhibitor, NF-κB overexpression plasmid, or siRNA against NF-κB. The results showed that the depression-like behaviors induced by UCMS in rats was successfully attenuated by SSd. In hippocampal neurons of rats treated with SSd, NF-κB was significantly downregulated while FGF2 was significantly upregulated. NF-κB targets miR-155 and negatively regulates the expression of FGF2. NF-κB knockdown resulted in reduced depression-like behaviors of rats. These findings provide evidence that SSd could ameliorate depression-like behaviors in the rats treated with UCMS by downregulating NF-κB and miR-155, and upregulating FGF2.

  • Adolescent Drug Exposure: A Review of Evidence for the Development of Persistent Changes in Brain Function
    Brain Res. Bull. (IF 3.103) Pub Date : 2020-01-08
    Hamed Salmanzadeh; S. Mohammad Ahmadi-Soleimani; Narges Pachenari; Maryam Azadi; Robert F. Halliwell; Tiziana Rubino; Hossein Azizi

    Over the past decade, many studies have indicated that adolescence is a critical period of brain development and maturation. The refinement and maturation of the central nervous system over this prolonged period, however, makes the adolescent brain highly susceptible to perturbations from acute and chronic drug exposure. Here we review the preclinical literature addressing the long-term consequences of adolescent exposure to common recreational drugs and drugs-of-abuse. These studies on adolescent exposure to alcohol, nicotine, opioids, cannabinoids and psychostimulant drugs, such as cocaine and amphetamine, reveal a variety of long-lasting behavioral and neurobiological consequences. These agents can affect development of the prefrontal cortex and mesolimbic dopamine pathways and modify the reward systems, socio-emotional processing and cognition. Other consequences include disruption in working memory, anxiety disorders and an increased risk of subsequent drug abuse in adult life. Although preventive and control policies are a valuable approach to reduce the detrimental effects of drugs-of-abuse on the adolescent brain, a more profound understanding of their neurobiological impact can lead to improved strategies for the treatment and attenuation of the detrimental neuropsychiatric sequelae.

  • Cerebral ischemia-reperfusion causes a down regulation of HCN1 expression via enhancing the nuclear NRSF-HDAC4 gathering that contributes to neuron damage
    Brain Res. Bull. (IF 3.103) Pub Date : 2020-01-07
    Pan Luo; Xiaopei Fu; Mujun Chang; Li Zhang; Lianjun Guo

    Cerebral ischemia-reperfusion (I/R) can trigger neuronal death through several biologically plausible pathways, but its underlying neurobiological mechanisms remain unclear. In this study, we tested whether hyperpolarization-activated cyclic nucleotide-gated channel 1 (HCN1) is altered in I/R that contributes to neuron damage and further clarified the mechanisms underlying this process. Cerebral I/R injury was induced by middle cerebral artery occlusion (MCAO) surgery followed by reperfusion in rats or simulated by oxygen-glucose deprivation/reoxygenation (OGD/R) in cultured cell. After reperfusion, the mRNA and protein levels of HCN1 were tested by RT-PCR and Western blot (WB). The histone deacetylases 4 (HDAC4) shuttling and the nuclear neuron-restrictive silencer factor (NRSF) expression were evaluated by WB and immunohistochemistry. Our data showed that I/R caused a strong decrease of HCN1 subunit in both hippocampus and cortex of rat. Additionally, the nuclear expression of HDAC4 and NRSF were significantly increased. In vitro OGD/R model, the gathering of HDAC4 and NRSF to nuclei was further confirmed. Valproic acid (VPA), a HDAC4 inhibitor, could reverse the decreased HCN1 and protect neuron damage from OGD/R injury. Collectively, these results demonstrated that I/R cause a decrease of HCN1 expression via enhancing nuclear HDAC4-NRSF gathering and might contribute to neuron damage.

  • Validation of reference genes for gene expression analysis following experimental traumatic brain injury in a pediatric mouse model
    Brain Res. Bull. (IF 3.103) Pub Date : 2020-01-02
    Akram Zamani; Kim L. Powell; Ashleigh May; Bridgette D. Semple

    Quantitative polymerase chain reaction (qPCR) is the gold standard method in targeted analysis of messenger RNA (mRNA) levels in a tissue. To minimize methodological errors, a reference gene (or a combination of reference genes) is routinely used for normalization to account for technical variables such as RNA quality and sample size. While presumed to have stable expression, reference genes in the brain can change during normal development, as well as in response to injury, such as traumatic brain injury (TBI). This study is the first to evaluate the stability of reference genes in a controlled cortical impact (CCI) model in the pediatric mouse brain, using two methods of qPCR normalization for optimal reference gene selection. Three week old mice were subjected to unilateral CCI at two severity of injuries (mild or severe), compared to sham controls. At 1 and 8 weeks post-injury, the ipsilateral hemisphere was analyzed to determine reference gene stability. Five commonly-used reference genes were compared: tyrosine 3 monooxygenase/tryptophan 5 monooxygenase activation protein zeta (Ywhaz), cyclophilin A (Ppia), hypoxanthine phosphoribosyl transferase (Hprt), glyceraldehyde-3-phosphate dehydrogenase (Gapdh) and β-actin (Actb). Ppia and Hprt were chosen as the most stable combination of genes using GeNORM software analysis. These results highlight the instability of several commonly used reference genes after TBI, and provide a selection of validated genes for future gene expression analyses in the injured pediatric mouse brain.

  • Alterations of Thyroidal Status in Brain Regions and Hypothalamo-Pituitary-Blood-Thyroid-axis Associated with Dopaminergic Depletion in SubstantiaNigra and ROS Formation in Different Brain Regions after MPTP Treatment in Adult Male Mice
    Brain Res. Bull. (IF 3.103) Pub Date : 2019-12-28
    Priyobrata Sinha; Nilkanta Chakrabarti; Nabanita Ghosh; Soham Mitra; Shauryabrota Dalui; Arindam Bhattacharyya

    MPTP produces oxidative stress, damages niagrostriatal dopaminergic neurons and develops Parkinsonism in rodents. Due to paucity of information, the thyroidal status in brain regions and peripheral tissues during different post-treatment days in MPTP-induced mice had been executed in the present study. MPTP depleted tyrosine hydroxylase protein expressions that signify the dopaminergic neuronal damage in substantia nigra. MPTP elevated ROS formation differentially in brain regions (cerebral cortex, hippocampus, substantia nigra) with maximal elevation at hippocampus. The changes in thyroid hormone (T4 and T3) levels indicate that brain regions might combat the adverse situation by keeping the levels of thyroid hormones either unchanged or in the elevated conditions in the latter phases (day-3 and day-7), apart from the depletion of thyroid hormones in certain brain regions (T4 in SN and hippocampus, T3 in hippocampus) as the immediate (day-1) effects after MPTP treatment. MPTP caused alterations of cellular morphology, RNA:Protein ratio and TPO protein expression concomitantly depleted TPO mRNA expression and elevated TSH levels in the thyroid gland. Although T4 levels changed differentially, T3 levels remained unaltered in thyroid gland throughout the post-treatment days. Results have been discussed mentioning the putative role of T4 and TSH in apoptosis and/or proliferation/differentiation of thyrocytes. In blood, T4 levels remained unchanged while the changes in T3 and TSH levels did not signify the clinical feature of hypo/hyperthyroidism of animals. In the pituitary, both T4 and T3 levels remained elevated where TSH differentially altered (elevated followed by depletion) during post-treatment days. Notably, T4, T3 and TSH levels did not alter in hypothalamus except initial (day-1) depletion of the T4 level. Therefore, the feedback control mechanism of hypothalamo-pituitary-blood-thyroid-axis failed to occur after MPTP treatment. Overall, MPTP altered thyroidal status in the brain and peripheral tissues while both events might occur in isolation as well.

