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Objective: In the present study, the regulation mechanism of NAA10 (N-Alpha-Acetyltransferase 10) in sevoflurane preconditioning induced neuroprotective effect was explored., Methods: Firstly, si-NAA10 or negative control (NC) were constructed for cell transfection and injected into intracerebroventricular of rats. Oxygen-glucose deprivation/reperfusion (OGD/R) model in vitro and middle cerebral artery occlusion (MCAO) model in vivo were established to simulate cerebral I/R injury. QRT-PCR analysis and western blotting assay were performed to assess the expression of NAA10. TTC staining, neurological evaluation and cell counting kit-8 (CCK-8) were performed to evaluate the effect of NAA10 on sevoflurane induced neuroprotection. TUNEL assay and flow cytometry were used to detect the apoptosis in vivo and in vitro., Results: It showed that sevoflurane preconditioning increased the expression of NAA10 in MCAO rats. TTC staining, TUNEL assay and neurological evaluation results suggested that si-NAA10 attenuated the neuroprotective effect of sevoflurane preconditioning against MCAO. CCK-8 assay, flow cytometry, qRT-PCR and western blot results showed that NAA10 mediated sevoflurane preconditioning-induced neuroprotection in vitro. Furthermore, western blot results showed that down-regulation of NAA10 could reverse the attenuation of ERK1/2 phosphorylation induced by sevoflurane preconditioning in vivo or in vitro., Conclusion: Down-regulation of NAA10 regulated ERK1/2 phosphorylation mediating sevoflurane preconditioning induced neuroprotective effects. The results revealed the regulatory mechanism of NAA10 in the neuroprotective effect of sevoflurane preconditioning., (Copyright © 2021. Published by Elsevier B.V.)

Central sensitization is one of the important pathological mechanisms of chronic migraine (CM). Metabolic glutamate receptor 5 (mGluR5) mediates pain by activating various intracellular pathways. However, whether mGluR5 contributes to central sensitization in CM and the exact mechanism remains unclear. Male rats were used to establish a CM model by repeated infusions of inflammatory soup (IS) for 7 days to stimulate the activation of the dural nociceptor. The mechanical and thermal thresholds were used to evaluate allodynia, and central sensitization was assessed by measuring calcitonin gene-related peptide (CGRP) and substance P (SP). Microtubule associated protein 1 light chain 3 (LC3) and p62/SQSTM1 were used to assess autophagy. We found that the expression of mGluR5 in the trigeminal nucleus caudalis (TNC) of CM rats was significantly increased. In addition, the downregulation of mGluR5 activated autophagy by inhibiting the mTOR pathway. Moreover, the activation of autophagy alleviated allodynia and central sensitization in CM rats. This study identified a novel strategy for the treatment of CM; the downregulation of mGluR5 in a rat model of CM decreased the expression of the inflammatory factor interleukin-1 beta (IL-1β) and the central sensitization-associated proteins CGRP and SP by activating autophagy via inhibiting the mTOR pathway., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Recent studies have reported that microRNAs are abnormally expressed in brain tissues of Alzheimers disease (AD) patients. However, the accurate function of miR-20b-5p in AD has not been elucidated. We intended to investigate the role and underlying mechanism of miR-20b-5p in AD. The expression of miR-20b-5p was increased, and the expression of RhoC was decreased in the hippocampus of Appswe/PS△E 9 mice. In order to construct a cell model in vitro to study the underlying action mechanism, PC12 cells were treated with Aβ 25-35 . The cell apoptosis detected by flow cytometry and the expression of cleaved-caspase-3 detected by western blot were both remarkably increased in PC12 cells treated with Aβ 25-35 , but they were reduced by miR-20b-5p inhibitor. In addition, MTT test showed that the cell survival rate in Aβ 25-35 + miR-20b-5p inhibitor group was higher than that in Aβ 25-35 + NC inhibitor group. Double luciferase reporter gene analysis confirmed that the binding site of miR-20b-5p was in 3'- UTR of RhoC mRNA. Knockdown of RhoC increased neuronal apoptosis induced by Aβ25-35 and the expression of cleaved-caspase-3, while miR-20b-5p inhibitor reversed these effects. Knockdown of RhoC aggravated the inhibition effect on cell viability induced by Aβ 25-35 , while miR-20b-5p inhibitor diminished these effects. In conclusion, inhibition of miR-20b-5p attenuates apoptosis induced by Aβ 25-35 in PC12 cells through targeting RhoC. Therefore, miR-20b-5p may be a perspective curative target for AD., (Copyright © 2020 Elsevier B.V. All rights reserved.)

