bluuebunny/crossref_metadata_2025 huggingface dataset:
Novel VCP mutations in inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia
Authors: Watts GDJ , Thomasova D , Ramdeen SK , Fulchiero EC , Mehta SG , Drachman DA , Weihl CC , Jamrozik Z , Kwiecinski H , Kaminska A , Kimonis VE
Published: July 2010

Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia (IBMPFD, OMIM 167320) has recently been attributed to eight missense mutations in valosin‐containing protein (VCP). We report novel VCP mutations N387H and L198W in six individuals from two families who presented with proximal muscle weakness at a mean age of diagnosis of 40 years, most losing the ability to walk within a few years of onset. Electromyographic studies in four individuals were suggestive of ‘myopathic’ changes, and neuropathic pattern was identified in one individual in family 1. Muscle biopsy in four individuals showed myopathic changes characterized by variable fiber size, two individuals showing rimmed vacuoles and IBM‐type cytoplasmic inclusions in muscle fibers, and electron microscopy in one individual revealing abundant intranuclear inclusions. Frontotemporal dementia associated with characteristic behavioral changes including short‐term memory loss, language difficulty, and antisocial behavior was observed in three individuals at a mean age of 47 years. Detailed brain pathology in one individual showed cortical degenerative changes, most severe in the temporal lobe and hippocampus. Abundant ubiquitin‐positive tau‐, α‐synuclein‐, polyglutamine repeat‐negative neuronal intranuclear inclusions and only rare intracytoplasmic VCP positive inclusions were seen. These new mutations may cause structural changes in VCP and provide some insight into the functional effects of pathogenic mutations.
The role of common genetic risk variants in Parkinson disease
Authors: Tan E‐K
Published: July 2010

Despite the discovery of at least five pathogenic genes in Parkinson disease (PD), the genetic etiology in the vast majority of PD remains to be clarified. Common genetic variants could act as susceptibility risk factors. Our previous meta‐analysis of PD genetic association studies, over a 30‐year period yielded four genes (N‐acetylcysteine 2, monoamine oxidase B, glutathione transferase, and mitochondrial tRNA), as their common variants were found to be associated with PD. More recently, international collaborative studies and meta‐analysis have identified the S18Y variant of ubiquitin carboxy‐terminal hydrolase L1, Rep 1 variant of alpha‐synuclein and tau H1 haplotype to be genetic susceptibility risk/protective factors. However, the most significant, common genetic risk factor in PD has been its association with the leucine‐rich repeat kinase‐2 (LRRK2) G2385R variant. We conducted an analysis of independent studies involving 2205 PD and 1817 controls and found the average carrier rate of G2385R variant to be about 9% in PD and 4% in controls (p < 0.001; odds ratio: 2.27; 95% confidence interval: 1.78–2.9). A higher frequency of G2385R carriers has been observed in familial PD when compared with sporadic patients. Based on current evidence, certain common genetic variants are likely to modulate the risk of PD.
Pallister–Killian syndrome: tetrasomy of 12pter→12p11.22 in a boy with an analphoid, inverted duplicated marker chromosome
Authors: Huang X‐L , Isabel de Michelena M , Leon E , Maher TA , McClure R , Milunsky A
Published: July 2010

Supernumerary marker chromosomes (SMCs) without detectable alphoid DNA are predicted to have a neocentromere and have been referred to as mitotically stable neocentromere marker chromosomes (NMCs). Here we report the molecular cytogenetic characterization of a new case of Pallister–Killian syndrome (PKS) in a boy with an analphoid, inverted duplicated NMC derived from 12pter→12p11.22 in his fibroblasts by using high‐resolution comparative genetic hybridization (HR‐CGH), multiplex fluorescent in situ hybridization (FISH) and bacterial artificial chromosome (BAC)‐FISH mapping analyses with various alpha‐satellite DNA probes, subtelomere probes and BAC‐DNA probes. Precise identification of SMCs and NMCs is of essential importance in genetic counseling. HR‐CGH is a more informative and often a faster way of precisely identifying the origin of SMCs. This case is the third report of PKS with an NMC containing an inverted duplication of partial 12p with available clinical data. These observations may help to determine the critical region for PKS and the mechanisms leading to the origin of the NMC derived from 12pter→12p11.22 – a region that appears to be susceptible to the formation of neocentromeres. The use of subtelomeric probe PCP12p in buccal cells appears superior to the use of the centromere probe D12Z3 for the diagnosis of the PKS.
Non‐neuronopathic Gaucher disease due to saposin C deficiency
Authors: Tylki‐Szymańska A , Czartoryska B , Vanier M‐T , Poorthuis BJMH , Groener JAE , Ługowska A , Millat G , Vaccaro AM , Jurkiewicz E
Published: July 2010