  • Cerebral ischemia-reperfusion aggravated cerebral infarction injury and possible differential genes identified by RNA-Seq in rats
    Brain Res. Bull. (IF 3.103) Pub Date : 2019-12-23
    Xiao Cheng; Ying-Lin Yang; Wei-Han Li; Man Liu; Yue-Hua Wang; Guan-Hua Du

    Numerous studies have shown that local excessive inflammatory response in brain tissue was an important pathogenesis of secondary injury following cerebral ischemia-reperfusion (I/R). However, the inflammatory-related targets and pathways after cerebral I/R injury are still unclear. This study was to investigate possible targets and mechanisms after cerebral I/R injury. Rats were subjected to transient or permanent middle cerebral artery occlusion (MCAO). Neurological deficit scores test was used to evaluate neurological function. Cerebral infarction was evaluated by MRI, TTC staining and Nissl staining. Microglia activation was detected by immunofluorescence using Iba-1 antibody. Inflammatory factors was detected by ELISA assay. RNA-sequencing transcriptome analysis was processed and the differential genes were verified by real-time quantitative PCR (qPCR) and Western blotting. The results showed that neurological function of rats in I/R group was more severe than that of in I group on the 7th after cerebral I/R. Therefore, the differences between cerebral ischemia and cerebral I/R for 7 days were studied in further study. The results showed that the levels of pro-inflammatory factors in I/R group were higher and the levels of anti-inflammatory factors were lower than that of in I group. KEGG pathway and gene network enrichment analysis revealed that some common differential up- and down-regulated genes were involved in most of significant pathways. These common differential up-regulated genes belonged to TLR4/MYD88 inflammatory signaling pathway and common differential down-regulated genes belonged to HRAS/RAF1 neurotrophic signaling pathway. Interestingly, according to the genetic interaction analysis of string database, these up-regulated differential genes might promote the development of inflammation, while the down-regulated differential genes might inhibit the development of inflammation. Furthermore, qPCR and WB results verified that these pro-inflammatory genes in the I/R group was higher than that in the I group, while possible anti-inflammatory genes in the I/R group was lower than that in the I group. It is concluded that TLR4/MYD88 inflammatory signaling pathway and HRAS/RAF1 neurotrophic signaling pathway may be play different roles after cerebral I or I/R and may be therapeutic targets for stroke recovery.

  • Molecular targets and therapeutic interventions for Iron induced neurodegeneration
    Brain Res. Bull. (IF 3.103) Pub Date : 2019-12-19
    Siddhi Bagwe-Parab; Ginpreet Kaur
  • Characterization of Transection Spinal Cord Injuries by Monitoring Somatosensory Evoked Potentials and Motor Behavior
    Brain Res. Bull. (IF 3.103) Pub Date : 2019-12-19
    Angelo H. All; Hasan Al Nashash; Hasan Mir; Shiyu Luo; Xiaogang Liu

    Standardization of spinal cord injury (SCI) models is crucial for reproducible injury in research settings and their objective assessments. Basso, Beattie and Bresnahan (BBB) scoring, the traditional behavioral evaluation method, is subjective and susceptible to human error. On the other hand, neuro-electrophysiological monitoring, such as somatosensory evoked potential (SSEP), is an objective assessment method that can be performed continuously for longitudinal studies. We implemented both SSEP and BBB assessments on transection SCI model. Five experimental groups are designed as follows: left hemi-transection at T8, right hemi-transection at T10, double hemi-transection at left T8 and right T10, complete transection at T8 and control group which receives only laminectomy with intact dura and no injury on spinal cord parenchyma. On days 4, 7, 14 and 21 post-injury, first BBB scores in awake and then SSEP signals in anesthetized rats were obtained. Our results show SSEP signals and BBB scores are both closely associated with transection model and injury progression. However, the two assessment modalities demonstrate different sensitivity in measuring injury progression when it comes to late-stage double hemi-transection, complete transection and hemi-transection injury. Furthermore, SSEP amplitudes are found to be distinct in different injury groups and the progress of their attenuation is increasingly rapid with more severe transection injuries. It is evident from our findings that SSEP and BBB methods provide distinctive and valuable information and could be complementary of each other. We propose incorporating both SSEP monitoring and conventional BBB scoring in SCI research to more effectively standardize injury progression.

  • Prolonged febrile seizure history exacerbates seizure severity in a pentylenetetrazole rat model of epilepsy
    Brain Res. Bull. (IF 3.103) Pub Date : 2019-12-14
    Oluwole Ojo Alese; Cleopatra Rakgantsho; Nombuso V. Mkhize; Simo Zulu; Musa V. Mabandla

    Epilepsy is a debilitating neurological illness that affects all aspect of an individual life. Despite advancement in research there is little reduction in the incidence of this disease. Prolonged febrile seizure (PFS) has been linked to epilepsy however, the pathophysiology of this is still not clear. We therefore looked at the effect of PFS on the development of epilepsy in a pentylenetetrazole (PTZ) rat model of epilepsy. A total of 42 male Sprague–Dawley rats were used for the experiment. On post-natal day (PND) 14, PFS was induced in 14 rats. This was followed by the induction of epilepsy in the 14 PFS animal and 14 animals from the remaining 28 rats by an initial injection of PTZ at a dose of 60 mg/kg on day one followed by 35 mg/kg on alternate day until kindle. We looked at the effect of PFS on the onset and the stage of convulsion at kindle. We also observed it effect on the hippocampal glial fibrillary acidic protein (GFAP), synaptophysin and metabotropic glutamate receptor 3 (mGluR3) expression measured with immunofluorescence, LI Cor Tissue florescence and immunohistochemistry respectively. Our study showed that PFS reduced seizure threshold by decreasing the time it took animals to kindle and also increased the stage of convulsion. The hippocampal GFAP, synaptophysin and mGluR3 expressions where upregulated in PTZ rats with PFS history when compared to PTZ rats alone.These findings indicated that PFS may increase the severity of epilepsy and alter brain expression of GFAP, synaptophysin and mGluR3 proteins.

  • Inhibiting nuclear factor-κB at different stages after intracerebral hemorrhage can influence the hemorrhage-induced brain injury in experimental models in vivo
    Brain Res. Bull. (IF 3.103) Pub Date : 2019-12-16
    Zeli Zhang; Song Yan; Feng Li; Zhenkuan Xu; Qibing Huang

    Objective Nuclear factor-κB (NF-κB) is a critical regulator of inflammatory responses after ICH, and different subunits may have different influences on the cell death and prognosis. The aim of the present study is to clarify whether the prognosis can be influenced by inhibiting NF-κB activation and subunits expression using PDTC at different stages after ICH. Methods Rats were divided into sham group, ICH group, early interference group and late interference group. At preset time points after ICH, the ipsilateral striatum and tissue around was obtained for detection of NF-κB activation, cell death, and expression of caspase-3, bcl-2, and NF-κB subunits, to evaluate of the effect of PDTC. Results NF-κB subunit p65 mainly expressed at the early stage after ICH, and c-Rel at the late stage. NF-κB activation can be inhibited at the early stage after ICH by administrating PDTC at 10 min, 1d and 2d after ICH, and at the late stage at 6d,7d and 8d. NF-κB activation inhibition at the early stage was due to p65, and c-Rel at the late stage. Inhibiting p65 expression at the early stage after ICH can reduce the apoptotic factor caspase-3 expression and cell death, and raise the antiapoptotic factor bcl-2. Meanwhile, inhibiting c-Rel expression at the late stage after ICH can lead to the opposite result. Conclusion Measures of inhibiting NF-κB subunits can be performed to influence the secondary brain damage and prognosis of ICH. We can also speculate that early inhibition of p65 expression and late promotion of c-Rel expression may be a more efficient method to improve the prognosis of ICH.

  • Transcranial near-infrared stimulation may increase cortical excitability recorded in humans
    Brain Res. Bull. (IF 3.103) Pub Date : 2019-12-16
    Penghui Song; Tao Han; Hua Lin; Siran Li; Qian Huang; Xiaona Dai; Rong Wang; Yuping Wang

    Objective Transcranial near-infrared stimulation (tNIRS) can penetrate the scalp and skull and can reach the superficial layers of the cerebral cortex. In this study, we evaluated whether an 820-nm tNIRS can modulate the excitability of the primary motor cortex (M1) as measured by transcranial magnetic stimulation (TMS). Methods tNIRS was applied at a wavelength of 820-nm for 4 minutes over the representation of the right first dorsal interosseous muscle (FDI) in the left M1, in 12 healthy right-handed participants. Motor evoked potentials (MEPs) from the FDI elicited by single-pulse TMS were measured at baseline and up to 30 minutes after the tNIRS. Results The ΔMEPs percentage was evaluated, and a significant increase in amplitude was observed 10 to 20 minutes post-stimulation compared to that in sham. Conclusion This study provides evidence that an 820-nm tNIRS induces transitory increase in the excitability of the stimulated cortex.