GABA A receptors are targets of different pharmacologically relevant drugs, such as barbiturates, benzodiazepines, and anesthetics. In particular, benzodiazepines are prescribed for the treatment of anxiety, sleep disorders, and seizure disorders. Benzodiazepines potentiate GABA responses by binding to GABA A receptors, which are mainly composed of α (1-3, 5), β2, and γ2 subunits. Prolonged activation of GABA A receptors by endogenous and exogenous modulators induces adaptive changes that lead to tolerance. For example, chronic administration of benzodiazepines produces tolerance to most of their pharmacological actions, limiting their usefulness. The mechanism of benzodiazepine tolerance is still unknown. To investigate the molecular basis of tolerance, we studied the effect of sustained exposure of rat cerebral cortical neurons to diazepam on the GABA A receptor. Flunitrazepam binding experiments showed that diazepam treatment induced uncoupling between GABA and benzodiazepine sites, which was blocked by co-incubation with flumazenil, picrotoxin, or nifedipine. Diazepam also produced selective transcriptional down-regulation of GABA A receptor α1 subunit gene through a mechanism dependent on the activation of L-type voltage-gated calcium channels. These findings suggest benzodiazepine-induced stimulation of calcium influx through L-type voltage-gated calcium channels triggers the activation of a signaling pathway that leads to uncoupling and an alteration of receptor subunit expression. Insights into the mechanism of benzodiazepine tolerance will contribute to the design of new drugs that can maintain their efficacies after long-term treatments., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The ephrin family of receptors (Eph) and their ephrin ligands are involved in pain associated hyperalgesia, but the underlying mechanisms involved have not been fully elucidated. The EphB6 receptor is a distinctive member of the EphB subclass in that its kinase domain contains several alterations in the conserved amino acids and thus lacks catalytic activity. We sought to identify a role for EphB6 in inflammatory pain, with the murine dextran sulfate sodium (DSS) colitis model of inflammatory bowel disease (IBD). Colitis, induced with the administration of 4% (wt./vol.) DSS in the drinking water, significantly decreased EphB6 protein expression levels in neurons of the lower thoracic superficial layers of spinal dorsal horns, the location of neurons that receive the majority of nociceptive information from the colon, via the primary afferents. A shift towards increased EphB/ephrinB forward signaling, mediated by EphB6 down-regulation in neurons of the dorsal horn, may play a role in inflammatory pain caused by IBD., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Contactin associated protein (Caspr), an adhesion molecule, plays roles in formation of paranodal junctions in myelinated axons, neurite outgrowth, synaptic plasticity in nervous system. Here we have shown a novel function of Caspr in pathogenesis of Alzheimer's disease (AD). Caspr distributes around amyloid plaques in APP/PS1 mice. Levels of Caspr increase in the cerebral cortex of 7-month-old APP/PS1 mice comparing to wild-type littermates. Caspr decreased protein levels of APP in both HEK-293 cells stably transfected with Indiana mutant APP (V717F; HEK-APP) and CHO cells which express endogenous APP, while it did not alter mRNA levels of APP. Furthermore, Caspr co-localizes and interacts with APP. Amyloid-β (Aβ) 40 and Aβ42 generation were also reduced in HEK-APP cells by Caspr overexpression., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Sirtuin 2 (SIRT2), a sirtuin family protein, is a tubulin deacetylase. Recent studies have indicated that SIRT2 plays a key role in programmed necrosis, and the SIRT2 inhibitor AGK2 can decrease the cell death both in a cellular model of Parkinson's disease and in an animal model of myocardial ischemia-reperfusion. However, there has been little information regarding the role of SIRT2 in microglial survival and functions, which play critical roles in multiple neurological disorders. Our current study found that AGK2 at 10 μM - a widely used AGK2 concentration - can induce both late-stage apoptosis and necrosis, as well as a decrease in the intracellular ATP levels of microglial BV2 cells. Our study also showed that both the AGK2-induced cell death and the AGK2-induced ATP decline are mediated by poly(ADP-ribose) polymerase (PARP) activation. Collectively, our study has provided the first evidence suggesting a significant role of SIRT2 in the basal survival of microglia, as well as a mechanism accounting for the effects of SIRT2 on intracellular ATP levels., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Insulin-like growth factor-1 (IGF-1) has been demonstrated to have neuroprotective effects, but little is known concerning its role in vascular dementia (VaD). This study aimed to evaluate expression of IGF-1 signaling in hippocampus in rat model of VaD, and probe the underlying mechanisms. Permanent occlusion of bilateral common carotid arteries (2-VO) was used as VaD model. Learning and memory functions were declined significantly in 2-VO rats, and these impairments were further deteriorated with the prolongation of 2-VO treatment. IGF-1, IGF-1 receptor (IGF-1R), total Akt and phosphorylated Akt (p-Akt) were all measured at 1, 2 and 4 months following 2-VO injury. Compared with controls, IGF-1, IGF-1 mRNA and p-Akt expression were significantly decreased in hippocampus of 2-VO rats. However, changes of IGF-1R and total Akt levels were not significant. These results suggest that down-regulation of IGF-1 and p-Akt may contribute to the impairments of learning and memory functions after 2-VO. IGF-1/IGF-1R signaling system may involved in the onset and development of VaD., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Anaphase-promoting complex (APC) and its coactivator Cdh1 are required for maintaining cells in G1 phase of cell cycle in proliferating cells. Recent studies showed that Cdh1-APC was active in post-mitotic neurons, which regulates neuronal survival, differentiation, axonal growth and synaptic development. However, the possible function of Cdh1-APC in ischemic brain injury has not been determined. This study aimed to investigate changes in the activity of Cdh1-APC in hippocampus after global cerebral ischemia in rat. We found that, compared with sham group, the expression of Cdh1 in hippocampus was significantly decreased on 1 and 3 days of reperfusion in ischemia group (P<0.05), while neuronal apoptosis were found in hippocampal CA1 region and the two downstream substrates of Cdh1-APC (SnoN and Skp2) were significantly increased after global cerebral ischemia (P<0.05). This study demonstrates that the down-regulation of Cdh1-APC is associated with neuronal apoptosis in hippocampus following global cerebral ischemia. It brings a prospect to explore the further function of Cdh1-APC in the injured nervous system., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Microglial activation and blood brain barrier dysfunction are significant hallmarks in an array of neurodegenerative disorders. A leaky blood brain barrier potentially allows infiltration of blood-borne proteins into the CNS parenchyma, and previous studies have shown that the blood borne protein fibrinogen (FG) can activate microglia to produce a neurotoxic phenotype. Here we show that FG-mediated neurotoxicity and ERK1/2 phosphorylation in neuronal cultures is significantly attenuated by activation of metabotropic glutamate receptor 5 (mGluR5) but not mGluR2. Furthermore, FG-mediated microglial activation was down-regulated by direct mGluR5 activation on these cells but not by mGluR2, suggesting that targeting microglial mGluR5 provides neuronal protection against blood protein-triggered innate inflammatory responses., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Schizophrenia (SZ) is a chronic severe mental disorder. Increased inflammatory processes have been shown in acute and chronic SZ. Apoptotic processes may alter the neuronal network and are involved in the pathogenesis of several neurodegenerative diseases, such as SZ. Annexin-V seems to have a role on inhibition of pro-inflammatory activities during apoptosis. Tumor necrosis factor (TNF-alpha) is a cytokine involved in systemic inflammation and is a member of a group of cytokines which stimulate acute phase reactions. A chronic immune activation in SZ has been shown. The aim of this study was to compare annexin-V and TNF-alpha serum levels in chronic medicated patients with SZ and healthy controls. Thirty-eight outpatients from the HCPA Schizophrenia Program and 38 healthy controls were enrolled to this study protocol. Annexin-V and TNF-alpha serum levels were measured with ELISA. Serum annexin-V levels were significantly higher in patients with SZ than in controls (p<0.001) and TNF-alpha significantly lower (p<0.001). The present result of increased annexin-V and decreased serum levels of TNF-alpha compared to controls may be a result of the stabilization phase of psychosis and a reduction in metabolic brain aggression. In this complex picture, increased levels of annexin-V and decreased levels of TNF-alpha in our sample would be explained by illness stability and chronic treatment. Our findings support the hypothesis of a state dependant process of inflammation in SZ. Further prospective studies to clarify the findings described in this paper are needed., (Copyright © 2011. Published by Elsevier Ireland Ltd.)

Vasopressin V1a receptors (V1aR) were found in the cerebellum but their functional role has not been determined. As V1aR are engaged in the central regulation of the cardiovascular system and anxiogenic behavior and their role increases in the heart failure and stress, we decided to find out whether expression of V1aR is altered after myocardial infarction and chronic stressing. RT-PCR and Western blot analysis were performed to determine V1aR mRNA and protein expression in the cerebellum of four groups of rats (control sham-operated, infarcted, chronically stressed and infarcted chronically stressed). The myocardial infarct was produced by left coronary artery ligation, and chronic stressing by exposing the rat for four weeks to different types of mild stressors. The rats were sacrificed four weeks after the myocardial surgery or sham operation. Expressions of V1aR mRNA and protein were significantly lower in the infarcted and infarcted chronically stressed rats than in the sham-operated controls and chronically stressed not infarcted rats. No significant differences were found between the sham-operated controls and chronically stressed rats and between the infarcted rats and infarcted rats exposed to chronic stressing. It is concluded that V1aR mRNA and protein expressions are significantly down-regulated in the rats with the post-infarct heart failure but they are not affected by mild chronic stressing., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

