bluuebunny/crossref_metadata_2025 huggingface dataset:
The effect of adding intrathecal magnesium sulphate to bupivacaine–fentanyl spinal anaesthesia
Authors: Özalevli M. , Cetin T. O. , Unlugenc H. , Guler T. , Isik G.
Published: July 2010

Background:  The addition of intrathecal (IT) magnesium to spinal fentanyl prolongs the duration of spinal analgesia for vaginal delivery. In this prospective, randomized, double‐blind, controlled study, we investigated the effect of adding IT magnesium sulphate to bupivacaine–fentanyl spinal anaesthesia.

Methods:  One hundred and two ASA I or II adult patients undergoing lower extremity surgery were recruited. They were randomly allocated to receive 1.0 ml of preservative‐free 0.9% sodium chloride (group S) or 50 mg of magnesium sulphate 5% (1.0 ml) (group M) following 10 mg of bupivacaine 0.5% plus 25 µg of fentanyl intrathecally. We recorded the following: onset and duration of sensory block, the highest level of sensory block, the time to reach the highest dermatomal level of sensory block and to complete motor block recovery and the duration of spinal anaesthesia.

Results:  Magnesium caused a delay in the onset of both sensory and motor blockade. The highest level of sensory block was significantly lower in group M than in group S at 5, 10 and 15 min (P < 0.001). The median time to reach the highest dermatomal level of sensory block was 17 min in group M and 13 min in group S (P < 0.05). The mean degree of motor block was also lower in group M at 5, 10 and 15 min (P < 0.001). The median duration of spinal anaesthesia was longer in group M (P < 0.001).

Conclusion:  In patients undergoing lower extremity surgery, the addition of IT magnesium sulphate (50 mg) to spinal anaesthesia induced by bupivacaine and fentanyl significantly delayed the onset of both sensory and motor blockade, but also prolonged the period of anaesthesia without additional side‐effects.
Prevalence and causative fungal species of tinea capitis among schoolchildren in Gabon
Authors: Hogewoning A. A. , Adegnika A. A. , Bouwes Bavinck J. N. , Yazdanbakhsh M. , Kremsner P. G. , van der Raaij‐Helmer E. M. H. , Staats C. C. G. , Willemze R. , Lavrijsen A. P. M.
Published: July 2010

Tinea capitis is endemic among schoolchildren in tropical Africa. The objective was to determine the prevalence of symptomatic tinea capitis in schoolchildren in Gabon. A cross‐sectional study was conducted with 454 children aged 4–17 years, attending a rural school and an urban school. The diagnosis of tinea capitis was based on clinically manifest infection, direct microscopic examination using 20% potassium hydroxide (KOH) solution and fungal culture. Based on clinical examination, 105 (23.1%) of 454 children had tinea capitis. Seventy‐four (16.3%) children were positive by direct examination (KOH) and/or fungal culture. The prevalence of tinea capitis depended on the school studied and ranged from 20.4% in the urban school with a higher socioeconomic status to 26.3% in the rural school with a lower socioeconomic status. Similarly, the spectrum of causative species varied between the different schools. Taken the schools together, Trichophyton soudanense (29.4%) was the most prominent species, followed by Trichophyton tonsurans (27.9%) and Microsporum audouinii (25.0%). Clinically manifest tinea capitis is endemic among schoolchildren in the Lambaréné region in Gabon. The prevalence of tinea capitis and the causative species depended on the type of school that was investigated.
Cure rate, duration required for complete cure and recurrence rate of onychomycosis according to clinical factors in Korean patients
Authors: Ko Joo Yeon , Lee Ha Eun , Jae Hur , Oh Dae Heon , Kim Joung Soo , Yu Hee Joon
Published: July 2010

Many factors affect the cure rate (CR), duration required for complete cure (DC) and the recurrence rate (RR) of onychomycosis. The aim of this study was to evaluate the CR, DC and RR in onychomycosis according to various clinical factors. We retrospectively reviewed medical records of 637 Korean patients with onychomycosis between December 2000 and December 2006. We examined six clinical factors to evaluate the effects on the CR, DC and RR: age, sex, clinical type, treatment pattern, presence of diabetes mellitus (DM) and the extent of nail involvement. On the view of the clinical nail appearance and potassium hydroxide (KOH) preparation, we designated the CR, DC and RR. In addition, we examined the differences in the CR, DC and RR in terms of the above‐mentioned clinical factors. A total of 207 eligible patients were finally analysed. The CR as a whole was 78.3%, the DC was 31.7 ± 18.4 weeks and the RR was 36.0%. There were significant differences in the CR, DC and RR according to the extent of nail involvement. Age affects the CR and DC, and DM also affects the DC and RR. We found that the extent of nail involvement, age and DM affect the CR, DC and RR of onychomycosis.
Redox regulation, gene expression and longevity
Authors: Honda Yoko , Tanaka Masashi , Honda Shuji
Published: July 2010