  • The fluorescent dye 3,3′-diethylthiatricarbocyanine iodide is unsuitable for in vivo imaging of myelination in the mouse
    Brain Res. Bull. (IF 3.103) Pub Date : 2019-12-16
    Bálint Botz; István Zoárd Bátai; Tamás Kiss; Erika Pintér; Zsuzsanna Helyes; Kata Bölcskei

    There is a growing interest to use non-invasive optical imaging methods to study central nervous system diseases. The application of a myelin-binding fluorescent dye, 3,3-diethylthiatricarbocyanine iodide (DBT) was recently described for in vivo optical imaging of demyelination in the mouse. In the present study we aimed at adapting the method to our optical imaging systems, the IVIS Lumina II to measure epifluorescence and the fluorescent molecular tomograph (FMT) for 3-dimensional quantification of the fluorophore. Epifluorescent imaging was performed 5-30 min after DBT injection which was followed by FMT imaging at 40 min. Two mice also underwent micro-CT imaging in the FMT cassette for the purpose of FMT-CT co-registration. Ex vivo imaging of the brain and other tissues of the head and neck was carried out 1 h after injection. Both the FMT-CT co-registration and the ex vivo imaging of organs proved that DBT poorly crossed the blood-brain barrier. The dye did not accumulate in the myelin sheath of the sciatic nerve. In contrast, there was an intense accumulation in the pituitary and salivary glands. The FMT-CT co-registration unequivocally demonstrated that the signal localized to the head did not originate from beyond the blood-brain barrier. No myelin binding was demonstrated by the ex vivo imaging either. In conclusion, DBT is unsuitable for in vivo imaging of myelination due to its poor BBB penetration, accumulation in other structures of the head and neck region and lack of selective binding towards myelin in vivo.

  • Differential susceptibility of human neural progenitors and neurons to ischaemic injury
    Brain Res. Bull. (IF 3.103) Pub Date : 2019-12-16
    Ye Liu; Anna E. Michalska; Mirella Dottori; Emma Eaton; Jo-Maree Courtney; Ana Antonic; David W. Howells

    Background Neuroprotection for stroke has shown great promise but has had little translational success. Developing drugs for humans logically requires human tissue evaluation. Human embryonic stem cell (hESC)-derived neuronal cultures at different developmental stages were subject to oxygen glucose deprivation (OGD) to determine how developing maturity altered response to ischemic injury. Methods H9 hESCs were induced by Noggin to generate neural progenitors (NPs) and highly arbourised structurally complex neurons. They were both subjected to OGD or OGD with reoxygenation (OGD-R) for 1-6 hours. Mild hypothermia (33 °C) was used to assess neuroprotective potential in the structurally mature neurons after 1 or 4 hours OGD-R. Outcome was assessed by measures of cell death, survival and morphology. Results NPs did not die after OGD but experienced progressive loss of metabolic activity. Highly arbourised neurons showed minimal cell death initially but 44% and 78% died after 4 and 6 h OGD. Metabolic dysfunction was greater in these more mature neurons (∼70%) than in NPs and evident after 1 h OGD, before detection of neuronal death at 4 h. OGD-R salvaged metabolic activity but not cell death in mature neurons. In NPs there was little metabolic salvage and cell death was induced (50% and 65% at 4 and 6 h OGD-R, respectively). Conclusions Highly arbourised neurons are more sensitive to ischaemic injury than NPs which did however develop marked vulnerability to prolonged injury with reoxygenation. These observations imply that therapeutic potential may be highly dependent of the developmental state of the neurons we aim to protect.

  • Resveratrol Attenuates Neuroinflammation after Deep Hypothermia with Circulatory arrest in Rats
    Brain Res. Bull. (IF 3.103) Pub Date : 2019-12-14
    Qiang Chen; Kai-Peng Sun; Jiang-Shan Huang; Zeng-Chun Wang; Zhi-Nuan Hong
  • Analysis of knowledge bases and research focuses of cerebral ischemia-reperfusion from the perspective of mapping knowledge domain
    Brain Res. Bull. (IF 3.103) Pub Date : 2019-12-13
    Yi Qin; Qing Zhang; Yaru Liu

    Cerebral ischemia-reperfusion (IR) has attracted wide attention as a serious clinical problem. So far, the field has accumulated a large amount of scientific research literature. To clarify the temporal and spatial distribution characteristics of research resources, knowledge bases and research focuses, a visual analysis was performed on 5814 articles cited in the WoS databases from 2004 to 2019. This analysis was based on bibliometrics and mapping knowledge domain (MKD) analysis with VOSviewer, and CiteSpace 5.4.R4. The results can be elaborated from four aspects. First, the volume of publications in this area is on the rise. Second, the United States and China are the active regions. The USA is the central region of cerebral ischemia-reperfusion research. Third, the knowledge bases of IR have focused on five major areas of “Suitable small-animal models”, “A framework with further study”, “Molecular signaling targets by oxidative stress”, “Finding new potential targets for therapy” and “Protective effect of multiple transient ischemia”. Fourth, the research focuses consist of three representative areas: “Oxidative stress closelyd with cerebral ischemia-reperfusion”, “Neuronal apoptosis and neuronal protection”, and “Neuroprotective effect of the blood-brain barrier”.

  • Sleep and Neurochemical Modulation by Cannabidiolic Acid Methyl Ester in Rats
    Brain Res. Bull. (IF 3.103) Pub Date : 2019-12-12
    Eric Murillo-Rodríguez; Gloria Arankowsky-Sandoval; Roger G. Pertwee; Linda Parker; Raphael Mechoulam

    Cannabidiolic acid methyl ester (HU-580) is a more stable compound than cannabidiolic acid (CBDA) which has been shown to be effective in reducing nausea, anxiety, depression behaviors in animal models. Here we extend the investigation of this compound to determine its effect on the sleep-wake cycle in male Wistar rats. HU-580 dose-dependently (0.1, 1.0 or 100 µg/Kg, i.p.) prolonged wakefulness (W) and decreased slow wave sleep (SWS) duration whereas rapid eye movement sleep (REMS) showed no statistical change. In addition, the brain microdialysis probes either placed at nucleus accumbens (NAc) or into the basal forebrain in freely moving animals were used to evaluate the effects of HU-580 treatment on neurotransmitters related to the sleep-wake cycle modulation. HU-580 enhanced extracellular levels of dopamine, serotonin collected from NAc while adenosine and acetylcholine were increased in basal forebrain. In summary, HU-580 seems to possess wake-promoting pharmacological properties and enhances the levels of wake-related neurochemicals. This is the first report of effects of HU-580 on sleep modulation expanding the very limited existent data on the neurobiological effects of HU-580 on rats.

  • Analysis of genes involved in cell proliferation, adhesion, and control of apoptosis during embryonic neurogenesis in Induced Pluripotent Stem Cells (iPSCs) from patients with Focal Cortical Dysplasia
    Brain Res. Bull. (IF 3.103) Pub Date : 2019-12-06
    Daniel Rodrigo Marinowic, Fernanda Majolo, Gabriele Goulart Zanirati, Ismael Plentz, Eliseu Paglioli Neto, André Luís Fernandes Palmini, Denise Cantarelli Machado, Jaderson Costa Da Costa

    Focal cortical dysplasia (FCD) is a malformation of cortical development which is strongly associated with drug-refractory epilepsy. Certain studies have demonstrated an increase in mTOR signaling in patients with FCD on the basis of observation of phosphorylated molecules. The aim of the present study was to verify the differences in genes involved in cell proliferation, adhesion, and control of apoptosis during embryonic neurogenesis in iPSCs derived from the Focal Cortical Dysplasia. Fibroblasts were obtained from the skin biopsies of patients with FCD (n = 2) and controls (n = 2). iPSCs were generated by exposing the fibroblasts to viral vectors that contained the Yamanaka factors (OCT4, SOX2, KLF4, and c-MYC genes) responsible for promoving cell reprogramation. The fibroblasts and iPSCs were tested during different phases of neurodifferentiation for migration capacity and expression of the genes involved in the PI3K pathway. Fibroblasts of patients with FCD migrated with greater intensity during the first two time points of analyses. iPSCs did not exhibit any difference in cell migration between the groups. Fibroblasts, brain tissue, and iPSCs of the patients with FCD exhibited a significant reduction in the relative expression values of 4EBP–1. During neurodevelopment, the iPSCs from patients with FCD exhibited a reduction in the expression of cIAP–1, cIAP–2, PI3K, β-Catenin and 4EBP–1 gene. We suggest that the differences observed in the migration potential of adult cells and in the gene expression related to the fundamental processes involved in normal brain development during the neurodifferentiation process might be associated with cortical alteration in the patients with FCD.

  • The role of the endogenous neurotransmitters associated with neuropathic pain and in the opioid crisis: the innate pain-relieving system
    Brain Res. Bull. (IF 3.103) Pub Date : 2019-12-06
    E.Gy Bán, A. Brassai, E.S. Vizi

    Neuropathic pain is a chronic pain caused by central and peripheral nerve injury, long-term diabetes or treatment with chemotherapy drugs, and it is dissimilar to other chronic pain conditions. Chronic pain usually seriously affects the quality of life, and its drug treatment may result in increased costs of social and medical care. As in the USA and Canada, in Europe, the demand for pain-relieving medicines used in chronic pain has also significantly increased, but most European countries are not experiencing an opioid crisis. In this review, the role of various endogenous transmitters (noradrenaline, dopamine, serotonin, met- and leu-enkephalins, β-endorphin, dynorphins, cannabinoids, ATP) and various receptors (α2, μ, etc.) in the innate pain-relieving system will be discussed. Furthermore, the modulation of pain processing pathways by transmitters, focusing on neuropathic pain and the role of the sympathetic nervous system in the side effects of excessive opioid treatment, will be explained.