Gaucher disease is generally caused by a deficiency of the lysosomal enzyme glucocerebrosidase. The degradation of glycosphingolipids requires also the participation of sphingolipid activator proteins. The prosaposin PSAP gene codes for a single protein which undergoes post‐translational cleavage to yield four proteins named saposins A, B, C and D. Saposin (SAP‐) C is required for glucosylceramide degradation, and its deficiency results in a variant form of Gaucher disease. In this report, we present clinical, biochemical, and molecular findings in a 36‐year‐old man and his 30‐year‐old sister with non‐neuronopathic Gaucher disease due to SAP‐C deficiency. Very high levels of chitotriosidase activity, chemokine CCL18, and increased concentration of glucosylceramide in plasma and normal β‐glucosidase activity in skin fibroblasts were observed in the patients. A molecular genetics study of the PSAP gene enabled the identification of one missense mutation, p.L349P, located in the SAP‐C domain and another mutation, p.M1L, located in the initiation codon of the prosaposin precursor protein. The presented findings describe the first cases where the non‐neuronopathic Gaucher disease has been definitely demonstrated to be a consequence of SAP‐C deficiency. Three previously described cases in the literature displayed a Gaucher type 3 phenotype.
Germline mutation prevalence in the base excision repair gene, MYH, in patients with endometrial cancer
Authors: Barnetson RA , Devlin L , Miller J , Farrington SM , Slater S , Drake AC , Campbell H , Dunlop MG , Porteous ME
Published: July 2010

Germline mutations in the base excision repair gene, MutY human homolog (MYH), have recently been associated with a recessively inherited multiple adenoma polyposis syndrome and colorectal cancer. The spectrum of extracolonic lesions is still being characterized, although preliminary reports suggest that bi‐allelic mutation carriers may share some of the clinical features of other hereditary colon cancer syndromes. Of 225 endometrial cancer patients, we identified one individual as a compound heterozygote, carrying mutations Y165C and G382D of MYH, and five individuals with heterozygous defects (three G382D and two Y165C). The patient with the bi‐allelic Y165C/G382D mutation also had a sebaceous carcinoma, a feature of Muir–Torre syndrome. Although several intronic polymorphisms were detected in the heterozygous carriers, no other pathogenic variants were identified. While not conclusive, this novel and interesting finding provides evidence that bi‐allelic germline mutations in MYH may increase susceptibility to endometrial cancer.
Transcriptional explorations of CAPN3 identify novel splicing mutations, a large‐sized genomic deletion and evidence for messenger RNA decay
Authors: Krahn M , Pécheux C , Chapon F , Béroud C , Drouin‐Garraud V , Laforet P , Romero NB , Penisson‐Besnier I , Bernard R , Urtizberea JA , Leturcq F , Lévy N
Published: July 2010

Mutations in the gene encoding calpain‐3 (CAPN3) cause autosomal recessive limb‐girdle muscular dystrophy type 2A (LGMD2A) and idiopathic eosinophilic myositis. Accurate diagnosis and genetic counselling are based on the identification of disease‐causing mutations on both alleles of CAPN3 in the patients. In the present study, we used transcriptional analysis as a complementary approach for patients suspected of being affected with LGMD2A, in whom initial denaturing high‐performance liquid chromatography genomic mutation screening evidenced no or only one CAPN3 mutation obviously considered as disease causing. This allowed to identify and characterize cDNA deletions. Further genomic analysis allowed to determine the origin of these deletions, either as splicing defects caused by intronic mutations or as an internal multi‐exonic deletion. In particular, we report two novel CAPN3 mutations (c.1745 + 4_1745 + 7delAGTG in IVS13 and c.2185‐16A>G in IVS20) and a recurrent large‐sized genomic deletion including exons 2–8 for which genomic breakpoints have been characterized. In addition, our results indicate nonsense‐mediated messenger RNA decay as a mechanism for under‐expression of CAPN3 associated to some specific variations.
Characteristics and long‐term outcome of acute exacerbations in chronic obstructive pulmonary disease: an analysis of cases in the Swedish Intensive Care Registry during 2002–2006
Authors: BERKIUS J. , NOLIN T. , MÅRDH C. , KARLSTRÖM G. , WALTHER S. M.
Published: July 2010

Background: Chronic obstructive pulmonary disease (COPD) represents a major and growing health problem. The purpose of this work was to examine characteristics, resource use and long‐term survival in patients with an acute exacerbation of COPD that were admitted to Swedish intensive care units (ICU).