Lifespan can be lengthened by genetic and environmental modifications. Study of these might provide valuable insights into the mechanism of aging. Low doses of radiation and short‐term exposure to heat and high concentrations of oxygen prolong the lifespan of the nematode Caenorhabditis elegans. These might be caused by adaptive responses to harmful environmental conditions. Single‐gene mutations have been found to extend lifespan in C. elegans, Drosophila and mice. So far, the best‐characterized system is the C. elegans mutant in the daf‐2, insulin/IGF‐I receptor gene that is the component of the insulin/IGF‐I signaling pathway. The mutant animals live twice as long as the wild type. The insulin/IGF‐I signaling pathway regulates the activity of DAF‐16, a FOXO transcription factor. However, the unified explanation for the function of DAF‐16 transcription targets in the lifespan extension is not yet fully established. As both of the Mn superoxide dismutase (MnSOD) isoforms (sod‐2 and sod‐3) are found to be targets of DAF‐16, we attempted to assess their functions in regulating lifespan and oxidative stress responsivity. We show that the double deletions of sod‐2 and sod‐3 genes induced oxidative‐stress sensitivity but do not shorten lifespan in the daf‐2 mutant background, indicating that oxidative stress is not necessarily a limiting factor for longevity. Furthermore, the deletion in the sod‐3 gene lengthens lifespan in the daf‐2 mutant. We conclude that the MnSOD systems in C. elegans fine‐tune the insulin/IGF‐I‐signaling based regulation of longevity by acting not as anti‐oxidants but as physiological‐redox‐signaling modulators. Geriatr Gerontol Int 2010; 10 (Suppl. 1): S59–S69.
CB1 receptor‐mediated control of the release of endocannabinoids (as assessed by microdialysis coupled with LC/MS) in the rat hypothalamus
Authors: Béquet Frédéric , Uzabiaga Françoise , Desbazeille Mathieu , Ludwiczak Pascal , Maftouh Mohamed , Picard Claudine , Scatton Bernard , Le Fur Gerard
Published: July 2010

In the present study, we examined the occurrence and potential regulation of endocannabinoid release by cannabinoid CB1 receptors in the rat brain. To this end, we developed a highly sensitive (limit of sensitivity 30–300 amol) new analytical method, combining online brain microdialysis with solid‐phase extraction–liquid chromatography–tandem mass spectrometry, which allowed the detection in real time of trace amounts of endocannabinoids in the extracellular fluid. In the hypothalamus, anandamide and 2‐arachidonoyl‐glycerol release was stimulated following depolarization via local administration of K+, with or without addition of Ca2+, or glutamate application. Inhibition of fatty acid amide hydrolase by systemic administration of intraperitoneal (i.p.) URB597 (0.5 mg/kg) induced an increase of anandamide, but not 2‐arachidonoyl‐glycerol, outflow. The CB1 receptor antagonist rimonabant (10 mg/kg i.p.) increased, whereas the CB1 agonist WIN55,212‐2 (2.5 mg/kg i.p.) decreased, anandamide release. Interestingly, the same treatments induced opposite changes in 2‐arachidonoyl‐glycerol release. At a dose of 3 mg/kg i.p., which by itself did not affect endocannabinoid release, rimonabant fully antagonized the effect of WIN55,212‐2 (2.5 mg/kg i.p.). Taken together, these results suggest that CB1 receptors are able to control the local release of endocannabinoids in the hypothalamus via a feedback mechanism and strengthen the view that anandamide and 2‐arachidonoyl‐glycerol have distinct physiological roles.
Calpain‐mediated cleavage of collapsin response mediator protein(CRMP)‐2 during neurite degeneration in mice
Authors: Touma Ekatherina , Kato Satoko , Fukui Koji , Koike Tatsuro
Published: July 2010

Axon or dendrite degeneration involves activation of the ubiquitin–proteasome system, failure to maintain neuritic ATP levels, microtubule fragmentation and a mitochondrial permeability transition that occur independently of the somal death programs. To gain further insight into the neurite degeneration mechanims we have compared two‐dimensional gel electrophoresis patterns of neurite proteins from suprior cervical ganglia during degeneration caused by nerve growth factor (NGF) deprivation. We show here that collapsin response mediator protein (CRMP)‐2 and CMRP‐4 protein patterns were altered during beading formation, an early hallmark of neurite degeneration, prior to neurite fragmentation, the final stage of degeneration. Western blotting using a monoclonal antibody against CRMP‐2 shows that the native form (64 kDa) was cleaved to generate a truncated form (58 kDa). No cleavage of CRMP‐2 or ‐4 occurred in NGF‐deprived neurites from Wld s (Wallerian degeneration slow) mutant mice in which neurite degeneration is markedly delayed. Using different protease inhibitors, purified calpain 1 protein and calpain 1‐specific siRNA, we have demonstrated that CRMP‐2 is a substrate for calpain 1. Indeed, caplain activity was activated at an early phase of neuronal degeneration in cerebellar granule neurons, and down‐regulation of caplain 1 expression suppressed CRMP‐2 cleavage. Furthermore, this cleavage occurred after vinblastine treatment or in vitro Wallerian degeneration, suggesting that it represents a common step in the process of dying neurites. CRMP‐2 and ‐4 play a pivotal role in axonal growth and transport, and the C‐terminus region of CRMP‐2 is essential for its binding to kinesin‐1. Hence, this cleavage will render them dysfunctional and subject to autophagic processing associated with beading formation, as evidenced by the finding that the truncated form was localized in the beadings.
Monocular deprivation reduces reliability of visual cortical responses to binocular disparity stimuli
Authors: Vorobyov Vasily , Schwarzkopf D. Samuel , Mitchell Donald E. , Sengpiel Frank
Published: July 2010