  • Role of the anterior agranular insular cortex in the modulation of fear and anxiety
    Brain Res. Bull. (IF 3.103) Pub Date : 2019-12-06
    Tianyao Shi, Shufang Feng, Mingxiao Wei, Wenxia Zhou

    The insular cortex, anatomically close to amygdala, is also an integrative hub for sensory, emotional and cognitive function. Growing body of evidences suggest that alterations in insular structure and function have also been implicated in anxiety disorders. However, the reciprocal connections and precise subdivision of insular cortex involved in anxiety activities remains mechanistically unclear. In the present study, using anterograde and retrograde tracing methods, we verified that the anterior (AIa) but not posterior (AIp) agranular insular cortex is a major source of projections to the amygdala. Consistently, excitotoxic lesions only in AIa induced the anxiolytic behaviors and impaired fear memory. Using optogenetics methods, we found that selectively photoactivation of AIa GABAergic neurons remarkably promoted cued fear extinction and relieved anxiety in PSTD mice model. Finally, the participation of AIa in the storage of learned fear is also supported by the abolished LTP after fear conditioning and decreased the cued freezing using protein synthesis inhibitor immediately following training. Our results underscore the importance of AIa in fear and anxiety behavior and suggest that the AIa might share functions and interaction with amygdala in in anxiety related disorders.

    Brain Res. Bull. (IF 3.103) Pub Date : 2019-12-05
    Mariana Zancan, Dinara J. Moura, Ana Moira Morás, Luiza Steffens, Ana Carolina de Moura, Márcia Giovenardi, Alberto A. Rasia-Filho

    The posterodorsal medial amygdala (MePD) has a high concentration of receptors for gonadal hormones, is a sexually dimorphic region and dynamically controls the reproductive behavior of both males and females. Neurotrophic factors can promote dendritic spine remodeling and change synaptic input strength in a region-specific manner. Here, we analyzed the gene and protein expression of brain-derived neurotrophic factor (BDNF), insulin-like growth factor-I (IGF-1), polysialylated neural cell adhesion molecule (PSA-NCAM) and Ephrin-A4 in the MePD of adult males and females in diestrus, proestrus and estrus using real-time qPCR and fluorescent immunohistochemistry. The first approach showed their amplification except for Igf1 and the latter revealed that BDNF, IGF-1, PSA-NCAM and Ephrin-A4 are expressed in the MePD of the adult rats. Protein expression of these neurotrophic factors showed no differences between groups. However, proestrus females displayed a higher number of labelled puncta than males for BDNF expression and diestrus females for IGF-1 expression. In conjunction, results indicate that IGF-1 might be released rather than synthetized in the MePD, and the expression of specific neurotrophic factors varies specifically during proestrus. The dynamic modulation of BDNF and IGF-1 during this cyclic phase is coincident with synaptic changes and spine density remodeling in the MePD, the disinhibition of gonadotrophin secretion for ovulation and the display of sexual behavior.

  • Enhanced functional recovery by levodopa is associated with decreased levels of synaptogyrin following stroke in aged mice
    Brain Res. Bull. (IF 3.103) Pub Date : 2019-12-02
    Jens Häggman Henrikson, Ana Rita Pombo Antunes, Tadeusz Wieloch, Karsten Ruscher

    Levodopa is a precursor to dopamine that has been shown to improve functional recovery following stroke partly achieved through mechanisms of brain plasticity. This study investigates if dopamine might affect plasticity by having a direct effect on synaptic plasticity through alterations in neurotransmitter release and re-uptake. Synaptogyrin is a synaptic vesicle protein that has been suggested to be involved in dopamine re-uptake in the synaptic terminal. Therefore, we investigated if levodopa has an effect on the expression of synaptogyrin 1. Thy1-YFP mice were subjected to photothrombosis as an experimental model of stroke. Starting two days after surgery they were treated with either levodopa or a vehicle solution (saline) on a daily basis until day seven following surgery. On day seven they were sacrificed and their brains stained for Dopamine 1 receptor (D1R), Dopamine 2 receptor (D2R) and Parvalbumin (PV). Neu-N stainings were used to estimate infarct size. A second group of mice were subjected to photothrombosis and also treated with either levodopa or a vehicle solution in the same manner as previously mentioned. On day seven they were then sacrificed, and samples of brain tissue were taken for protein determination. Western blots were carried out to investigate possible differences in synaptogyrin expression between the two groups. Immunofluorescent stains showed the presence of dopamine receptors on the YFP-positive neurons and on PV-expressing neurones. Our Western Blot analysis showed a significant decrease in the expression of synaptogyrin in levodopa-treated mice. Our stains showed co-localisation with Thy-1 neurones and PV-expressing neurones for both D1 and D2 receptors. This indicates that dopamine has the ability to bind to, and directly influence cortical neurons, as well as inhibitory interneurons. We discovered a considerable decrease in synaptogyrin expression through levodopa treatment, suggesting that this might be a mechanism for regulating brain plasticity.

  • TRPM2 ion channel is involved in the aggravation of cognitive impairment and down regulation of epilepsy threshold in pentylenetetrazole-induced kindling mice
    Brain Res. Bull. (IF 3.103) Pub Date : 2019-11-30
    Qianqian Zheng, Tao Zhu, Hui Hu, Yisha Zhao, Yingchao Ying, Xiaoying Luo, Yinjie Ling, Zhiyue Chen, Haoran Ji, Peifang Jiang

    Epilepsy is one of the most common neurological conditions. Recent findings suggest that one of the mechanisms promoting its existence is calcium influx. The transient receptor potential melastatin type 2 channel (TRPM2) is a Ca2+-permeable cation channel that contributes to cell apoptosis; its possible signaling pathway is the PARP1/BNIP3/AIF/Endo G pathway that may be related to epilepsy. The aim of this study was to investigate the TRPM2 channel’s involvement in epilepsy and how it works. We also explored the possible role of the TRPM2 channel on cognitive ability and emotion in epilepsy. To accomplish our goals, we used different animal epilepsy models to study the effect of the TRPM2 channel on epilepsy. The results showed that the knockout (KO) of the TRPM2 gene might play a protective role in epilepsy. Considering the advantages attributed to pentylenetetrazole (PTZ)-induced kindling mouse model, we used the model for the following assessments: 1. to observe changes in cognition and anxiety between wild type (WT) mice and TRPM2-KO mice with the recognition of new things trial and elevated plus-maze; 2. to determine the expression of apoptosis-associated proteins (PARP1, BNIP3, AIF, and Endo G) using Reverse transcription-polymerase chain reaction (RT-PCR) and Western blot; 3. to observe neurons pathologic damages and astrocyte activation in each group. The main findings of our study were: (a) TRPM2-KO had a protective effect on epilepsy; (b) TRPM2-KO improved spatial memory deficits overtime during epilepsy, but it did not improve anxiety; (c) the protective effect probably occurred via the PARP1 downstream signaling pathway; (d) TRPM2-KO could ameliorate epilepsy-induced hippocampal pathological damages and weaken astrocyte activation. These findings may provide a new approach for the treatment of epilepsy and early intervention.

  • Vagal nerve stimulation as a promising tool in the improvement of cognitive disorders
    Brain Res. Bull. (IF 3.103) Pub Date : 2019-11-29
    A. Broncel, R. Bocian, P. Kłos-Wojtczak, K. Kulbat-Warycha, J Konopacki

    Vagal nerve stimulation (VNS) is known as an effective method of treatment in a number of neurological disorders. The low risk of side effects also makes it useful in clinical trials in other diseases. Branches of the vagal nerve innervate the anatomical structures known to be involved in memory processing. That is why it seems justified that several studies emphasize the impact of VNS on the cognitive and memory function in both healthy volunteers and patients with epilepsy and Alzheimer’s disease. Results have shown that VNS can modulate different types of memory depending the protocol of stimulation in non-demented patients after both short term and chronic VNS application. Transcutaneous vagal nerve stimulation (tVNS), which is a non-invasive method of VNS, opens up new perspectives for different clinical applications.