This study was performed to investigate the mechanism of the blood-brain tumor-barrier (BTB) permeability increase, which was induced by NS1619, a selective K(Ca) channel activator. Using a rat brain glioma (C6) model, we exam the expression of ZO-1 and occludin in mRNA and protein level at different time point after intracarotid infusion of NS1619 (30 μg/kg/min) to tumor sites via RT-PCR and Western blot analysis. The mRNA and protein expression of ZO-1 and occludin had no great change before infusion and began to decrease significantly after 2 h NS1619 infusion, which was significantly attenuated by reactive oxygen species (ROS) scavenger (N-2-mercaptopropionyl glycine, MPG). In addition, MPG also significantly inhibited the increase of BTB permeability and malonaldehyde (MDA) level induced by NS1619. This led to the conclusion that NS1619 could time-dependently increase the BTB permeability by down-regulating the expression of tight junction protein, and this effect could be reversed by ROS., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Recent investigations of rapid eye movement sleep (REMS) continuity have emphasized the importance of transitions both into and out of REMS. We have previously reported that, compared to Wistar rats (WIS), Wistar-Kyoto rats (WKY) responded to fear conditioning (FC) with more fragmented REMS. Gamma oscillations in the electroencephalogram (EEG) are synchronized throughout the brain in periods of focused attention, and such synchronization of cell assemblies in the brain may represent a temporal binding mechanism. Therefore, we examined the effects of FC on EEG gamma range activity (30-50Hz) at REMS transitions in WKY compared to WIS. Relative power in the gamma range (measured as a percent of total power) at Baseline and upon re-exposure to the fear-inducing conditioning stimulus was measured 35s before REMS onset to 105s after REMS onset (ARO) and 85s before REMS termination (BRT) to 35s after REMS termination. After baseline recording, rats received 10 tones, each co-terminating with an electric foot shock. On Days 1 and 14 post-conditioning, rats were re-exposed to three tones. Fast-Fourier transforms created power spectral data in the gamma frequency domain. Relative power was extracted from an average of 4-5 REMS transitions. Relative gamma power was always higher in WIS. On Day 14, at 15s and 25s ARO, WKY had significant increases in relative gamma power from Baseline. WIS had a significant increase on Day 1 at 25s ARO. Despite the increases in relative gamma power, WKY never achieved levels attained by WIS. Moreover, at 5s BRT, only WKY had a significant decrease in relative gamma power from Baseline to Day 14. Gamma range activity may indicate neural activity underlying maintenance of REMS continuity. Low relative gamma power at REMS transitions may be associated with increased REMS fragmentation in WKY after FC., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Diabetic neuropathic pain is a common clinical problem and remains difficult to treat with classic analgesics. Spinal dorsal horn neurons are important in mediating nociceptive signaling, and the hyperactivity of these neurons is critical in diabetic neuropathy. In this study, we determined the GABA(B) receptor expression level in dorsal horn neurons in streptozotocin (STZ)-induced diabetes in rats by using reverse-transcription polymerase chain reaction (RT-PCR) and western blot analyses. Mean blood glucose concentrations were significantly higher and the paw withdrawal threshold was significantly lower in STZ-treated rats than in saline-treated rats. Immunohistochemical staining showed that the GABA(B) receptor was extensively expressed in the spinal dorsal horn neurons. The GABA(B1) mRNA level decreased in a time-dependent manner in STZ-treated rats compared with saline-treated controls. Furthermore, the protein expression level revealed by western blot analysis was lower in STZ-treated rats than in saline-treated rats. These data suggest that GABA(B) receptors are downregulated in the spinal dorsal horn in this model of STZ-induced diabetic neuropathic pain. The reduction of GABA(B) expression may contribute to the hyperactivity of spinal dorsal horn neurons and diabetic neuropathic pain., (Crown Copyright © 2010. Published by Elsevier Ireland Ltd. All rights reserved.)

Alzheimer's disease (AD) is the most common form of dementia, and is characterized by the degeneration of neurons and their synapses, and a higher number of amyloid plaques and neurofibrillary tangles (NFTs) compared with that found in non-demented individuals. Amyloid-β-peptides (Aβ) are major components of amyloid plaques in AD brain whereas NFTs are composed of Tau and associated with ubiquitin. The aim of the present study was to analyze the levels of Aβ42, hTau (total Tau) and ubiquitin in CSF of North Indian population. CSF Aβ42, Tau and ubiquitin were measured in CSF of AD patients as well as controls using ELISA assays. Here we report low Aβ42 levels in AD patients (324.24±76.38pg/ml) as compared to those in non-AD (NAD) (668.34±43.13pg/ml), neurological controls (NCs) (727.28±46.49pg/ml) and healthy controls (HCs) (976.47±124.46pg/ml). In contrast, hTau and ubiquitin levels were significantly high (568.65±48.89pg/ml and 36.82±4.34ng/ml, respectively) in AD patients compared to those in NAD, NC and HC. The hTau levels were 267.37±36.64pg/ml, 167.34±44.27pg/ml and 107.62±24.27pg/ml in NAD, NC and HC, respectively. Similarly, ubiquitin levels were 23.57±2.32ng/ml, 19.76±3.64ng/ml and 13.24±4.56ng/ml in NAD, NC and HC, respectively. In conclusion, low Aβ42 and high Tau-ubiquitin levels were found in North Indian AD patients., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Marked alterations in astrocyte function are a universal response to disease or injury in the central nervous system. Affected astrocytes develop characteristic morphological changes known as "reactive astrogliosis", characterized by increased expression of the intermediate filament proteins, glial fibrillary acidic protein and vimentin. Reactive astrocytes also display alterations in other proteins including a rapid up-regulation of the gap junction protein, Connexin 43. The present study tests whether Connexin 43 is directly involved in the astrocytic response to injury. We have down regulated Connexin 43 expression using a microRNA generating plasmid and investigated the functional consequences of this treatment on the response of astrocytes in primary culture to a well-characterized scratch wound injury. The treatment resulted in more than 70% transfection efficiency and a near complete depletion of Connexin 43 in transfected cells. Compared to cells transfected with non-targeting microRNA, the cells depleted of Connexin 43 showed a slower wound closure and fewer transfected cells in the wound area. These changes were associated with decreased proliferation of the Connexin 43-depleted cells as well as shorter processes extending into the wound area suggesting a direct impairment of migration. The effects were independent of gap junction conductivity as exposure to the gap junction blocker carbenoxolone did not affect the rate of wound healing. The findings directly indicate a role for Connexin 43 in the astrocytic response to injury and suggest that modification of Connexin 43 expression might provide a therapeutic target to alter potentially deleterious astrocytic responses., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Previously, it was proposed that sedative and anesthetic effects of alpha2-adrenergic receptor (alpha2-AR) agonists may be exerted via neuronal networks normally implicated in the regulation of wakefulness. The aim of this study was to evaluate the role of A subtype of alpha2-ARs in the development of drug-independent anesthetic state induced by hypothermia in newborn rats. Using short interfering RNA (siRNA) gene-targeting strategy, we found that down-regulation of the brainstem alpha2A-AR expression resulted in a delay in the onset of hypothermia-induced anesthesia assessed by loss of righting reflex. Involvement of the brain alpha2A-ARs in this delay was confirmed by inability of clonidine, a subtype-nonselective alpha2-AR agonist, to prolong duration of hypothermia-induced anesthesia in siRNA-treated animals, while significant prolongation of this anesthetic state by the alpha2A-AR agonist was observed in control pups. The data suggest that negative regulation of the animal's waking state is an intrinsic function of the brainstem alpha2A-ARs activated by exogenous agonists, as well as by endogenous noradrenaline, also., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