While continuous monocular deprivation (MD) of patterned vision causes severe loss of visual cortical responses and visual acuity in the affected eye, these effects can be avoided by providing brief daily periods of binocular exposure [BE; D.E. Mitchell et al. (2003) Curr. Biol., 8, 1179–1182; D.E. Mitchell et al. (2006) Eur. J. Neurosci., 23, 2458–2466; D.S. Schwarzkopf et al. (2007) Eur. J. Neurosci., 25, 270–280]. In order to analyse binocular mechanisms involved in this phenomenon, we studied neuronal responses in primary visual cortex to binocular disparity stimuli in cats that had experienced mixed daily visual exposure (i.e. different amounts of daily binocular and monocular exposure). To examine whether binocular responses are as reliable in MD as in normal animals, we analysed single‐trial responses to spatial phase disparity stimuli. In cats with various amounts of daily binocular experience (3.5 h, 7 h or 12 h) alone, about half of neurons (47.9%) showed reliable phase‐specific binocular responses in two consecutive trials. The percentage of phase‐selective cells was reduced in cats with mixed visual exposure with a decrease in the duration of daily BE. Within these neurons, a ‘stable’ cell population, i.e. with identical relative phases eliciting the strongest and weakest responses in two trials, was also reduced. In other words, the responses of neurons recorded from deprived animals were more likely to show different preferred phases on successive trials, although their amplitude ratios in both trials were about equal. We suggest that the detrimental effect of MD on binocular vision may begin, at least in part, with a subtle disruption of the mechanism involved in discrimination of binocular disparity signals.
X chromosome‐linked inhibitor of apoptosis protein reduces oxidative stress after cerebral irradiation or hypoxia‐ischemia through up‐regulation of mitochondrial antioxidants
Authors: Zhu Changlian , Xu Falin , Fukuda Aya , Wang Xiaoyang , Fukuda Hirotsugu , Korhonen Laura , Hagberg Henrik , Lannering Birgitta , Nilsson Michael , Eriksson Peter S. , Northington Frances J. , Björk‐Eriksson Thomas , Lindholm Dan , Blomgren Klas
Published: July 2010

We demonstrate that X chromosome‐linked inhibitor of apoptosis protein (XIAP) counteracts oxidative stress in two essentially different disease‐related models of brain injury, hypoxia‐ischemia and irradiation, as judged by lower expression of nitrotyrosine (5‐fold) and 4‐hydroxy‐2‐nonenal (10‐fold) in XIAP‐overexpressing compared with wild‐type mice. XIAP overexpression induced up‐regulation of at least three antioxidants residing in mitochondria, superoxide dismutase 2, thioredoxin 2 and lysine oxoglutarate reductase. Cytochrome c release from mitochondria was reduced in XIAP‐overexpressing mice. Hence, in addition to blocking caspases, XIAP can regulate reactive oxygen species in the brain, at least partly through up‐regulation of mitochondrial antioxidants. XIAP‐induced prevention of oxidative stress was not secondary to tissue protection because although XIAP overexpression provides tissue protection after hypoxia‐ischemia, it does not prevent tissue loss after irradiation. This is a previously unknown role of XIAP and may provide the basis for development of novel protective strategies for both acute and chronic neurodegenerative diseases, where oxidative stress is an integral component of the injury mechanisms involved.
The transcriptional corepressor TPA‐inducible sequence 7 regulates adult axon growth through cellular retinoic acid binding protein II expression
Authors: Dieplinger Benjamin , Schiefermeier Natalia , Juchum‐Pasquazzo Michaela , Gstir Ronald , Huber Lukas A. , Klimaschewski Lars , Vietor Ilja
Published: July 2010

TPA‐inducible sequence 7 (TIS7) expression is regulated in epithelial cells and acts as a transcriptional corepressor. Using a TIS7 knock‐out mouse we demonstrated that TIS7 is involved in the process of muscle regeneration. In this study, we analysed the role of TIS7 in axon regeneration, applying primary neurone cultures derived from adult dorsal root ganglia (DRGs) of TIS7+/+ and TIS7–/– mice. TIS7–/– DRG neurones exhibited a significant decrease in axon initiation and maximal axon extension. In contrast, nerve growth factor‐induced axon initiation and branching were significantly enhanced in cultures obtained from TIS7–/– DRGs when compared with wildtype ganglia, suggesting an inhibitory effect of TIS7 on nerve growth factor‐stimulated axon growth. TIS7 overexpression in TIS7–/– DRG neurones caused their morphological appearance to revert back to the wildtype phenotype. Furthermore, the expression of cellular retinoic acid binding protein II (CRABP II), previously identified by us as a TIS7 target gene, was up‐regulated in adult DRG sensory neurones from TIS7–/– mice. Overexpression of CRABP II in TIS7+/+ neurones strongly increased the number of branch points, making them morphologically similar to TIS7–/– neurones. Based on these results we propose that TIS7 inhibits CRABP II expression during axonal regeneration, thereby modulating retinoic acid signalling. Hence, neurite initiation and branching are regulated by a negative feedback mechanism involving TIS7 and CRABP II.
Site‐specific effects of tau phosphorylation on its microtubule assembly activity and self‐aggregation
Authors: Liu Fei , Li Bin , Tung E‐Jan , Grundke‐Iqbal Inge , Iqbal Khalid , Gong Cheng‐Xin
Published: July 2010

Microtubule‐associated protein tau is abnormally hyperphosphorylated and aggregated into neurofibrillary tangles in brains with Alzheimer's disease. The phosphorylation sites of tau are mainly localized in the proline‐rich (residues 172–251) and C‐terminal tail (residues 368–441) regions, which flank the microtubule‐binding repeats. Here, we investigated the effects of tau phosphorylation at these distinct sites/regions on its activity of stimulating microtubule assembly and its self‐aggregation. We found that tau phosphorylation at the proline‐rich region by dual‐specificity tyrosine‐phosphorylated and ‐regulated kinase 1A inhibited its microtubule assembly activity moderately and promoted its self‐aggregation slightly. Tau phosphorylation at the C‐terminal tail region by glycogen synthase kinase‐3β increased its activity and promoted its self‐aggregation markedly. Tau phosphorylation at both regions plus the microtubule‐binding region by cAMP‐dependent protein kinase diminished its activity (∼70% inhibition) and disrupted microtubules. These studies reveal the differential regulation of tau's biological activity and self‐aggregation by phosphorylation at various sites/regions.
Olfactory bulb hypoplasia in Prokr2 null mice stems from defective neuronal progenitor migration and differentiation
Authors: Prosser Haydn M. , Bradley Allan , Caldwell Maeve A.
Published: July 2010