    Brain Res. Bull. (IF 3.103) Pub Date : 2019-11-29
    Anoop Narayanan V

    Nanotechnology, the investigation of little structures, ranging from the size of 1 nm to 100 nm presents a breakthrough in the field of targeted drug delivery. The microvasculature in the human brain along with the blood brain barrier (BBB) offers high resistance to the entry of therapeutics agents and other substances in to the brain. Nanoparticles have certain advantages as high permeability, reactivity, surface area and quantum properties and it also meets various medical challenges which may include poor bioavailability, difficulty in targeting, organ toxicity etc. The use of nanoparticles in pharmaceuticals has been inspired by various natural nanomaterials found in the body, which includes proteins, lipids etc. A brief explanation of different types of pharmaceutical approaches used in brain drug delivery is discussed here. Nanotechnology is used treatment of many illnesses which also include diseases related to the brain such as gliomas, epilepsy, migraine, cerebrovascular disease, Parkinson’s disease etc., Different type of nanoparticles are prepared, such as polymer-based nanoparticles, metallic nanoparticles, carbon-based nanoparticles, lipid-based nanoparticles, ceramic nanoparticles semiconductor nanoparticles and are studied for their usefulness in drug delivery. The primary function of nanoparticles is to deliver drug moiety to the desired targeted site by overcoming permeability issues. The shape, size and surface area nanoparticles help in increasing the bioavailability, drug retention and multiple drug delivery. Mechanisms of nanoparticles crossing BBB can be divided into passive and active transport, are briefly explained.

  • Glial Neuroimmune Signaling in Opioid Reward
    Brain Res. Bull. (IF 3.103) Pub Date : 2019-11-29
    Hong Zhang, Tally M. Largent-Milnes, Todd W. Vanderah

    The opioid epidemic is a growing public concern affecting millions of people worldwide. Opioid-induced reward is the initial and key process leading to opioid abuse and addiction. Therefore, a better understanding of opioid reward may be helpful in developing a treatment for opioid addiction. Emerging evidence suggests that glial cells, particularly microglia and astrocytes, play an essential role in modulating opioid reward. Indeed, glial cells and their associated immune signaling actively regulate neural activity and plasticity, and directly modulate opioid-induced rewarding behaviors. In this review, we describe the neuroimmune mechanisms of how glial cells affect synaptic transmission and plasticity as well as how opioids can activate glial cells affecting the glial-neuronal interaction. Last, we summarize current attempts of applying glial modulators in treating opioid reward.

  • Effect of Mild and Chronic Neonatal Hypothyroidism on Sensory Information Processing in a Rodent Model: A Behavioral and Electrophysiological Study
    Brain Res. Bull. (IF 3.103) Pub Date : 2019-11-28
    Mohammad Reza Afarinesh, Faezeh Shafiei, Mansoureh Sabzalizadeh, Tahereh Haghpanah, Mahdieh Taheri, Shahrnaz Parsania, Fatemeh Golshan, Vahid Sheibani

    Thyroid hormones are essential for neonatal brain development. It is well established that absence of thyroid hormones during critical periods of development can alter sensory functions such as visual and auditory processing, but there are few studies on rat somatosensory system development at mild, long-term, and irreversible neonatal hypothyroidism. Thus, the current study was conducted to investigate whether chronic thyroid hormone insufficiency would alter different cognitive aspects of tactile information processing and sensory motor filtering at behavioral or neuronal levels. Neonatal Wistar male rats were exposed to 0 and 6 ppm of propylthiouracil for 150 days. Behavioral tests including tactile discrimination tests and acoustic startle reflex test were performed. Using extracellular single unit recording technique, barrel cortex neurons’ excitatory and inhibitory responses to controlled displacement of whiskers were evaluated. Results indicated that percentage of correct choice in tactile learning and discrimination of a new texture decreased in hypothyroid group compared to the control group (P < 0.05). In addition, acoustic startle reflex of hypothyroid group significantly decreased compared to the control rats when the prepulse intensity was 71 dB (P < 0.05). Data obtained from electrophysiological tests showed that spontaneous activity and response magnitude of barrel cortex neurons decreased in hypothyroid group compared to the control group (P < 0.05). It is concluded that, thyroid hormones can regulate tactile and auditory sensory processing in male rats, and mild and long-term absence of these hormones can result in deficiency in natural functions of these sensory systems.

  • Cellular toxicity on C6 Glial cells induced by dextran stabilized fullerene C60
    Brain Res. Bull. (IF 3.103) Pub Date : 2019-11-28
    TE Biby, N. Prajitha, D. Sakthikumar, T. Maekawa, PV. Mohanan
  • Oligogenesis in the "oligovascular unit" involves PI3K/AKT/mTOR signaling in hypoxic-ischemic neonatal mice
    Brain Res. Bull. (IF 3.103) Pub Date : 2019-11-27
    Xiaozhou Wang, Yu Wang, Lei Wang, Senjun Shi, Cheng Yang, Wei Jiang, Zuo Luan, Lei Liu, Ruiqin Yao

    The "oligovascular unit" is a dynamic structural complex composed of endothelial cells (ECs) and oligodendrocyte progenitor cells (OPCs)/oligodendrocytes. By improving the microenvironment of OPCs in the "oligovascular unit" and promoting the proliferation and differentiation of OPCs, both myelination and white matter injury can be repaired. However, it is unclear what characteristic changes occur in the microenvironment of the "oligovascular unit" after preterm white matter injury (PWMI). Here, we demonstrate the changes in the "oligovascular unit" induced by hypoxia-ischemia (HI) and its underlying mechanism in PWMI mice. White matter injury and inhibited production of myelin from OPCs were observed by histopathological staining in HI neonatal mice. We further observed that the proliferation of OPCs and angiogenesis were increased after HI, which is considered the response of the body and cells to HI. HI-induced oligogenesis occurs around the vessels, indicating that "oligovascular units" exist and promote the proliferation and differentiation of OPCs after HI in the short term. We also determined that angiogenesis and oligogenesis induced by HI in the white matter are related to the PI3K/AKT/mTOR pathway. Furthermore, the myelin sheaths were shown to be disordered on the side of the surgery, and the myelin-dense layer was poorly developed at P14 and P28. Different degrees of damage to the vascular ECs and basement membrane on the surgical side were detected beginning at P4, indicating that EC injury is an early phenomenon that subsequently affects oligogenesis. Taken together, our findings indicate that the proliferation of OPCs and angiogenesis in white matter are increased in the early stage of HI involving PI3K/AKT/mTOR pathway activation. Promoting vascular endothelial function and angiogenesis may increase the proliferation and survival of OPCs via the "oligovascular unit," which suggests a potential method to repair injured white matter in the early stage of PWMI.

  • The role and pharmacological properties of the P2X7 receptor in neuropathic pain
    Brain Res. Bull. (IF 3.103) Pub Date : 2019-11-25
    Wen-jun Zhang, Zheng-ming Zhu, Zeng-xu Liu

    Neuropathic Pain (NPP) is caused by direct or indirect damage to the nervous system and is a common symptom of many diseases. Clinically, drugs are usually used to suppress pain, such as (lidocaine, morphine, etc.), but the effect is short-lived, poor analgesia, and there are certain dependence and side effects. Therefore, the investigation of the treatment of NPP has become an urgent problem in medical, attracting a lot of research attention. P2X7 is dependent on Adenosine triphosphate (ATP) ion channel receptors and has dual functions for the development of nerve damage and pain. In this review, we explored the link between the P2X7 receptor (P2X7R) and NPP, providing insight into the P2X7R and NPP, discussing the pathological mechanism of P2 X7R in NPP and the biological characteristics of P2X7R antagonist inhibiting its over-expression for the targeted therapy of NPP.

  • Toll-like receptor 4 (TLR4) influences the glial reaction in the spinal cord and the neural response to injury following peripheral nerve crush
    Brain Res. Bull. (IF 3.103) Pub Date : 2019-11-19
    Patrícia Ribeiro, Mateus V. Castro, Matheus Perez, Luciana P. Cartarozzi, Aline B. Spejo, Gabriela B. Chiarotto, Taize M. Augusto, Alexandre L.R. Oliveira

    After peripheral axotomy, there is a selective retraction of synaptic terminals in contact with injured motoneurons. This process, which actively involves glial cells, is influenced by the expression of immune-related molecules. Since toll-like receptors (TLRs) are upregulated by astrocytes and microglia following lesions, they might be involved in synaptic plasticity processes. Therefore, we administered lipopolysaccharide (LPS) to enhance TLR4 expression in mice and studied retrograde changes in the spinal cord ventral horn following sciatic nerve crush. To this end, adult C57BL/6 J male mice were subjected to unilateral sciatic nerve crush at the mid-thigh level and, after a survival time of seven and forty days (acute and chronic phases, respectively), the spinal cords were paraformaldehyde-fixed and dissected out for immunolabeling for synaptophysin, glial fibrillary acidic protein (GFAP) and ionized calcium-binding adapter molecule 1 (Iba1). The results show that TLR4 upregulation leads to synaptophysin downregulation close to spinal motoneuron cell bodies, indicating increased synaptic elimination. LPS exposure also further increases astrogliosis and microglial reactions in the both ventral and dorsal horns, especially ipsilateral to nerve axotomy, compared to those in untreated mice. Notably, LPS administration to TLR4-/- mice produces results similar to those observed in untreated wild-type counterparts, reinforcing the role of this receptor in the glial response to injury. Therefore, our results suggest that the overexpression of the TLR4 receptor results in augmented astrogliosis/microglial reactions and the excessive loss of synapses postinjury, which may, in turn, affect the motoneuronal regenerative response and functionality. Additionally, treatment with LPS increases the expression of β2-microglobulin, a subcomponent of MHC I. Importantly, the absence of TLR4 results in imbalanced axonal regeneration, inducing subsequent improvements and setbacks. In conclusion, our results show the involvement of TLR4 in the process of synaptic remodeling, indicating a new target for future research aimed at developing therapies for CNS and SNP repair.