5-Hydroxytryptamine (5-HT) is involved in a variety of different physiological processes and behaviors through the activation of equally diverse receptors subtypes. In this work we studied the changes on the expression of 5-HT(5A) receptors in rat hippocampus induced by leptin, an adipocyte-derived hormone that has been reported to participate in the modulation of food intake and in adult hippocampal neurogenesis. To study the effect of leptin on the 5-HT(5A) receptor gene expression a qRT-PCR was used and the distribution of those receptors in the hippocampus was visualized by immunohistochemistry. Rats were separated in four groups: control (untreated rats), leptin-treated, serotonin-treated and leptin+serotonin treated. The results showed that even though the 5-HT(5A) gene expression did not change in the hippocampus of any of the treated groups, in the rats treated with leptin and serotonin, the specific immunostaining for the 5-HT(5A) serotonin receptor decreased significantly in the dentate gyrus., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Heme is an essential cell metabolite, intracellular regulatory molecule, and protein prosthetic group. Given the known alterations in heme metabolism and redox metal distribution and the up-regulation of heme oxygenase enzyme in Alzheimer's disease (AD), we hypothesized that heme dyshomeostasis plays a key role in the pathogenesis. To begin testing this hypothesis, we used qRT-PCR to quantify the expression of aminolevulinate synthase (ALAS1) and porphobilinogen deaminase (PBGD), rate-limiting enzymes in the heme biosynthesis pathway. The relative expression of ALAS1 mRNA, the first and rate-limiting enzyme for heme biosynthesis under normal physiological conditions, was significantly (p<0.05) reduced by nearly 90% in AD compared to control. Coordinately, the relative expression of PBGD mRNA, which encodes porphobilinogen deaminase, the third enzyme in the heme synthesis pathway and a secondary rate-limiting enzyme in heme biosynthesis, was also significantly (p<0.02) reduced by nearly 60% in AD brain compared to control and significantly related to apolipoprotein E genotype (p<0.005). In contrast, the relative expression of ALAD mRNA, which encodes aminolevulinate dehydratase, the second and a non-rate-limiting enzyme for heme biosynthesis, was unchanged between the two groups. Taken together, our results suggest regulation of cerebral heme biosynthesis is profoundly altered in AD and may contribute toward disease pathogenesis by affecting cell metabolism as well as iron homeostasis.

GPCR interacting scaffold protein (GISP) is a multi-domain brain-specific scaffold protein that can regulate GABA(B) receptor complexes by both enhancing their surface expression and by inhibiting their lysosomal degradation. GISP retards degradation of GABA(B) receptors through its interaction with tumour susceptibility gene 101 (TSG101), a member of the endosomal sorting complex required for transport (ESCRT) lysosomal sorting machinery. We show that in addition to GABA(B), GISP exerts a more general role to increase the steady-state levels of several neurotransmitter receptors. Further, GISP delays TSG101-dependent agonist-induced EGFR down-regulation in human embryonic kidney (HEK) 293 cells whereas a mutant GISP lacking the TSG101 binding domain has no effect. These data suggest that GISP acts as a negative regulator of TSG101-dependent lysosomal degradation and plays an important role in determining the availability of neurotransmitter receptors.

H-reflex down-conditioning increases GABAergic terminals on spinal cord motoneurons. To explore the origins of these terminals, we studied the numbers and distributions of spinal cord GABAergic interneurons. The number of identifiable GABAergic interneurons in the ventral horn was 78% greater in rats in which down-conditioning was successful than in naive rats or rats in which down-conditioning failed. No increase occurred in other spinal lamina or on the contralateral side. This finding supports the hypothesis that the corticospinal tract influence that induces the motoneuron plasticity underlying down-conditioning reaches the motoneuron through GABAergic interneurons in the ventral horn.

The purpose of this study was to assess net corticomotor excitability during a painful stimulus before and after exercise. In the first study, 25 subjects participated in three sessions: one familiarization session and two experimental sessions. The two experimental sessions were randomized and involved measurement of pain perception before and after (1) a submaximal isometric fatiguing contraction with the left elbow flexor muscles and (2) 30 min of quiet rest. Pain perception was assessed using a pressure device applied to the right index finger for 2 min. Motor evoked potentials (MEPs) of the left brachioradialis muscle were measured following transcranial magnetic stimulation (TMS) which was delivered before, during, and after the 2 min pain test. In the second study, 12 subjects participated in one session which involved application of TMS to elicit MEPs at the same time points as in study one, before and after a submaximal fatiguing contraction, but in the absence of pain. In the absence of the mechanical noxious stimulus, MEP amplitude was reduced following the fatiguing contraction and unchanged over this time period. In study one, pain threshold increased and pain ratings decreased following the isometric contraction but not after 30 min of quiet rest. During application of the mechanical noxious stimulus to the right index finger, MEP amplitude of the left brachioradialis muscle increased indicating an increase in net corticomotor excitability. The pain-induced increase in MEPs was attenuated following the isometric fatiguing contraction and this occurred in parallel with the decrease in pain.

Short episodes of high intensity exercise transiently increase serum levels of BDNF in humans, but serum levels of BDNF at rest appear to be lower in more physically active humans with greater levels of energy expenditure. The relationship between serum BDNF concentration, cardio-respiratory fitness (Astrand-Rhyming test estimated VO2 max) and volume of long-term, regular exercise and sporting activity (Baecke Habitual Physical Activity Index) was investigated in 44 men and women between the age range of 18-57 years. In this group an inverse relationship between resting serum BDNF concentration and measures of both estimated VO2 max (r=-0.352; P<0.05) and long-term sporting activity (r=-0.428, P<0.01) was found. These results indicate that increased levels of cardio-respiratory fitness and habitual exercise are associated with lower resting levels of serum BDNF in healthy humans. This is the first study to demonstrate an inverse relationship between a physiological estimate of cardio-respiratory fitness and serum BDNF.

Experiments in rats have shown that chronic visceral hyperalgesia can be relieved by electro-acupuncture, but the efficacy of suspended moxibustion for relieving chronic visceral hyperalgesia is still unclear. The present study aimed to evaluate the effect of suspended moxibustion on rectal sensory thresholds and to analyze its possible mechanisms when treating chronic visceral hypersensitivity rats. Suspended moxibustion was administered once daily to 37-day-old chronic visceral hypersensitivity rats for 7 days. The two acupoints (ST25, bilateral) were simultaneously given suspended moxibustion. Each treatment lasted for 15 min. Rats in treatment of suspended moxibustion was not anesthetized. Untreated chronic visceral hypersensitivity rats and normal rats were used as controls. The abdominal withdrawal reflex was determined during 30-90 min after the first treatment. A 5-cm long segment of distal colon was harvested after seven treatments and 5-hydroxytryptamine concentrations in the colon were assayed by enzyme-linked immunosorbent assay. Abdominal withdrawal reflex scores from the rectus abdominis in response to colorectal distention were increased in rats with chronic visceral hypersensitivity, and the stimulation at strength of 20 mmHg was significantly depressed by suspended moxibustion. Suspended moxibustion increased the pain threshold and restored normal sensitivity by reducing 5-hydroxytryptamine concentrations in the colon of chronic visceral hypersensitivity rats.