New neurons are added on a daily basis to the olfactory bulb (OB) of a mammal, and this phenomenon exists throughout its lifetime. These new cells are born in the subventricular zone and migrate to the OB via the rostral migratory stream (RMS). To examine the role of the prokineticin receptor 2 (Prokr2) in neurogenesis, we created a Prokr2 null mouse, and report a decrease in the volume of its OB and also a decrease in the number of bromodeoxyuridine (BrdU)‐positive cells. There is disrupted architecture of the OB, with the glomerular layer containing terminal dUTP nick‐end labeling (TUNEL) ‐positive nuclei and also a decrease in tyrosine hydroxylase‐positive neurons in this layer. In addition, there are increased numbers of doublecortin‐positive neuroblasts in the RMS and increased PSA‐NCAM (polysialylated form of the neural cell adhesion molecule) ‐positive neuronal progenitors around the olfactory ventricle, indicating their detachment from homotypic chains is compromised. Finally, in support of this, Prokr2‐deficient cells expanded in vitro as neurospheres are incapable of migrating towards a source of recombinant human prokineticin 2 (PROK2). Together, these findings suggest an important role for Prokr2 in OB neurogenesis.
Developmental changes in the BDNF‐induced modulation of inhibitory synaptic transmission in the Kölliker–Fuse nucleus of rat
Authors: Kron Miriam , Zhang Weiqi , Dutschmann Mathias
Published: July 2010

The Kölliker–Fuse nucleus (KF), part of the pontine respiratory group, is involved in the control of respiratory phase duration, and receives both excitatory and inhibitory afferent input from various other brain regions. There is evidence for developmental changes in the modulation of excitatory inputs to the KF by the neurotrophin brain‐derived neurotrophic factor (BDNF). In the present study we investigated if BDNF exerts developmental effects on inhibitory synaptic transmission in the KF.

Recordings of inhibitory postsynaptic currents (IPSCs) in KF neurons in a pontine slice preparation revealed general developmental changes. Recording of spontaneous and evoked IPSCs (sIPSCs, eIPSCS) revealed that neonatally the γ‐aminobutyric acid (GABA)ergic fraction of IPSCs was predominant, while in later developmental stages glycinergic neurotransmission significantly increased. Bath‐application of BDNF significantly reduced sIPSC frequency in all developmental stages, while BDNF‐mediated modulation on eIPSCs showed developmental differences. The eIPSCs mean amplitude was uniformly and significantly reduced following BDNF application only in neurons from rats younger than postnatal day 10. At later postnatal stages the response pattern became heterogeneous, and both augmentations and reductions of eIPSC amplitudes occurred. All BDNF effects on eIPSCs and sIPSCs were reversed with the tyrosine kinase receptor‐B inhibitor K252a.

We conclude that developmental changes in inhibitory neurotransmission, including the BDNF‐mediated modulation of eIPSCs, relate to the postnatal maturation of the KF. The changes in BDNF‐mediated modulation of IPSCs in the KF may have strong implications for developmental changes in synaptic plasticity and the adaptation of the breathing pattern to afferent inputs.
Short light–dark cycles affect sleep in mice
Authors: Deboer Tom , Ruijgrok Guido , Meijer Johanna H.
Published: July 2010

Environmental light has a strong impact on human physiology and behaviour, including cognitive functioning and alertness. Previous studies have shown that short light–dark (LD) cycles influence sleep in the albino rat. Rapid eye movement (REM) sleep increases after the onset of darkness and increases after light onset. In the present study, we investigated whether light affects sleep in mice. To this purpose the electroencephalogram and electromyogram of nine adult male C57BL/6 mice was recorded under 12 : 12 h baseline LD conditions, followed by 24 h continuous darkness (DD) and 6 days with LD cycles of different durations (2 h, 30 min, 14 min, 10 min, 4 min and 2 min), presented in a randomized order. NREM sleep was evenly distributed over the light and dark intervals of all short LD cycles. REM sleep, however, was increased during the dark intervals of short (10–30 min) LD cycles. Analysis showed that in these LD cycles, the increment in REM sleep was maximal in the second minute after dark onset, where the percentage of epochs with REM sleep increased significantly to 175% of baseline values. This increase was attributable to an increase in REM sleep episode duration. The recorded responses show that sleep in mice is affected by photic stimulation. The results demonstrate that pigmented animals can show REM sleep induction after dark onset and indicate that light has significant effects on the regulation of sleep.
Complement activation contributes to leukocyte recruitment and neuropathic pain following peripheral nerve injury in rats
Authors: Li Man , Peake Philip W. , Charlesworth John A. , Tracey David J. , Moalem‐Taylor Gila
Published: July 2010