  • Minocycline treatment prevents depression and anxiety-like behaviors and promotes neuroprotection after experimental ischemic stroke
    Brain Res. Bull. (IF 3.103) Pub Date : 2019-11-19
    Quezya Mendes Camargos, Bruno Costa Silva, Daniele Gonçalves Silva, Eliana Cristina de Brito Toscano, Bruna da Silva Oliveira, Paula Maria Quaglio Bellozi, Bruna Lorrayne de Oliveira Jardim, Érica Leandro Marciano Vieira, Antônio Carlos Pinheiro de Oliveira, Lirlândia Pires Sousa, Antônio Lúcio Teixeira, Aline Silva de Miranda, Milene Alvarenga Rachid

    Depression and anxiety have been reported as the major neuropsychiatric consequences following stroke. Minocycline, a neuroprotective drug has minimized depressive symptoms in patients with major depressive disorders and anxiety-like symptoms. In addition, minocycline demonstrated efficacy and seemed a promising neuroprotective agent in acute stroke patients. The present studied evaluated the effects of minocycline treatment on the depression and anxiety-like behaviors, brain damage and expression of inflammatory and neuroprotective mediators after transient global cerebral ischemia in C57BL/6 mice. Brain ischemia was induced by bilateral occlusion of the common carotids (BCCAo) for 25 minutes and subsequent reperfusion. Sham and BCCAo animals received minocycline at a dose of 30 mg/kg by intraperitoneal injection during 14 days. The locomotor activity, depression and anxiety-like behaviors were assessed by open field, forced swim and elevated plus maze tests, respectively. Then, the brains were removed and processed to evaluate brain damage by histological and morphometric analysis, hippocampal neurodegeneration using Fluoro-Jade C histochemistry, microglial activity using iba-1 immunohistochemistry, brain levels of TNF, IFN-γ, IL-6, IL-10, IL-12p70 and CCL2 by CBA, CX3CL1 and BDNF by ELISA assays. The animals developed depression and anxiety-like behaviors post-stroke and minocycline treatment prevented those neurobehavioral changes. Moreover, minocycline-treated BCCAo animals showed less intense brain damage in the cerebral cortex, brainstem and cerebellum as well as significantly reduced hippocampal neurodegeneration. BCCAo groups exhibited up-regulation of some cytokines at day 14 after ischemia and brain levels of CX3CL1 and BDNF remained unaltered. Our data indicate that the depression and anxiety-like behavioral improvements promoted by minocycline treatment might be related to its neuroprotective effect after brain ischemia in mice.

  • Microstructure and functional connectivity-based evidence for memory-related regional impairments in the brains of pilocarpine-treated rats
    Brain Res. Bull. (IF 3.103) Pub Date : 2019-11-19
    Yin Jiang, De-Feng Liu, Xin Zhang, Huan-Guang Liu, Jian-Guo Zhang

    Patients with temporal lobe epilepsy (TLE) frequently suffer from memory disorders, and the pathological changes show widespread regional impairments in the brain. In lithium-pilocarpine (LIP)-treated rats with TLE, an abnormal hippocampal microstructure and functional connectivity have been observed. However, changes in other brain regions are still unclear. In the present study, diffusion tensor imaging and functional magnetic resonance imaging (MRI) signals were collected in LIP-TLE rats and controls using a 7.0 T MRI. Microstructural parameters and functional connectivity were calculated among regions of interest (ROIs), including the bilateral prefrontal cortex, amygdala, hippocampus and entorhinal cortex. A correlation analysis was further performed between the neuroimaging results and the behavioral performance in the novel object and novel location memory tests. In our results, TLE rats showed increased fractional anisotropy (FA) values in the hippocampus and decreased FA values in the amygdala and entorhinal cortex. In addition, decreased functional connectivity between the amygdala and the CA3, and increased connectivity between the prefrontal cortex and the CA1 were observed in the TLE rats compared to control rats. Moreover, FA values in the amygdala, the hippocampus and the entorhinal cortex, as well as the amygdala-CA3 and the prefrontal-CA1 connectivity correlated with the memory performance. Based on our results, both the microstructure and functional connections were impaired in memory-related brain regions of LIP-TLE rats. Furthermore, the abnormal changes in the microstructure and functional connectivity were related to behavioral deficits in object and location memory.

  • Citalopram prevents sleep-deprivation-induced reduction in CaMKII-CREB-BDNF signaling in mouse prefrontal cortex
    Brain Res. Bull. (IF 3.103) Pub Date : 2019-11-16
    Afzal Misrani, Sidra Tabassum, Meng Wang, Jian Chen, Li Yang, Cheng Long

    Curtailment of sleep in modern society leads to a spectrum of neuropsychiatric disorders. However, the molecular mechanisms underlying the effects of sleep deprivation (SD) remain elusive and currently there is no effective therapy to alleviate these effects. Here, we aimed to examine SD-induced cellular and molecular alterations in mouse prefrontal cortex (PFC) and whether subchronic citalopram (CTM) treatment can negate these alterations. Three-month-old C57BL/6 J mice were divided into control (Ctrl), SD, CTM alone and CTM + SD groups. CTM and CTM + SD group mice were treated with CTM for five consecutive days at a dose of 10 mg/kg per day before the experimental procedure. SD and CTM + SD group mice were sleep-deprived for 24 h using an automated treadmill method. We found that 24 h SD causes a marked reduction in the levels of phosphorylated calcium/calmodulin kinase II (pCaMKII), phosphorylated cyclic AMP-responsive element binding protein (pCREB) and brain-derived neurotrophic factor (BDNF) in mouse PFC. Patch clamp recording of pyramidal neurons from acute PFC slices revealed that SD decreases the amplitude of miniature excitatory postsynaptic currents (mEPSCs), suggesting a SD-induced postsynaptic alteration. Interestingly, subchronic CTM treatment prevents such SD-induced reductions in pCaMKII, pCREB and BDNF levels, and in mEPSC amplitude. These data suggest that CTM offers neuroprotection against SD-induced molecular and electrophysiological alterations.

  • CaSR is required for ischemia-induced proliferation and differentiation of white matter progenitor cells from neonatal rats
    Brain Res. Bull. (IF 3.103) Pub Date : 2019-11-15
    Feng-xia Mao, Cheng-han Luo, Hui-jin Chen, Yi-xia Zhang, Qian Zhang

    This study was designed to investigate whether calcium-sensing receptor (CaSR) could induce immture white matter progenitor cells proliferation and differentiation into oligodendrocyte(OL) precursor cells after oxygen-glucose deprivation (OGD) in vitro. Progenitor cells of immature white matter originating from five-day-old newborn rats were divided into control, OGD, control + CaSR silencing, OGD + CaSR silencing, control + adenosine triphosphate magnesium chloride (ATP-MgCl2) and OGD + ATP-MgCl2 groups. Immunofluorescence, real-time RT-PCR, gene silencing, Hoechst 33342/propidium iodide (PI) and Flow cytometry tests were used to examine the proliferation, differentiation and survival of the white matter progenitor cells in the different treatment groups. The results showed that normal immature white matter progenitor cells have certain ability of self-proliferation and differentiation in vitro. OGD could further induce progenitor cells proliferation and differentiation into O4 + OL precursor cells by activating CaSR, but OGD also induced more necrosis and apoptosis of newborn cells and less MBP + OL formation. The addition of ATP-MgCl2 as an activating agent of CaSR further promoted cell proliferation and differentiation both under normal and OGD conditions and reduced OGD-induced apoptosis and necrosis, while CaSR silenced resulted in minimal cell proliferation, differentiation and survival. This study suggests that CaSR plays an important role in the induction of immature white matter progenitor cells proliferation and differentiation into OL precursor cells after OGD, which may provide a new angle to further study whether CaSR initiates the intrinsic repair potential of immature white matter after ischemia in vivo.