Methods: Patient characteristics at admission, length of stay (LOS), resource use and outcome were collected for admissions due to COPD during 2002–2006 in the database of the Swedish Intensive Care Registry. Vital status was secured for 99.6% of the patients. Kaplan–Meier survival estimates were computed for index admissions only.

Results: We identified 1009 patients with 1199 admissions due to COPD (1.3% of all intensive care admissions). The mean (SD) age was 70.2 (9.1) years and the proportion of women were 61.5%. Mean (SD) Acute Physiology and Chronic Health Evaluation II probability of hospital death was 0.31 (0.19). Median LOS was 28 (interquartile range 52) h. The number of readmissions was 190 during the 5‐year study. Older patients had fewer readmissions (OR 0.96, 95% CI: 0.95–0.98/year increase in age). ICU mortality was 7.3% (87 of 1199 admissions) and 30‐day mortality was 26.0% (262 of 1009 index admissions). Median survival was 14.5 months and 31% of patients survived 3 years after the index admission.

Conclusions: Short (30 days) and long‐term survival is poor in acute COPD. Readmissions are frequent reflecting the severity of this chronic illness. Patients are less likely to be readmitted with increasing age which may be due to withholding of further intensive care.
Crossbreeding effects on milk yield traits and calving interval in spring‐calving dairy cows
Authors: Penasa M. , López‐Villalobos N. , Evans R.D. , Cromie A.R. , Dal Zotto R. , Cassandro M.
Published: July 2010

The aim of the study was to assess crossbreeding effects for 305‐day milk, fat, and protein yield and calving interval (CI) in Irish dairy cows (parities 1 to 5) calving in the spring from 2002 to 2006. Data included 188 927 records for production traits and 157 117 records for CI. The proportion of genes from North American Holstein Friesian (HO), Friesian (FR), Jersey (JE) and Montbéliarde (MO) breeds, and coefficients of expected heterosis for HO×FR, HO×JE and HO×MO crosses were calculated from the breed composition of cows’ parents. The model used to assess crossbreeding effects accounted for contemporary group, age at calving within parity, linear regression on gene proportions for FR, JE and MO, and linear regression on coefficients of expected heterosis for HO×FR, HO×JE and HO×MO, as fixed effects, and additive genetic, permanent environmental and residual as random. Breed effects for production traits were in favour of HO, while for CI were in favour of breeds other than HO. The highest heterosis estimates for production were for HO×JE, with first‐generation crosses yielding 477 kg more milk, 25.3 kg more fat, and 17.4 kg more protein than the average of the parental breeds. The highest estimate for CI was for HO×MO, with first‐generation crosses showing 10.2 days less CI than the average of the parental breeds. Results from this study indicate breed differences and specific heterosis effects for milk yield traits and fertility exist in Irish dairy population.
Random regression model estimation of genetic parameters for show‐jumping results of Hungarian Sporthorses
Authors: Posta J. , Malovhr S. , Mihók S. , Komlósi I.
Published: July 2010

The aim of this study was to estimate the genetic parameters for show‐jumping competition performance of Hungarian Sporthorses using a random regression model. There were 21 210 records from 739 horses collected in Hungary between 1996 and 2004. Performance was expressed as shifted Blom normalized ranks and as the difference between fence height and fault points. The random regression model (RRM) included fixed effects for sex, year, location, and obstacle height and random effects for animal, rider and permanent environment. Regressions for the random effects in the RRM were modelled with Legendre polynomials from first to fifth order of fit. The model focused on performance of horses from 4 to 11 years of age, with heterogeneous residual variances considered. The heritabilities were low to moderate for both variables. Genetic and phenotypic correlations between different ages decreased with increasing distance between the ages.
No interference of the 1,3‐β‐d‐glucan containing nutritional supplement ImunixX with the 1,3‐β‐d‐glucan serum test
Authors: Spriet Isabel , Desmet Stephanie , Willems Ludo , Lagrou Katrien
Published: July 2010

The detection of 1,3‐β‐d‐glucan serum levels may permit establishing the diagnosis of invasive fungal infections more early. We tested in six healthy volunteers whether the intake of a 1,3‐β‐d‐glucan‐containing nutritional supplement leads to false‐positive 1,3‐β‐d‐glucan levels. All levels were negative, even in two different dosing regimens.
Molecular phylogenetics ofFonsecaeastrains isolated from chromoblastomycosis patients in South Korea
Authors: Lim Sung‐Wook , Suh Moo‐Kyu , Kang Gyo‐Shin , Ha Gyoung‐Yim , Kim Heesoo , Choi Jong‐Soo , Kim Young‐Sik
Published: July 2010