Complement activation triggers inflammation and has been implicated in neurological diseases associated with pain. However, the role of complement in neuropathic pain has not been clearly defined. In this study, we tested whether complement is activated by partial ligation of the rat sciatic nerve, a widely used model of neuropathic pain, and whether complement activation or inhibition in peripheral nerve influences leukocyte recruitment and neuropathic pain. We found that C3 deposition significantly increased from 6 h to 7 days in the injured nerve and was associated with the extent of thermal hyperalgesia and mechanical allodynia. However, no deposition of the membrane attack complex was detected. Complement activation by endoneurial injection of aggregated rat immunoglobulin G into normal sciatic nerve produced significant thermal hyperalgesia and mechanical allodynia of the ipsilateral hindpaw at 2–7 days after injection. This was accompanied by increased deposition of C3 and recruitment of macrophages at 7 days following injection. Complement inhibition using systemic injections of soluble complement receptor 1 (AVANT Immunotherapeutics, Inc., Needham, USA) into rats markedly suppressed C3 deposition and T‐cell and macrophage recruitment to the injured nerve, and produced significant alleviation of thermal hyperalgesia and mechanical allodynia. These results demonstrate that C3 activation in the nerve contributes to increased infiltration of inflammatory cells and to neuropathic pain behaviors following peripheral nerve injury. Complement inhibition may be a potential therapeutic treatment for neuropathic pain.
Effect of minocycline on inflammation‐induced damage to the blood–brain barrier and white matter during development
Authors: Stolp H. B. , Ek C. J. , Johansson P. A. , Dziegielewska K. M. , Potter A. M. , Habgood M. D. , Saunders N. R.
Published: July 2010

Damage to white matter in some premature infants exposed to intrauterine infections is thought to involve disruption of the blood–brain barrier. We have examined the effect of minocycline, an agent reported to reduce brain damage resulting from inflammation, on inflammation‐induced disruption of the blood–brain barrier and damage to white matter. Post‐natal marsupial opossums (Monodelphis domestica) were studied as most brain development in this species occurs after birth. Single intraperitoneal lipopolysaccharide (LPS) injection (0.2 mg/kg) with or without minocycline (45 mg/kg) at post‐natal day (P)35 caused short‐lasting barrier breakdown to plasma proteins but not to 14C‐sucrose. By P44, blood–brain barrier integrity was intact but a reduced volume of white matter was present. At P44 after prolonged inflammation (5 × 0.2 mg/kg LPS at 48 h intervals), proteins from blood were observed within brain white matter and permeability to 14C‐sucrose in the hindbrain increased by 31%. The volume of the external capsule and the proportion of myelin were 70 and 57%, respectively, of those in control animals. Minocycline administered during prolonged inflammation restored blood–brain barrier integrity but not LPS‐induced damage to white matter. These data suggest that long‐term changes in blood–brain barrier permeability occur only after a prolonged period of inflammation during development; however, damage to white matter can result from even a short‐lasting breakdown of the barrier. Manipulation of the inflammatory response may have implications for prevention of some developmentally induced neurological conditions.
Insulin and IGF‐1 enhance the expression of the neuronal monocarboxylate transporter MCT2 by translational activation via stimulation of the phosphoinositide 3‐kinase–Akt–mammalian target of rapamycin pathway
Authors: Chenal Julie , Pierre Karin , Pellerin Luc
Published: July 2010

MCT2 is the main neuronal monocarboxylate transporter essential for facilitating lactate and ketone body utilization as energy substrates. Our study reveals that treatment of cultured cortical neurons with insulin and IGF‐1 led to a striking enhancement of MCT2 immunoreactivity in a time‐ and concentration‐dependent manner. Surprisingly, neither insulin nor IGF‐1 affected MCT2 mRNA expression, suggesting that regulation of MCT2 protein expression occurs at the translational rather than the transcriptional level. Investigation of the putative signalling pathways leading to translation activation revealed that insulin and IGF‐1 induced p44‐ and p42 MAPK, Akt and mTOR phosphorylation. S6 ribosomal protein, a component of the translational machinery, was also strongly activated by insulin and IGF‐1. Phosphorylation of p44‐ and p42 MAPK was blocked by the MEK inhibitor PD98058, while Akt phosphorylation was abolished by the PI3K inhibitor LY294002. Phosphorylation of mTOR and S6 was blocked by the mTOR inhibitor rapamycin. In parallel, it was observed that LY294002 and rapamycin almost completely blocked the effects of insulin and IGF‐1 on MCT2 protein expression, whereas PD98059 and SB202190 (a p38K inhibitor) had no effect on insulin‐induced MCT2 expression and only a slight effect on IGF‐1‐induced MCT2 expression. At the subcellular level, a significant increase in MCT2 protein expression within an intracellular pool was observed while no change at the cell surface was apparent. As insulin and IGF‐1 are involved in synaptic plasticity, their effect on MCT2 protein expression via an activation of the PI3K–Akt–mTOR–S6K pathway might contribute to the preparation of neurons for enhanced use of nonglucose energy substrates following altered synaptic efficacy.
Preoptic neuronal nitric oxide synthase induction by testosterone is consistent with a role in gating male copulatory behavior
Authors: Sanderson Nicholas S. R. , Le Brandon , Zhou Zifei , Crews David
Published: July 2010

Copulatory behaviors are generally dependent on testicular androgens in male vertebrates, being eliminated by castration and re‐instated by testosterone administration. It is postulated that a critical factor in this hormonal gating is up‐regulation of neuronal nitric oxide synthase (nNOS) in the preoptic area, and consequent enhanced nitric oxide synthesis in response to stimuli associated with a receptive female. Previous studies have suggested that nNOS protein is more abundant in behaviorally relevant preoptic regions of testosterone‐exposed animals than in hormone‐deprived controls. This study sought to elucidate the molecular events underlying this apparent up‐regulation by examining preoptic nNOS mRNA abundance at several time points following testosterone administration in a castration and replacement paradigm. Castrated male whiptails (Cnemidophorus inornatus) were implanted with testosterone, and at four time points over the subsequent 18 days their sexual behavior was tested. A rostral periventricular area previously implicated in hormonal gating of male‐typical copulatory behavior was then excised by laser microdissection, and nNOS transcript abundance was assessed by quantitative PCR. As neither this technique nor nNOS mRNA measurements have previously been performed in this area of the brain, expression was concommitantly assayed on adjacent sections by in situ hybridization or NADPH diaphorase histochemistry. Results are consistent with transcriptional up‐regulation of nNOS by testosterone and a central role for the enzyme in mediating hormonal gating of copulatory behavior.
Reduced saccadic resilience and impaired saccadic adaptation due to cerebellar disease
Authors: Golla Heidrun , Tziridis Konstantin , Haarmeier Thomas , Catz Nicolas , Barash Shabtai , Thier Peter
Published: July 2010