The nitric oxide donor, nitroglycerin (NTG) can trigger a migraine attack, after a delay of several hours in migraineurs, but not in healthy people. This long delay does not favor a pure vasodilatatory action. In rats, subcutaneous administration of NTG (10mg/kg) significantly and selectively increases the number of calmodulin-dependent protein kinase II alpha (CamKIIalpha)-immunoreactive neurons in the trigeminal caudal nucleus (TNC) after 4h. The aim of our study was to determine if any isoforms of the cyclooxygenase (COX) enzyme might have a role in the NTG-induced increase of CamKIIalpha expression. In our experiments, we demonstrated that pretreatment with NS398, the selective COX-2 inhibitor attenuated the NTG-induced CamKIIalpha expression in the TNC at doses of 3 and 5mg/kg. In contrast, SC560, a selective COX-1 inhibitor failed to modulate this phenomenon in any of the dosages used (1, 5 and 10mg/kg). These findings suggest that COX-2, but not COX-1 derived metabolites are important factors in the NTG-induced CamKIIalpha expression. Thus this isoform may play a significant role in the induction of migraine. These data could help in the better understanding of the pathogenesis of headaches and the action of antimigraine drugs.

Alzheimer's disease (AD) is characterized by the deposition of amyloid beta-peptide (Abeta), derived from amyloid precursor protein (APP). Membrane states, such as lipid components or membrane fluidity, are important for enzymes related to APP processing in meeting their substrates efficiently. We analyzed the effects of triglycerides combined with polyunsaturated fatty acids (PUFAs) and/or caprylic acids on APP proteolysis. Our results showed that 1,3-capryloyl-2-arachidonoyl glycerol (8A8) moderately increased alpha-secretase activity (18%) in A172 cells. beta-Secretase activity was not statistically significantly changed in HEK293 cells stably expressing BACE1. However, Abeta40 secretion decreased by 22%. Thus, we conclude that 8A8 is a useful lipid compound for activating alpha-secretase activity and suppressing Abeta40 secretion.

The association of alpha-synuclein (alpha-syn) neuropathology with Parkinson's disease (PD) and several related disorders has led to an intense research effort to develop cerebrospinal fluid (CSF)- or blood-based alpha-syn biomarkers for these types of diseases. Recent studies show that alpha-syn is present in CSF and possible to measure using enzyme-linked immunosorbent assay (ELISA). Here, we describe a novel ELISA that allows for quantification of alpha-syn in CSF down to 50pg/mL. The diagnostic value of the test was assessed using CSF samples from 66 Alzheimer's disease (AD) patients, 15PD patients, 15 patients with dementia with Lewy bodies (DLB) and 55 cognitively normal controls. PD and DLB patients and controls displayed similar CSF alpha-syn levels. AD patients had significantly lower alpha-syn levels than controls (median [inter-quartile range] 296 [234-372] and 395 [298-452], respectively, p<0.001). Moreover, AD patients with mini-mental state examination (MMSE) scores below 20 had significantly lower alpha-syn than AD patients with MMSE scores of 20 or higher (p=0.02). There was also a tendency towards a negative correlation between alpha-syn levels and disease duration in the AD group (r=-0.247, p=0.06). Altogether, our results speak against CSF alpha-syn as a reliable biomarker for PD and DLB. The lower alpha-syn levels in AD, as well as the association of alpha-syn reduction with AD severity, approximated by MMSE, suggests that it may be a general marker of synapse loss, a hypothesis that warrants further investigation.

Cocaine addiction is associated with an increase in actin cycling and alterations in dendritic spines in the nucleus accumbens. Both actin polymerization and spine morphology are regulated in part by beta-(beta) integrins. Mice were administered acute or daily injections of cocaine or saline for 7 days. After 3 weeks of withdrawal, the level of beta-integrins in the postsynaptic density enriched subfraction from nucleus accumbens tissue was quantified by immunoblotting at 0, 30 or 120min following an a cocaine challenge injection. After chronic treatment and withdrawal the basal level of beta1-integrin was increased while beta3-integrin was unaltered. However, following a cocaine challenge in chronic cocaine, but not saline-treated animals, beta3-integrin was transiently up-regulated while beta1-integrin was transiently downregulated. These data demonstrate a bidirectional regulation of beta-integrins by chronic cocaine treatment that may contribute to cocaine-induced changes in actin cycling and dendrite morphology.

Acupuncture-related effects on autonomic function have been explored via biological and neurophysiologic studies. The hypothalamus, known to regulate the autonomic nervous system, is likely affected by acupuncture treatment that modulates sympathetic functions. The aim of this study was to investigate the effect of electroacupuncture at the Jogsamni point (ST36, an acupoint known to modulate autonomic function) on expression of neuronal nitric oxide synthase (nNOS) in the hypothalamus of spontaneously hypertensive rat. Nitric oxide, which is produced by nNOS activity, plays an important role in the regulation of many physiologic processes, including sympathetic activities, in the hypothalamus and other parts of the brain. nNOS expression was assessed by immunohistochemistry of nNOS and histochemistry of nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d). The staining intensities of nNOS-positive neurons and NADPH-d-positive neurons were quantitatively assessed using microdensitometry to measure changes in optical density. The results show that electroacupuncture at ST36 reduced the expression and activity of nNOS in the hypothalamus of spontaneously hypertensitive rats. These findings suggest that the electroacupuncture at ST36 results in modulation of the activity of nNOS in the hypothalamus of spontaneously hypertensive rat.

Large-conductance calcium-activated potassium channels (BK channels) have been suggested to play a substantial role in synaptic transmission in the spinal cord dorsal horn. In the present experiments, we attempted to clarify the physiological significance of BK channels in the modulation of synaptic transmission in the superficial dorsal horn where nociceptive information is processed. Spontaneously occurring excitatory postsynaptic currents (sEPSCs) were recorded from the neurons located in the superficial dorsal horn of a mouse spinal cord slice, and the effects of iberiotoxin, a BK channel blocker, on sEPSCs were analyzed. The frequency of sEPSCs was significantly higher in the peripheral nerve-ligated neuropathic mice than in the sham-operated control mice, but the amplitude of sEPSCs was equivalent between the two groups. Iberiotoxin increased the frequency of sEPSCs in the control mice to the same level as that in the neuropathic mice without affecting the amplitude of sEPSCs. In contrast, iberiotoxin did not show any significant effects on the sEPSCs in the neuropathic mice. These findings suggest that the BK channels that are located in presynaptic terminals control synaptic transmission in the superficial dorsal horn, and that functional downregulation of BK channels accompanies the neuropathic pain induced by peripheral nerve injury. This downregulation was confirmed by real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR) analysis of the BK channel alpha subunit. Taken together, our present results indicate that BK channels play crucial roles in the synaptic transmission of nociceptive information in the superficial dorsal horn.