Fonsecaeastrains isolated from chromoblastomycosis patients in Korea and morphologically identified asFonsecaea pedrosoiwere re‐evaluated for typing by sequencing the ribosomal internal transcribed spacer (ITS) regions. The ITS sequences of five Korean isolates and two reference strains were determined and then aligned with those of 11 related strains deposited in GenBank. In a phylogenetic tree constructed from these 18 strains, the Korean isolates and the references were clustered into two groups: Group A representingF. pedrosoi; Group B representingFonsecaea monophora. These groups could be further divided into A1 and A2 subgroups and B1, B2 and B3 subgroups. Among five Korean strains, two isolates belonged to A1 subgroup, while one belonged to B1 subgroup and two to B2 subgroup. Despite the low numbers of Korean isolates and the small size of the Korean territory, this result indicates that theFonsecaeastrains prevalent in Korea are more diverse compared with those isolated in Japan and China. Moreover,F. monophoraisolates, which had been reported to cause cutaneous infections as well as opportunistic neurotropic infections, were responsible for chromoblastomycosis in immunocompetent patients in Korea. In conclusion, ITS sequence analysis provided useful information not only for typing ofFonsecaeaisolates in Korea but also regarding the geographical sources of these strains.
Novel therapeutic option for orbital atypical lymphoid hyperplasia
Authors: Talaulikar Dipti , Tridgell David , Leong David , Dahlstrom Jane E , Cherian Maya , Prosser Ian , Sunderland Ken
Published: July 2010

Abstract

Ocular lymphoid tumours represent a spectrum of lymphoproliferative disease and can be subdivided into benign or reactive lymphoid hyperplasia, indeterminate or atypical lymphoid proliferations and malignant lymphoma. Treatment options include a wait and watch approach, systemic steroids, local radiotherapy or systemic chemotherapy. We describe a case of bilateral atypical lymphoid hyperplasia treated successfully with combination immunotherapy and radiotherapy. A 60‐year‐old lady presented with proptosis and left supra‐orbital mass and was diagnosed to have bilateral atypical lymphoid hyperplasia. She had extensive extraocular facial infiltrates but no other sites of involvement on staging investigations. She was treated with eight doses of rituximab 375 mg/m2 at weekly intervals with a good partial response, followed by consolidative radiotherapy. Rituximab may be an effective treatment adjunct/alternative for patients with atypical lymphoid hyperplasia of the orbit, particularly where widespread lesions preclude the use of initial radiotherapy.
Modulation of human corticomuscular beta‐range coherence with low‐level static forces
Authors: Witte Matthias , Patino Luis , Andrykiewicz Agnieszka , Hepp‐Reymond Marie‐Claude , Kristeva Rumyana
Published: July 2010

Although corticomuscular synchronization in the beta range (15–30 Hz) was shown to occur during weak steady‐state contractions, an examination of low‐level forces around 10% of the maximum voluntary contraction (MVC) is still missing. We addressed this question by investigating coherence between electroencephalogram (EEG) and electromyogram (EMG) as well as cortical spectral power during a visuomotor task. Eight healthy right‐handed subjects compensated isometrically static forces at a level of 4% and 16% of MVC with their right index finger. While 4% MVC was accompanied by low coherence values in the middle to high beta frequency range (25–30 Hz), a significant increase of coherence mainly confined to low beta frequencies (19–20 Hz) was observed with force of 16% MVC. Furthermore, this increase was associated with better performance, as reflected in decreased relative error in force during 16% MVC. We additionally show that periods of good motor performance within each condition were associated with higher values of EEG–EMG coherence and spectral power. In conclusion, our results suggest a role for beta‐range corticomuscular coherence in effective sensorimotor integration, thus stabilizing corticospinal communication.
Dopamine gene predicts the brain's response to dopaminergic drug
Authors: Cohen Michael X , Krohn‐Grimberghe Artus , Elger Christian E. , Weber Bernd
Published: July 2010