The term short‐term saccadic adaptation (STSA) captures our ability to unconsciously move the endpoint of a saccade to the final position of a visual target that has jumped to a new location during the saccade. STSA depends on the integrity of the cerebellar vermis. We tested the hypothesis that STSA reflects the working of a cerebellar mechanism needed to avoid ‘fatigue’, a gradual drop in saccade amplitude during a long series of stereotypic saccades. To this end we compared the kinematics of saccades of 14 patients suffering from different forms of cerebellar disease with those of controls in two tests of STSA and a test of saccadic resilience. Controls showed an increase in saccade amplitude (SA) for outward adaptation, prompted by outward target shifts, due to an increase in saccade duration (SD) in the face of constant peak velocity (PV). The decrease in SA due to inward adaptation was, contrariwise, accompanied by a drop in PV and SD. Whereas patients with intact vermis did not differ from controls, those with vermal pathology lacked outward adaptation: SD remained constant, as did SA and PV. In contrast, vermal patients demonstrated a significant decrease in SA, paralleled by a decrease in PV but mostly unaltered SD in the inward adaptation experiment as well as in the resilience test. These findings support the notion that inward adaptation is at least partially based on uncompensated fatigue. On the other hand, outward adaptation reflects an active mechanism for the compensation of fatigue, residing in the cerebellum.
A cell adhesion molecule mimetic, FGL peptide, induces alterations in synapse and dendritic spine structure in the dentate gyrus of aged rats: a three‐dimensional ultrastructural study
Authors: Popov Victor I. , Medvedev Nikolay I. , Kraev Igor V. , Gabbott Paul L. , Davies Heather A. , Lynch Marina , Cowley Thelma R. , Berezin Vladimir , Bock Elisabeth , Stewart Michael G.
Published: July 2010

The FGL peptide is a neural cell adhesion molecule (NCAM) mimetic comprising a 15‐amino‐acid‐long sequence of the FG loop region of the second fibronectin type III module of NCAM. It corresponds to the binding site of NCAM for the fibroblast growth factor receptor 1. FGL improves cognitive function through enhancement of synaptic function. We examined the effect of FGL on synaptic and dendritic structure in the brains of aged (22‐month‐old) rats that were injected subcutaneously (8 mg/kg) at 2‐day intervals until 19 days after the start of the experiment. Animals were perfused with fixative, brains removed and coronal sections cut at 50 µm. The hippocampal volume was measured, tissue embedded and ultrathin sections viewed in a JEOL 1010 electron microscope. Analyses were made of synaptic and dendritic parameters following three‐dimensional reconstruction via images from a series of ∼100 serial ultrathin sections. FGL affected neither hippocampal volume nor spine or synaptic density in the middle molecular layer of the dentate gyrus. However, it increased the ratio of mushroom to thin spines, number of multivesicular bodies and also increased the frequency of appearance of coated pits. Three‐dimensional analysis showed a significant decrease in both post‐synaptic density and apposition zone curvature of mushroom spines following FGL treatment, whereas for thin spines the convexity of the apposition zone increased. These data indicate that FGL induces large changes in the fine structure of synapses and dendritic spines in hippocampus of aged rats, complementing data showing its effect on cognitive processes.
The glutamate receptor 2 subunit controls post‐synaptic density complexity and spine shape in the dentate gyrus
Authors: Medvedev Nikolay I. , Rodríguez‐Arellano José J. , Popov Victor I. , Davies Heather A. , Tigaret Cezar M. , Schoepfer Ralf , Stewart Michael G.
Published: July 2010

In adult brain the majority of AMPA glutamate receptor (GluR) subunits contain GluR2. In knock‐out (KO) mice the absence of GluR2 results in consequences for synaptic plasticity including cognitive impairments. Here the morphology of dendritic spines and their synaptic contacts was analysed via three‐dimensional reconstruction of serial electron micrographs from dentate gyrus (DG) of adult wild type (WT) and GluR2 KO mice. Pre‐embedding immunocytochemical staining was used to examine the distribution and subcellular localization of AMPA receptor GluR1 and N‐methyl‐d‐aspartate receptor NR1 subunits. There were no significant changes in synapse density in the DG of GluR2 KO compared with WT mice. However, in GluR2 KO mice there was a significant decrease in the percentage of synapses on mushroom spines but an increase in synapses on thin spines. There was also a large decrease in the proportion of synapses with complex perforated/segmented post‐synaptic densities (PSDs) (25 vs. 78% in WT) but an increase in synapses with macular PSDs (75 vs. 22%). These data were coupled in GluR2 KO mice with significant decreases in volume and surface area of mushroom spines and their PSDs. In both GluR2 KO and WT mice, NR1 and GluR1 receptors were present in dendrites and spines but there was a significant reduction in NR1 labelling of spine membranes and cytoplasm in GluR2 KO mice, and a small decrease in GluR1 immunolabelling in membranes and cytoplasm of spines in GluR2 KO compared with WT mice. Our data demonstrate that the absence of GluR2 has a significant effect on both DG synapse and spine cytoarchitecture and the expression of NR1 receptors.
PPARγ agonist pioglitazone rescues neuronal cell damage after transient global cerebral ischemia through matrix metalloproteinase inhibition
Authors: Lee Kyung‐Jae , Jang Young‐Ho , Lee Hyung , Yoo Ho‐Sang , Lee Seong‐Ryong
Published: July 2010