  • Minocycline Protects Neurons against Glial Cells-mediated Bilirubin Neurotoxicity
    Brain Res. Bull. (IF 3.103) Pub Date : 2019-11-13
    Changwei Zhou, Rong Sun, Chongyi Sun, Minghao Gu, Chuan Guo, Jiyan Zhang, Yansheng Du, Huiying Gu, Qingpeng Liu

    Unconjugated bilirubin, the end product of heme catabolism and antioxidant, induced brain damage in human neonates is a well-recognized clinical syndrome. However, the cellular and molecular mechanisms underlying bilirubin neurotoxicity remain unclear. To characterize the sequence of events leading to bilirubin-induced neurotoxicity, we investigated whether bilirubin-induced glial activation was involved in bilirubin neurotoxicity by exposing co-cultured rat glial cells and cerebellar granule neurons (CGN) to bilirubin. We found that bilirubin could markedly induce the expression of TNF-α and iNOS in glial cells, and even at low concentrations, the co-culture of glial cells with neurons significantly enhances neurotoxicity of bilirubin. Pretreatment of the co-cultured cells with minocycline protected CGN from glia-mediated bilirubin neurotoxicity and inhibited overexpression of TNF-α and iNOS in glia. Furthermore, we found that high doses of bilirubin were able to induce glial injury, and minocycline attenuated bilirubin-induced glial cell death. Our data suggest that glial cells play an important role in brain damage caused by bilirubin, and minocycline blocks bilirubin-induced encephalopathy possibly by directly and indirectly inhibiting neuronal death pathways.

  • FGF9 knockout in GABAergic neurons induces apoptosis and inflammation via the Fas/caspase-3 pathway in the cerebellum of mice
    Brain Res. Bull. (IF 3.103) Pub Date : 2019-11-11
    Moran Guo, Huifang Chen, Weisong Duan, Zhongyao Li, Yuanyuan Li, Yanqin Ma, Xiangyang Xu, Le Yi, Yue Bi, Yakun Liu, Jie Zhang, Chunyan Li

    Fibroblast growth factor 9 (FGF9) is a member of the fibroblast growth factor family and is widely expressed in the central nervous system (CNS). However, it is not clear how the working mechanism of FGF9 is involved in cerebellar development. To address this question, we deleted the Fgf9 gene specifically in GABAergic neurons or glutamatergic neurons, and demonstrated that Fgf9 ablation in GABAergic neurons rather than the glutamatergic neurons caused severe ataxia. We showed that FGF9 played a key role in the survival and development of Purkinje cells. GABAergic neuron-specific knockout of FGF9 (Fgf9VGAT) significantly affected the survival and development of Purkinje cells, disrupting Bergmann fiber scaffold formation and granule neuron migration in mice. RNA sequencing revealed that 976 differentially expressed genes (DEGs) were identified between Fgf9VGAT and control mice. The DEGs with significantly upregulated expression were found to be involved in apoptotic and inflammatory signaling. Selected genes including Fas, Bid, Caspase3, Cxcl10, CCl2, Bik and Fos, were validated by qRT-PCR and exhibited increases in expression in Fgf9VGAT mice compared to control mice similar to those seen in the RNA-sequencing data. The expression levels of apoptosis- and inflammation-related proteins were also increased, especially those of Fas and caspase-3 pathway related proteins. Interestingly, activated ERK signaling has been observed in apoptosis and inflammatory responses induced by deleting Fgf9 in GABAergic neurons.

  • A Single-Nucleotide Polymorphism Induced Alternative Splicing in Tacr3 Involves in Hypoxic-ischemic Brain Damage
    Brain Res. Bull. (IF 3.103) Pub Date : 2019-11-10
    Lu-Lu Xue, Fang Wang, Liu-Lin Xiong, Ruo-Lan Du, Hao-Li Zhou, Yu Zou, Ma-Xiu Wu, Ming-An Yang, Jing Dai, Man-Xi He, Ting-Hua Wang

    Single-nucleotide polymorphism (SNP) and Alternative splicing (AS) were found to be implicated in certain diseases, nevertheless, the contributions of mRNA SNPs and AS to pathogenesis in developing rat brains with hypoxic-ischemic encephalopathy (HIE) remained largely vague. Additionally, the disease associated with Tacr3 was normosmic congenital hypogonadotropic hypogonadism, while the relationship between HIE and Tacr3 remained largely elusive. The current study was designed to investigate the differentially expressed mRNAs and related SNPs as well as AS in neonatal rats subjected to HIE to identify if the exhibition of AS was associated with SNPs under pathological condition. Firstly, we used postnatal day 7 Sprague-Dawley rats to construct neonatal HIE model, and analyzed the expression profiles of SNP mRNA in hypoxic-ischemic (HI) and sham brains by using RNA sequencing. Then four genes, including Mdfic, Lpp, Bag3 and Tacr3, connecting with HIE and exhibiting SNPs and AS were identified by bioinformatics analysis. Moreover, combined with exonic splicing enhancer (ESE) and alternative splice site predictor (ASSP) analysis, we found that Tacr3 is associated specifically with HIE through 258547789 G > A SNP in inside the Alt First Exon and 258548573 G > A SNP in outside the Alt First Exon. Taken together, our study provides new evidence to understand the role of Tacr3 in HIE and it is possibly a potential target for the treatment of HIE in future clinic trial.

  • Resolvin D1 suppresses inflammation-induced hyperexcitability of nociceptive trigeminal neurons associated with mechanical hyperalgesia
    Brain Res. Bull. (IF 3.103) Pub Date : 2019-11-10
    Anjyu Ikeda, Akari Muroki, Chie Suzuki, Yoshihito Shimazu, Mamoru Takeda

    7S,8R,17S-trihydroxy-4Z,9E,11E,13Z,15E,19Z-docosahexaenoic acid (resolvin D1 [RvD1]) is biosynthesized from docosahexaenoic acid (DHA), and belongs to a novel family of lipid mediators showing remarkable anti-inflammatory effects; however, the effect of RvD1 on inflammation-induced hyperexcitability of nociceptive neurons under in vivo conditions remains to be determined. The present study, therefore, investigated whether under in vivo conditions, systemic administration of RvD1 could attenuate the inflammation-induced hyperexcitability of spinal trigeminal nucleus caudalis (SpVc) wide-dynamic range (WDR) neurons associated with hyperalgesia in rats. The threshold of escape from mechanical stimulation applied to the orofacial area in rats with complete Freund’s adjuvant-induced inflammation was significantly lower than in naïve rats. The lowered mechanical threshold in rats with inflammation was returned to control levels following administration of RvD1 (3 ng/kg, i.p.) for 3 days. The mean discharge frequency of SpVc WDR neurons in rats with inflammation was significantly decreased after RvD1 administration for both non-noxious and noxious mechanical stimuli. Increased spontaneous discharge of SpVc WDR neurons in rats with inflammation was also significantly decreased after RvD1 administration. Noxious pinch-evoked afterdischarge frequency and occurrence in rats with inflammation was significantly diminished after RvD1 administration. Expansion of the receptive field in rats with inflammation also returned to control levels after RvD1 administration. These results suggest that administration of RvD1 attenuates inflammation-induced hyperexcitability of SpVc WDR neurons associated with inflammatory hyperalgesia. These findings support the idea that RvD1, derived from DHA, as well as DHA itself, are potential complementary or alternative therapeutic agents for the alleviation of inflammatory hyperalgesia.

  • MST4 modulates the neuro-inflammatory response by regulating IκBα signaling pathway and affects the early outcome of experimental ischemic stroke in mice
    Brain Res. Bull. (IF 3.103) Pub Date : 2019-11-10
    Di Luan, Yuanxiang Zhang, Lili Yuan, Zhaohu Chu, Lingsong Ma, Yang Xu, Shoucai Zhao

    MST4 limits peripheral, macrophage-dependent inflammatory responses through direct phosphorylation of the adaptor TRAF6; though its role in neuro-inflammation is unclear. We investigated microglia expression of MST4 and whether is attenuates neuro-inflammatory response after cerebral ischemia-reperfusion injury in mice. Adult male C57BL6 mice were subjected to a 90-minute middle cerebral artery occlusion (MCAO) followed by a 72 -h reperfusing. The results showed that MST4 was involved in the pathological process after cerebral ischemia-reperfusion and was expressed in microglia. MST4-Adeno Associated Virus attenuated brain damage after MCAO and reduced expression of p-IκBα, p-ERK and p-JNK, while MST4 shRNA aggravated brain damage after MCAO and increased expression of p-IκBα, p-ERK and p-JNK. Our results show that MST4 inhibits neuro-inflammatory response in cerebral ischemia-reperfusion injury, improves neurological deficits, and reduces cerebral infarction volume in mice. Strategies to enhance MST4 in response to ischemic stroke may be a potential therapeutic strategy.