Data on neurobiological differences between major depression (MD) and double depression (DD) are scarce. We examined the striatum dopamine (DAT) and midbrain serotonin transporter (SERT) binding of [123I] nor-beta-CIT in DD patients (n=8) and compared it to that in MD patients (n=11) and healthy controls (n=19). Drug-naïve patients and controls were imaged by single-photon emission computed tomography at baseline, and the patients also after one year of psychodynamic psychotherapy. Both DD and MD groups had lower midbrain [123I] nor-beta-CIT binding compared with the controls. Baseline 17-item Hamilton Depression Rating Scale (HAM-D-17) scores significantly decreased in both groups after one year of psychotherapy (DD: t=3.55, p=0.009; MD: t=5.86, p<0.001). No differences between the DD and MD groups were observed in age-adjusted baseline striatum or midbrain [123I] nor-beta-CIT binding or its change during psychotherapy. Age-adjusted baseline striatum [123I] nor-beta-CIT binding correlated inversely with the duration of both dysthymia (rho=-0.76, p=0.03) and MD (rho=-0.83, p=0.01) in the DD group. No such finding was observed in the MD group (rho=0.26, p=0.44). Baseline HAM-D-17 did not correlate with the change in striatum or midbrain [123I] nor-beta-CIT binding in either group. In conclusion, our findings suggest that when using midbrain [123I] nor-beta-CIT binding as a marker of SERT binding, no differences are detectable between patients with DD and MD. However, low striatum [123I] nor-beta-CIT binding, a marker of DAT binding, may be associated with a longer illness duration in dysthymia.

In this study we examined the role of apoE on the rate of synaptic recovery in the olfactory bulb (OB) following olfactory epithelium (OE) lesioning in mice. We used both immunoblotting and immunohistochemical techniques to compare the density of OB synaptophysin (Syn, a synaptic marker) in apoE-gene deficient/knockout (KO) mice and wild-type (WT) mice following OE lesion. We found that the whole bulb concentrations of Syn, measured by immunoblotting, declined sharply following injury in both WT and KO mice during the degenerative phase (3-7 days). After this initial decline, the Syn concentration gradually increased to normal levels by 56 days in WT mice. In contrast, Syn concentration in KO mice did not recover by day 56 when Syn density in WT was essentially normal. Glomerular Syn density, measured by immunohistochemistry, found a lower density in KO mice at all time points post-lesion. This lower concentration of whole bulb Syn parallels the slower recovery of glomerular area in KO mice. The data indicate that apoE deficiency in KO mice is associated with a delayed recovery of the glomerular area and a slower recovery in Syn concentration in the OB.

Anti-inflammatory action of estrogen is involved in neuroprotection but the effects of estrogen on IL-1beta and its endogenous antagonist (IL-1 ra) have not been clearly defined in the ischemic brain. This study was performed to evaluate whether estrogen affects the expression of IL-1beta or IL-1ra and the ratio of the two in the ischemic hippocampus. Rat organotypic hippocampal slices were treated with 17beta estradiol (E2, 1 nM) for 7 days, exposed to oxygen-glucose deprivation (OGD) for 30 min, and then reperfused for 72 h. CA1 neuronal death quantified by propidium iodide (PI) staining and expressions of IL-1beta and IL-1ra in slices measured by real-time PCR and Western blotting were examined. PI intensities in CA1 in slices treated with E2 were significantly reduced at 24 h and 72 h post-OGD, and IL-1beta mRNA expressions were reduced at 6 h and 24 h post-OGD. In addition, IL-1ra mRNA was significantly overexpressed and the ratio of IL-1beta to IL-1ra mRNA expression was reduced by E2 especially at 24 h. In terms of protein levels, E2 downregulated IL-1beta but upregulated IL-1ra and thereby decreased the IL-1beta/IL-1 ra ratio at 24h. These findings demonstrate that estrogen-induced protection is associated with a decrease in IL-1beta and an increase in IL-1ra expression in the ischemic hippocampus during early reperfusion periods, which suggests that modulation of IL-1beta/IL-1ra might be a part of anti-inflammatory effects of estrogen.

It is well known that acute cocaine administration increases c-Fos expression that is involved in cocaine-induced persistent changes in the central nervous system. In the present study, we investigated a possible involvement of extracellular signal-regulated protein kinase (ERK) in induction of c-fos expression in response to acute cocaine treatment in nucleus accumbens (NAc). We found that inhibition of ERK activation significantly attenuated cocaine-induced c-fos expression at both protein and mRNA levels in the NAc. Furthermore, using an immunofluorescent staining approach, we found that inhibition of ERK activation completely abolished cocaine-induced increase in number of c-Fos-positive cells in the core region of NAc, whereas, in shell region of NAc, inhibition of ERK activation partially attenuated cocaine-induced c-Fos expression. Our findings suggest that ERK might participate in cocaine-induced c-fos expression in the NAc, particularly in the core region of NAc.

Oxidative stress is believed to contribute to neuronal damage induced by cerebral ischemia/reperfusion (I/R) injury. The present study was undertaken to evaluate the possible antioxidant neuroprotective effect of genistein against neuronal death in hippocampal CA1 neurons following transient global cerebral ischemia in the rat. Transient global cerebral ischemia was induced in male Sprague-Dawley rats by four-vessel-occlusion for 10min. At various times of reperfusion, the histopathological changes and the levels of mitochondria-generated reactive oxygen species (ROS), malondialdehyde (MDA), cytosolic cytochrome c and caspase-3 activity in hippocampus were measured. We found extensive neuronal death in the CA1 region at day 5 after I/R. The ischemic changes were preceded by increases in ROS generation and MDA concentration and followed by increased cytosolic cytochrome c, and subsequently caspase-3 activation and apoptosis. Treatment with genistein (15mg/kg, i.p.) significantly attenuated ischemia-induced neuronal death. Genistein administration also decreased ROS generation, MDA concentration and the apoptotic indices. These results suggest that genistein protects neurons from transient global cerebral I/R injury in rat hippocampus by attenuating oxidative stress, lipid peroxidation and the signaling cascade leading to apoptotic cell death.

Cerebral responses to traumatic brain injury (TBI) include up- and downregulation of a vast number of proteins involved in endogenous inflammatory responses and defense mechanisms developing postinjury. The present study analyzed the global gene expression profile in response to cryo-induced TBI by means of microarray analysis. Adolescent rats were subjected to TBI and treated with either placebo or a neural cell adhesion molecule (NCAM)-derived fibroblast growth factor receptor (FGFR) agonist, FGL peptide, which has been demonstrated to have neuroprotective effects. mRNA levels were measured at various time-points postlesion (6 h, 1 day and 4 days). The effects of injury, treatment, and injury-treatment interaction were observed. TBI alone rendered a large number of genes affected. Analysis of lesion and treatment interactions resulted in a clear effect of the interaction between injury and FGL-treatment compared to injury and placebo-treatment. Genes affected by TBI alone included inflammation markers, protein kinases, ion channel members and growth factors. Genes encoding regulators of apoptosis, signal transduction and metabolism were altered by the interaction between FGL-treatment and TBI. FGL-treatment in non-injured animals rendered genes regulating signaling, transport and cytoskeleton maintenance significantly increased. Thus, the hypothesis of a putative neuroprotective role of FGL was supported by our findings.