Previous studies have demonstrated that pioglitazone, a peroxisome proliferator‐activated receptor gamma (PPARγ) agonist, inhibits ischemia‐induced injury in various tissues including neural tissue. Pioglitazone has also been shown to reduce matrix metalloproteinase (MMP) activity. Because MMP is known to play a major role in the pathophysiology of brain ischemia, the present study was undertaken to test whether pioglitazone attenuates ischemic neuronal damage through MMP inhibition. C57BL/6 mice were subjected to global brain ischemia for 20 min. Animals were killed 72 h after ischemia. Oral pioglitazone (40 mg/kg/day, as a suspension in 0.5% carboxymethylcellulose) was administered to mice twice daily for 3 days before ischemia and twice daily after ischemia until the animals were killed. We investigated gelatinase activity by zymography and laminin immunohistochemistry. Histological analysis was also performed to test the protective effect of pioglitazone on neuronal damage. Mice treated with pioglitazone had attenuated gelatinase activity. Gelatin gel and in situ zymography showed up‐regulation of gelatinase activity after ischemia. Pioglitazone significantly inhibited ischemia‐induced elevation of the active form of MMP‐9. Pioglitazone also reduced up‐regulation of in situ gelatinase activity and laminin breakdown induced by ischemia in the hippocampus. There was marked neuronal damage in the CA1 and CA2 areas after ischemia. Neuronal damage in mice was significantly decreased by pioglitazone treatment, compared with vehicle‐treated mice. Pioglitazone also inhibited TdT‐mediated dUTP nick end labeling staining in CA1 and CA2 areas. Pioglitazone, a PPARγ agonist, reduces delayed neuronal damage induced by global ischemia through inhibition of MMP‐9 activity.
Interaction of visual hemifield and body view in biological motion perception
Authors: De Lussanet Marc H. E. , Fadiga Luciano , Michels Lars , Seitz Rüdiger J. , Kleiser Raimund , Lappe Markus
Published: July 2010

The brain network for the recognition of biological motion includes visual areas and structures of the mirror‐neuron system. The latter respond during action execution as well as during action recognition. As motor and somatosensory areas predominantly represent the contralateral side of the body and visual areas predominantly process stimuli from the contralateral hemifield, we were interested in interactions between visual hemifield and action recognition. In the present study, human participants detected the facing direction of profile views of biological motion stimuli presented in the visual periphery. They recognized a right‐facing body view of human motion better in the right visual hemifield than in the left; and a left‐facing body view better in the left visual hemifield than in the right. In a subsequent fMRI experiment, performed with a similar task, two cortical areas in the left and right hemispheres were significantly correlated with the behavioural facing effect: primary somatosensory cortex (BA 2) and inferior frontal gyrus (BA 44). These areas were activated specifically when point‐light stimuli presented in the contralateral visual hemifield displayed the side view of their contralateral body side. Our results indicate that the hemispheric specialization of one's own body map extends to the visual representation of the bodies of others.
The axon‐guidance roundabout gene alters the pace of the Drosophila circadian clock
Authors: Berni Jimena , Beckwith Esteban J. , Fernández María Paz , Ceriani María Fernanda
Published: July 2010

Great efforts have been directed to the dissection of the cell‐autonomous circadian oscillator in Drosophila. However, less information is available regarding how this oscillator controls rhythmic rest–activity cycles. We have identified a viable allele of roundabout, robohy, where the period of locomotor activity is shortened. From its role in axon‐pathfinding, we anticipated developmental defects in clock‐relevant structures. However, robohy produced minor defects in the architecture of the circuits essential for rhythmic behaviour. ROBO's presence within the circadian circuit strengthened the possibility of a novel role for ROBO at this postdevelopmental stage. Genetic interactions between pdf 01 and robohy suggest that ROBO could alter the communication within different clusters of the circadian network, thus impinging on two basic properties, periodicity and/or rhythmicity. Early translocation of PERIOD to the nucleus in robohy pacemaker cells indicated that shortened activity rhythms were derived from alterations in the molecular oscillator. Herein we present a mutation affecting clock function associated with a molecule involved in circuit assembly and maintenance.
Depolarization promotes GAD 65‐mediated GABA synthesis by a post‐translational mechanism in neural stem cell‐derived neurons
Authors: Gakhar‐Koppole Nidhi , Bengtson C. Peter , Parlato Rosanna , Horsch Kerstin , Eckstein Volker , Ciccolini Francesca
Published: July 2010

Neuronal activity regulates neurogenesis and neuronal differentiation in the mammalian brain. The commencement of neurotransmitter expression establishes the neuronal phenotype and enables the formation of functional connectivity between neurons. In addition, release of neurotransmitters from differentiating neurons may modulate the behaviour of neural precursors. Here, we show that neuronal activity regulates γ‐aminobutyric acid (GABA) expression in neurons generated from stem cells of the striatum and adult subventricular zone (SVZ). Differentiating neurons display spontaneous Ca2+ events, which are voltage‐gated calcium channel (VGCC) dependent. Depolarization increases both the frequency of Ca2+ transients and the amount of Ca2+ influx in differentiating neurons. We show that depolarization‐dependent GABA expression is regulated by the amplitude and not by the frequency of Ca2+ influx. Brief activation of VGCCs leads to Ca2+ influx that in turn promotes a rapid expression of GABA. Depolarization‐dependent GABA expression does not require changes in gene expression. Instead, it involves cAMP‐dependent protein kinase (PKA) and Ca2+ and phospholipid‐dependent protein kinase (PKC) signalling. Activity increases the number of glutamic acid decarboxylase (GAD) 65‐immunoreactive neurons in a PKA‐dependent manner, without altering the expression of GAD 65, suggesting that depolarization promotes recruitment of GAD 65 by a post‐translational mechanism. In line with this, depolarization does not permanently increase the expression of GABA in neurons derived from neural stem cells of the embryonic striatum, cortex and adult SVZ. Thus, neuronal activity does not merely accelerate neuronal differentiation but it may alter the mechanism of GABA synthesis in newly generated neurons.
A neuroanatomically grounded Hebbian‐learning model of attention–language interactions in the human brain
Authors: Garagnani Max , Wennekers Thomas , Pulvermüller Friedemann
Published: July 2010