  • Neuroprotective effects of N-acetylcysteine via inhibition of matrix metalloproteinase in a mouse model of transient global cerebral ischemia
    Brain Res. Bull. (IF 3.103) Pub Date : 2019-11-10
    Lee Yoon-Hyung, Lee Seong-Ryong

    N-acetylcysteine (NAC) is known to serve many biological functions including acting as an antioxidant, and electing antiinflammatory effects. Previous reports have revealed that NAC may have neuroprotective effects against the deleterious effects of brain ischemia. Despite of this, the mechanism by which NAC prevents neuronal damage after brain ischemia remains unclear. The current study aimed to investigate this mechanism in a mouse model of transient global brain ischemia. In the present study, mice were subjected to 20 min of transient global brain ischemia, proceeded by intraperitoneal administration of NAC (150 mg/kg) in one group. The mice were then euthanized 72 h after this ischemic insult for collection of experimental tissues. The effect of NAC on neuronal damage and matrix metalloproteinase (MMP)-9 activity were assessed and immunofluorescence, and hippocampal terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) assay experiments were conducted and results compared between NAC- and vehicle-treated groups. Neuronal damage was primarily observed in the hippocampal CA1 and CA2 regions. In NAC-treated mice, neuronal damage was significantly reduced after ischemia when compared to vehicle-treated animals. NAC also inhibited increased MMP-9 activity after global brain ischemia. NAC increased laminin and NeuN expression and inhibited increases in TUNEL-positive cells, all in the hippocampus. These results suggest that NAC reduces hippocampal neuronal damage following transient global ischemia, potentially via reductions in MMP-9 activity.

  • The effect of high mobility group box-1 protein on cerebral edema, blood-brain barrier, oxidative stress and apoptosis in an experimental traumatic brain injury model
    Brain Res. Bull. (IF 3.103) Pub Date : 2019-11-09
    Sevket Evran, Fatih Calis, Enes Akkaya, Oguz Baran, Serdar Cevik, Salim Katar, Ebru Gurel Gurevin, Hakan Hanimoglu, Mustafa Aziz Hatiboglu, Elif Ilkay Armutak, Ersin Karatas, Abdurrahim Kocyigit, Mehmet Yasar Kaynar

    Traumatic brain injury (TBI) is one of the important reason of morbidity and mortality. While the primary injury due to mechanical impact is unavoidable, the secondary injury which is formed as a result of primary injury and thought to occur due to neuroinflammation in the forefront can be prevented and by this way mortality and morbidity can be reduced. High mobility group box-1 (HMGB1) is a protein that triggers the neuroinflammatory process by being released from the nucleus of necrotic tissues after primary injury. The aim of this study is to investigate the effects of HMGB1 on its receptors TLR4 and RAGE, cerebral edema, blood-brain barrier, oxidative stress and apoptosis causing secondary damage in an experimental traumatic brain injury model. Weighing between 280-320 g, 10 to 12 weeks-old, a total of 30 adult male Sprague-Dawley rats were used for the experiments. The rats were randomly assigned to 3 groups: 1) Control, 2) TBI and 3) TBI + ethyl pyruvate group (n = 10 per group). Right parietal cortical contusion was made by using a weight-dropping TBI method. Brain samples were harvested from pericontusional area at 24 h after TBI. HMGB1, TLR4, RAGE, occludin, claudin-5, ZO-1 levels are investigated by western blot analyses and immunohistochemistry examinations. HMGB-1, TLR4 and RAGE expressions increased after TBI. Major tight junction proteins in the blood-brain barrier: occludin, claudin-5 and ZO-1 expressions decreased after TBI. Brain edema increased after TBI. Also, proapoptotic bax and active caspase 3 expressions increased, antiapoptotic bcl-2 levels decreased after TBI. Total oxidant status and oxidative stress increased, total antioxidant status decreased after TBI. HMGB-1 protein plays a key role in the pathophysiology of traumatic brain injury.

  • Involvement of NLRC4 inflammasome through caspase-1 and IL-1β augments neuroinflammation and contributes to memory impairment in an experimental model of Alzheimer's like disease
    Brain Res. Bull. (IF 3.103) Pub Date : 2019-11-09
    Mahdiye Saadi, Ahmad Karkhah, Fereshteh Pourabdolhossein, Amin Ataie, Mastura Monif, Hamid Reza Nouri
  • Ginsenoside Rb1 Promotes Motor Functional Recovery and Axonal Regeneration in Post-stroke Mice through cAMP/PKA/CREB Signaling Pathway
    Brain Res. Bull. (IF 3.103) Pub Date : 2019-11-09
    Xuan Gao, Xiangjian Zhang, Lili Cui, Rong Chen, Cong Zhang, Jing Xue, Lan Zhang, Weiliang He, Jiamin Li, Shanshan Wei, Mengmeng Wei, Hemei Cui
  • Longitudinal tracing of white matter integrity on diffusion tensor imaging in the chronic cerebral ischemia and acute cerebral ischemia
    Brain Res. Bull. (IF 3.103) Pub Date : 2019-11-09
    Shengxiang Liang, Jiayong Zhang, Qingqing Zhang, Le Li, Yuhao Zhang, Tingting Jin, Bingxue Zhang, Xiaojun He, Lewen Chen, Jing Tao, Zuanfang Li, Weilin Liu, Lidian Chen

    Brain ischemia leads to insufficient oxygen supply or hypoxia and thus to ischemic stroke or chronic hypoperfusion, which results in neuronal death and white matter damage is irreversible or partially recoverable under the interruption of blood flow more than a few minutes. The present study investigated the abnormal characteristics of white matter integrity after the chronic cerebral ischemia in a mouse model of bilateral carotid artery stenosis and the acute cerebral ischemia in a mouse model of middle cerebral artery occlusion via longitudinal diffusion tensor imaging, which revealed that the mean diffusivity of corpus callosum (cc) was decreased as early as the 1 st day after chronic cerebral ischemia, and then the damage gradually aggravated and lasted to the 28th day. Moreover, the brain regions, including cingulum (cg), dorsal hippocampal commissure (dhc), forceps major of the corpus callosum (fmj), alveus of the hippocampus (alv) and medial lemniscus (ml), were damaged in duration of 7∼28 days after chronic cerebral ischemia. Oppositely, white matter signals in the contralateral hemisphere appeared compensatory increase in the internal capsule (ic) at the 1 st day after acute cerebral ischemia, simultaneously the ipsilateral hemisphere signals were decreased in alv, cerebral peduncle (cp), external capsule (ec), ml, fimbria of the hippocampus (fi), ic, forceps minor of the corpus callosum (fmi) and dhc. While these regional white matter signals were decreased in the bilateral hemisphere at the 7th day after acute cerebral ischemia. In addition, the motor function was impaired after acute cerebral ischemia, and cognitive function were impaired after chronic and acute cerebral ischemia. Furthermore, voxel-wise analysis revealed the obvious differences of white matter integrity in these two models of ischemia. The chronic cerebral ischemia showed better white matter integrity in the ipsilateral hemisphere of acute cerebral ischemic model at the 1 st day after surgery, but worse in the contralateral hemisphere. Subsequently, these differences were reduced significantly and just only the ipsilateral cp and bilateral ml signals were higher in chronic cerebral ischemia. Taken together, the present study demonstrates that the chronic and acute cerebral ischemia cause progressive damages of white matter that are irreversible in a relatively long time, of which the contralateral white matter present transient compensation in acute cerebral ischemia but not in chronic cerebral ischemia. These might be helpful to better diagnosis of clinical different cerebral ischemia.

  • In deep evaluation of the neurotoxicity of orally administered TiO2 nanoparticles
    Brain Res. Bull. (IF 3.103) Pub Date : 2019-11-09
    Intissar Grissa, Jaber ElGhoul, Rhizlaine Mrimi, Lassaad El Mir, Hassen Ben Cheikh, Patricia Horcajada
  • Corrigendum to "Age-dependent changes at the blood-brain barrier. A comparative structural and functional study in young adult and middle aged rats" [Brain Res. Bull. 139C (2018) 269-277].
    Brain Res. Bull. (IF 3.103) Pub Date : null
    Luca Bors,Kinga Tóth,Estilla Zsófia Tóth,Ágnes Bajza,Attila Csorba,Krisztián Szigeti,Domokos Máthé,Gábor Perlaki,Gergely Orsi,Gábor K Tóth,Franciska Erdő

  • Corrigendum to "Neural circuitry among connecting the hippocampus, prefrontal cortex and basolateral amygdala in a mouse depression model: Associations correlations between BDNF levels and BOLD - fMRI signals" [Brain Res. Bull. 142(2018) 107-115].
    Brain Res. Bull. (IF 3.103) Pub Date : 2019-11-09
    Peng Huang,Tingting Gao,Zhaoyang Dong,Chuying Zhou,Yuling Lai,Ting Pan,Yuan Liu,Xiaoshan Zhao,Xuegang Sun,Heyu Hua,Ge Wen,Lei Gao,Zhiping Lv

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上海纽约大学William Glover