Homeostatic plasticity is a powerful cellular mechanism through which neurons adjust intracellular and intercellular resources to stabilize their functional output through the ever-changing environment. Here, we report a novel form of homeostatic plasticity that nucleus accumbens (NAc) neurons use to regain their functionally active state once it is lost. In vivo, NAc neurons periodically alternate between a functionally active upstate and a functionally quiescent downstate. The upstate of NAc neurons is immediately lost following severe environmental changes, such as deep anesthesia and truncation of excitatory synaptic inputs. Using short-term slice cultures, our current study demonstrates that NAc neurons initially lose but gradually recover their upstate-downstate cycling after shifting to the in vitro condition. Furthermore, we show that this homeostatic recovery of the upstate is mediated by increased synchronization of presynaptic activity. Given that being in the upstate is required for in vivo NAc neurons to fire action potentials, the homeostatic recovery of upstate may underlie an important cellular mechanism for NAc neurons to maintain their functional output against severe environmental fluctuations.

In tauopathies such as Alzheimer's disease (AD), the moleccular mechanisms of tau protein agregation into neurofibrillary tangles (NFTs) and their contribution to neurodegeneration are not fully understood. Recent studies indirectly demonstrated that tau, regardless of its aggregation, might represent a key mediator of neurodegeneration, especially that induced by the amyloid (Abeta) pathology. Lithium is a medication for bipolar mood disorders. Its therapeutic mechanism of action remains unclear, in part because of the large number of biochemical effects attributed to lithium. Since lithium directly inhibits glycogen synthase kinase-3beta (GSK3beta), a key enzyme involved in tau phosphorylation, it was suggested that the therapeutic use of lithium could be expanded from mood disorders to neurodegenerative conditions. Lithium has been also reported to protect cultured neurons against Abeta toxicity, and to prevent NFTs accumulation and cognitive impairments in transgenic models of tauopathies. However, the exact mechanism of neuroprotection provided by lithium remains unknown. Here, we show that exposure of cultured cortical neurons to lithium decreased tau protein levels. This decrease was not linked to the activation of proteolytic processes including calpains, caspases and proteasome or to neuronal loss, but was rather associated with a reduction in tau mRNA levels. Moreover, prior exposure to lithium, at concentrations effective in reducing tau protein levels, markedly reduced pre-aggregated Abeta-induced neuronal apoptosis. Our findings raise the possibility that lithium could exert its neuroprotective effect against Abeta toxicity through the downregulation of tau proteins and that, at least, by acting at the level of tau mRNA.

Encephalopathy may accompany acute or chronic renal failure, and the mechanisms responsible for neurological complications in patients with renal failure are poorly known. Considering that creatine kinase (CK) is important for brain energy homeostasis and is inhibited by free radicals, and that oxidative stress is probably involved in the pathogenesis of uremic encephalopathy, we measured CK activity (hippocampus, striatum, cerebellum, cerebral cortex and prefrontal cortex) in brain if rats submitted to renal ischemia and the effect of administration of antioxidants (N-acetylcysteine, NAC and deferoxamine, DFX) on this enzyme. We verified that CK activity was not altered in cerebellum and striatum of rats. CK activity was inhibited in prefrontal cortex and hippocampus of rats 12h after renal ischemia. The treatment with antioxidants prevented such effect. Cerebral cortex was also affected, but in this area CK activity was inhibited 6 and 12h after renal ischemia. Moreover, only NAC or NAC plus DFX were able to prevent the inhibition on the enzyme. Although it is difficult to extrapolate our findings to the human condition, the inhibition of brain CK activity after renal failure may be associated to neuronal loss and may be involved in the pathogenesis of uremic encephalopathy.

Repeated exposure to nicotine induces adaptive changes in the central nervous system including the mesolimbic dopamine (DA) projections from the ventral tegmental area (VTA) to the nucleus accumbens (NAc). These modifications can modulate nicotine reward and reinforcement, but also anxiety and depression-related behaviors. The development of addiction-related phenotypes is known to be modulated by regulation of glutamate receptors, as well as activation of transcription factors including cAMP response element-binding protein (CREB), in the NAc. We investigated the effects of nicotine pre-exposure on nicotine preference and levels of GluR1/2 and CREB in the mesolimbic system in male mice C57BL/6J and BALB/c inbred mice. We also evaluated locomotor activity, anxiety-like and depression-like behaviors known to be affected by nicotine. There were few behavioral changes in mice subjected to chronic nicotine exposure, but there was a marked regulation of GluR2 in the mesolimbic system. Both treated and non-treated animals showed a significant preference for nicotine when facing a choice with a control solution. These results suggest that voluntary nicotine drinking induces nicotine preference in mice, but does not alter a number of affective behaviors. In addition, alterations in CREB and GluR1 levels are not sufficient to explain preference for nicotine in a 2-bottle choice paradigm.

The aim of this study was to investigate the effect of extremely low-frequency electromagnetic field (ELF-EMF) exposure during morphine treatment on dopamine D2 receptor (D2R) density in the rat dorsal hippocampus following withdrawal. Rats were exposed to ELF-EMF (20 Hz, 14 mT) or sham exposed for 1h per day before injection of morphine (10mg/kg, i.p.) once daily for 12 days. The saline control group was sham exposed for the same period. Immunohistochemistry was used to detect the density of D2Rs on the 1st, 3rd and 5th morphine withdrawal days. The results showed that the density of D2Rs in sham-exposed morphine-treated rats on the 1st and 3rd days of morphine withdrawal was significantly lower than that of the saline control group. The ELF-EMF-exposed morphine group also exhibited a significantly lower density of D2Rs on the 1st and 3rd withdrawal days relative to the sham-exposed morphine group. However, the D2R density in both groups tended to recover as morphine withdrawal days increased. The results suggest that dorsal hippocampal D2Rs are sensitive to morphine withdrawal and that this is potentiated by ELF-EMF pre-exposure during morphine treatment.

We used a complete spinal cord transection model in which the T8 spinal segment was removed to study the effect of combined treatment of peripheral nerve graft and application of FGF-1 on the glial environment. The combined treatment resulted in reduced astrocytic glial scarring, reactive macrophage gliosis, and inhibitory proteoglycan in the back-degenerated white matter tract. While the macrophage activities in the back-degenerative tract were down-regulated, those in the grafted peripheral nerves and in the distal Wallerian degenerative tracts were not. We concluded that the combined treatment changed the glial environment in the back-degenerative tract, and differentially regulated the macrophage activities in the system, in favor of CNS regeneration.