Meaningful familiar stimuli and senseless unknown materials lead to different patterns of brain activation. A late major neurophysiological response indexing ‘sense’ is the negative component of event‐related potential peaking at around 400 ms (N400), an event‐related potential that emerges in attention‐demanding tasks and is larger for senseless materials (e.g. meaningless pseudowords) than for matched meaningful stimuli (words). However, the mismatch negativity (latency 100–250 ms), an early automatic brain response elicited under distraction, is larger to words than to pseudowords, thus exhibiting the opposite pattern to that seen for the N400. So far, no theoretical account has been able to reconcile and explain these findings by means of a single, mechanistic neural model. We implemented a neuroanatomically grounded neural network model of the left perisylvian language cortex and simulated: (i) brain processes of early language acquisition and (ii) cortical responses to familiar word and senseless pseudoword stimuli. We found that variation of the area‐specific inhibition (the model correlate of attention) modulated the simulated brain response to words and pseudowords, producing either an N400‐ or a mismatch negativity‐like response depending on the amount of inhibition (i.e. available attentional resources). Our model: (i) provides a unifying explanatory account, at cortical level, of experimental observations that, so far, had not been given a coherent interpretation within a single framework; (ii) demonstrates the viability of purely Hebbian, associative learning in a multilayered neural network architecture; and (iii) makes clear predictions on the effects of attention on latency and magnitude of event‐related potentials to lexical items. Such predictions have been confirmed by recent experimental evidence.
Nature's food anticipatory experiment: entrainment of locomotor behavior, suprachiasmatic and dorsomedial hypothalamic nuclei by suckling in rabbit pups
Authors: Caba Mario , Tovar Anibal , Silver Rae , Mogado Elvira , Meza Enrique , Zavaleta Yael , Juárez Claudia
Published: July 2010

In nature and under laboratory conditions, dams nurse rabbit pups once daily for a duration of fewer than 5 min. The present study explored neural mechanisms mediating the timing of nursing in this natural model of food anticipatory activity, focussing on the suprachiasmatic nucleus (SCN), the locus of the master circadian clock and on the dorsomedial hypothalamic nucleus (DMH), a region implicated in timing of food‐entrained behavior. Rabbit pups are born in the dark, with eyelids closed. Nursing visits to the litters also occurs during the dark phase. To explore the effect of the timing of feeding, pups were maintained in constant darkness, while females housed in a light–dark cycle were permitted to nurse their pups either during the night (night‐fed group) or day (day‐fed group). All pups exhibited anticipatory locomotor activity before daily nursing. In the SCN, PER1 and FOS peaked during the night in both groups, with a longer duration of elevated protein expression in the night‐fed group. In contrast, DMH peak PER1 expression occurred 8 h after pups were fed, corresponding to the shift in timing of nursing. Comparison of nursed and 48 h fasted pups indicates that the timing of PER1 expression was similar in the SCN and DMH, with fewer PER1‐positive cells in the latter group. The results indicate that rabbit pups show food anticipatory activity, and that timing of nursing differentially affects PER1 expression in the SCN and DMH.
Prior pallidotomy reduces and modifies neuronal activity in the subthalamic nucleus of Parkinson's disease patients
Authors: Zaidel A. , Moran A. , Marjan G. , Bergman H. , Israel Z.
Published: July 2010

Parkinson's disease (PD) patients with prior radio‐frequency lesions in the internal segment of the globus pallidus (GPi, pallidotomy), whose symptoms have deteriorated, may be candidates for further invasive treatment such as subthalamic deep brain stimulation (STN DBS). Six patients with prior pallidotomy (five unilaterally; one bilaterally) underwent bilateral STN DBS. The microelectrode recordings (MERs, used intraoperatively for STN verification), ipsilateral and contralateral to pallidotomy, and MERs from 11 matched PD patients who underwent bilateral STN DBS without prior pallidotomy were compared. For each trajectory, average, variance and mean successive difference (MSD, a measure of irregularity) of the root mean square (RMS) of the STN MER were calculated. The RMS in trajectories ipsilateral to pallidotomy showed significant reduction of the mean average and MSD of STN activity when compared with trajectories from patients without prior pallidotomy. The RMS parameters contralateral to pallidotomy tend to lie between those ipsilateral to pallidotomy and those without prior pallidotomy. The average STN power spectral density of oscillatory activity was notably lower ipsilateral to pallidotomy than contralateral, or without prior pallidotomy. The finding that pallidotomy reduces STN activity and changes firing characteristics, in conjunction with the effectiveness of STN DBS despite prior pallidotomy, calls for reappraisal and modification of the current model of the basal ganglia (BG) cortical network. It highlights the critical role of direct projections from the BG to brain‐stem structures and suggests a possible GPi–STN reciprocal positive‐feedback mechanism.