In this study we employed multiscale entropy (MSE) measurement to assess the long-range temporal correlation (LRTC) of multifibre renal sympathetic nerve activity (RSNA) signals in conscious and anaesthetized Wistar rats. It was found that both groups presented more complex MSE profiles than an uncorrelated process. Moreover, the results of MSE analysis of RSNA demonstrated that the entropy values, derived from the conscious group, increased on small time scales and then stabilized to a relatively constant value, however, the entropy measure, derived from animals with anaesthesia, almost monotonically decreased. The present study shows that while LRTC in the temporal dynamics of energy fluctuations of RSNA does not implicate a unique mechanism, the data for the first time provide evidence of much less temporal correlation in anaesthetized condition. This suggests the fractal properties of underlying dynamical system have been effectively eliminated by anaesthesia. These results demonstrate that apparently random fluctuations in multifibre RSNA are dictated by a complex deterministic process that imparts "long-term" memory to the dynamic system. However, this memory is significantly weakened by anaesthesia.

Although fragrances have long been known to influence stress-induced psychosomatic disorders, the neurophysiological mechanism remains unclear. We evaluated the effect of fragrance on the relation between the level of sebum secretion in the facial skin and the stress-induced prefrontal cortex (PFC) activity, which regulates the activity of the hypothalamic-pituitary-adrenal axis. Employing near infrared spectroscopy, we measured hemoglobin concentration changes in the bilateral PFC during a mental arithmetic task in normal adults (n=31), and evaluated asymmetry of the PFC activity in terms of the laterality index (i.e., [(right-left)/(right+left)]) of oxyhemoglobin concentration changes (LI-oxyHb). We measured the level of sebum secretion in the facial skin before the task performance. There was a significant positive correlation between the LI-oxyHb and the level of sebum secretion (r=+0.44, p=0.01). We selected the subjects who exhibited high levels of sebum secretion and right-dominant PFC activity for the study on the fragrance effect (n=12). Administration of fragrance for four weeks significantly reduced the level of sebum (p=0.02) in the fragrance group (n=6). In addition, the LI-oxyHb decreased significantly from 0.11+/-0.07 to -0.10+/-0.18 (p=0.01), indicating that the dominant side of the stress-induced PFC activity changed from the right to left side. In contrast, neither LI-oxyHb nor the levels of sebum secretion changed significantly in the control group (n=6). These results suggest that administration of fragrance reduced the level of sebum secretion by modulating the stress-induced PFC activity. The PFC may be involved in the neurophysiological mechanism of fragrance effects on systemic response to mental stress.

In the adult retina, N-methyl-D-aspartate (NMDA) neurotoxicity induces Müller cell reactive gliosis which is characterized by changes in gene expression that lead to proliferation and affect retinal physiology. The amino acid D-serine is synthesized in Müller cells and modulates these processes acting as a coagonist of NMDA receptors. We have found that the transcription factor DREAM (downstream regulatory element antagonist modulator), which acts as a transcriptional repressor by binding as a tetramer to regulatory elements located in the promoter region of target genes, is expressed in these cells and that its DNA-binding activity is modulated by NMDA receptor activation. Consistently, immunocytochemical analysis demonstrates that NMDA receptor activation induces changes in the nuclear localization of this transcription factor. DREAM is a pleiotropic transcription factor capable to repress and activate genes involved in several physiological events in different tissues. These results link, for the first time, this transcription factor with NMDA-receptor activation. Given the relevance of glutamatergic transmission in the retina and the remarkable functional plasticity of Müller cells, these findings support the notion that the NMDA receptor-dependent modulation of DREAM activity could play a role in relevant physiological processes ranging from retinal response to injury to differentiation capacity of retinal progenitor cells.

Sodium-dependent glutamate transporters expressed in astroglial cells and neurons are essential for clearance of extracellular glutamate. In the present study, we found elevation of extracellular glutamate concentration associated with concomitant downregulation of glutamate transporters following rat microsphere embolism (ME). A marked increase in extracellular glutamate in the rat striatum was observed by microdialysis immediately after ME induction, and glutamate remained elevated at least 12h after ischemia. Concomitantly, impairment of high KCl (146 mM)-induced glutamate release was observed in the striatum 12h after ME. Consistent with the persistent increase in extracellular glutamate, expression of the glutamate transporters EAAC1 and GLT-1 significantly decreased 6h after insult without a change in GLAST levels. GLT-1 expression was restored to basal levels within 48 h, whereas EAAC1 expression remained decreased up to at least 72 h after ME. Restoration of GLT-1 was associated with increased expression of the astroglial marker GFAP, whereas markedly reduced EACC1 levels were correlated with reduced levels of the neuronal marker MAP2, likely due to loss of vulnerable neurons. Taken together, downregulation of glutamate transporters after ME is associated with dysregulation of basal glutamate concentrations and KCl-induced glutamate release in the brain.

The fibroblast growth factor (FGF) system has previously been found to be altered in post-mortem brains of individuals with major depressive disorder (MDD). The present study tested whether the FGF system is altered following acute social defeat. Rats were exposed to four consecutive days of either a social defeat paradigm or novel cages. Animals were sacrificed after the last social defeat session and gene expression was assessed in the hippocampus by mRNA in situ hybridization. Molecular components of the FGF system were significantly downregulated following social defeat. Specifically, FGF2 and FGFR1 mRNA expression was decreased in various subfields of the hippocampus. Decreased tone of the FGF system following an acute social stressor is congruent with human post-mortem results of FGF system downregulation in depression. These findings suggest that modulating the FGF system may have therapeutic value in the treatment of MDD.

It has been reported that music may have physiological effects on blood pressure, cardiac heartbeat, respiration, and improve mood state in people affected by anxiety, depression and other psychiatric disorders. However, the physiological bases of these phenomena are not clear. Hypothalamus is a brain region involved in the regulation of body homeostasis and in the pathophysiology of anxiety and depression through the modulation of hypothalamic-pituitary-adrenal (HPA) axis. Hypothalamic functions are also influenced by the presence of the neurotrophins brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), which are proteins involved in the growth, survival and function of neurons in the central nervous system. The aim of this study was to investigate the effect of music exposure in mice on hypothalamic levels of BDNF and NGF. We exposed young adult mice to slow rhythm music (6h per day; mild sound pressure levels, between 50 and 60 dB) for 21 consecutive days. At the end of the treatment mice were sacrificed and BDNF and NGF levels in the hypothalamus were measured by enzyme-linked immunosorbent assay (ELISA). We found that music exposure significantly enhanced BDNF levels in the hypothalamus. Furthermore, we observed that music-exposed mice had decreased NGF hypothalamic levels. Our results demonstrate that exposure to music in mice can influence neurotrophin production in the hypothalamus. Our findings also suggest that physiological effects of music might be in part mediated by modulation of neurotrophins.

Parkinson's disease patients sometimes experience deterioration of motor function to below their baseline "off" state, termed the "super-off" state. We used low subthreshold (0.05 mg/kg) to threshold (0.10 and 0.20 mg/kg) doses of apomorphine to demonstrate the "super-off" state in MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-lesioned mice. Twenty-four mice were randomized to receive apomorphine or vehicle. Within 20 min of administration, 0.10 and 0.20 mg/kg apomorphine-treated mice had less locomotion than controls. At the 100 min time point, 0.10 mg/kg apomorphine-treated mice had greater locomotion than controls. One week of suprathreshold levodopa pretreatment did not alter the response to these low apomorphine doses. Our results suggest that low doses of apomorphine can initially depress locomotion and subsequently stimulate locomotion, in a manner similar to what is seen in Parkinson's disease patients.