Dopamine is critical for reward‐based decision making, yet dopaminergic drugs can have opposite effects in different individuals. This apparent discrepancy can be accounted for by hypothesizing an ‘inverted‐U’ relationship, whereby the effect of dopamine agents depends on baseline dopamine system functioning. Here, we used functional MRI to test the hypothesis that genetic variation in the expression of dopamine D2 receptors in the human brain predicts opposing dopaminergic drug effects during reversal learning. We scanned 22 subjects while they engaged in a feedback‐based reversal learning task. Ten subjects had an allele on the Taq1A DRD2 gene, which is associated with reduced dopamine receptor concentration and decreased neural responses to rewards (A1+ subjects). Subjects were scanned twice, once on placebo and once on cabergoline, a D2 receptor agonist. Consistent with an inverted‐U relationship between the DRD2 polymorphism and drug effects, cabergoline increased neural reward responses in the medial orbitofrontal cortex, cingulate cortex and striatum for A1+ subjects but decreased reward responses in these regions for A1– subjects. In contrast, cabergoline decreased task performance and fronto‐striatal connectivity in A1+ subjects but had the opposite effect in A1– subjects. Further, the drug effect on functional connectivity predicted the drug effect on feedback‐guided learning. Thus, individual variability in how dopaminergic drugs affect the brain reflects genetic disposition. These findings may help to explain the link between genetic disposition and risk for addictive disorders.
Role of the amygdaloid cholecystokinin (CCK)/gastrin‐2 receptors and terminal networks in the modulation of anxiety in the rat. Effects of CCK‐4 and CCK‐8S on anxiety‐like behaviour and [3H]GABA release
Authors: Pérez de la Mora Miguel , Hernández‐Gómez Ana María , Arizmendi‐García Yexel , Jacobsen Kirsten X. , Lara‐García Daniel , Flores‐Gracia Candy , Crespo‐Ramírez Minerva , Gallegos‐Cari Andrea , Nuche‐Bricaire Avril , Fuxe Kjell
Published: July 2010

The amygdala plays a key role in fear and anxiety. The intercalated islands are clusters of glutamate‐responsive GABAergic neurons rich in cholecystokinin (CCK)‐2 receptors which control the trafficking of nerve impulses from the cerebral cortex to the central nucleus of amygdala. In this study, the nature of the CCK–glutamate–GABA interactions within the rat rostral amygdala, and their relevance for anxiety, were studied. CCK/gastrin‐like immunoreactive nerve terminals were found to be mainly restricted to the paracapsular intercalated islands and the rostrolateral part of the main intercalated island. Behaviourally, the bilateral microinjection of CCK‐4 (0.043–4.3 pmol/side) or CCK‐8S (4.3 pmol/side) into the rostrolateral amygdala reduced the open‐arm exploration in the elevated plus‐maze without affecting locomotion. In contrast, neither CCK‐4 nor CCK‐8S (0.043–4.3 pmol/side) had any effects in the shock‐probe burying test as compared with their saline‐treated controls. Biochemically, CCK‐4 (0.3 and 1.5 µm), unlike CCK‐8S, enhanced significantly the K+‐stimulated release of [3H]GABA from amygdala slices. These effects were fully prevented by prior superfusion of the slices with either the selective CCK‐2 receptor antagonist CR2945 (3 µm), or 6,7‐dinitroquinoxaline‐2,3(1H,4H)‐dione (DNQX), 10 µm, a glutamatergic (+/–)‐α‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionic acid (AMPA)/kainate receptor antagonist. It is suggested that CCK modulates glutamate‐GABA mechanisms by acting on CCK‐2 receptors via volume transmission occurring at the level of the basolateral amygdaloid nucleus and/or by synaptic or perisynaptic volume transmission in the region of the rostrolateral main and paracapsular intercalated islands, resulting in subsequent disinhibition of the central amygdaloid nucleus and anxiety or panic‐like behaviour.
Up‐regulation of adenosine A1receptors in frontal cortex from Pick's disease cases
Authors: Albasanz José Luis , Rodríguez Agustín , Ferrer Isidro , Martín Mairena
Published: July 2010

The adenosine A1receptor (A1R)–adenylyl cyclase (AC) pathway was studied in post‐mortem human frontal and occipital cortex from Pick's disease (PiD) cases and age‐matched nondemented controls. In frontal cortex, the main brain area affected in PiD, A1Rs, determined by radioligand binding, Western blotting and real‐time PCR assays, were significantly increased in PiD samples, suggesting up‐regulation of this receptor. AC activity was determined in basal and stimulated conditions via stimulatory guanine nucleotide binding proteins (Gs) using GTP, or directly with forskolin. Basal AC activity was reduced in brains from PiD cases. This agrees with the decrease in AC type I (AC I) level detected by Western blotting. However, inhibition of forskolin‐stimulated AC activity by a selective A1R agonist was significantly increased in brains from PiD. In occipital cortex, adenosine A1R numbers were similar in control and PiD cases, and no significant differences were found in A1R‐mediated AC inhibition. These results show that the adenosine A1R–AC transduction pathway is specifically up‐regulated and sensitized in frontal cortex brain in PiD.
Brief treatment with the glucocorticoid receptor antagonist mifepristone normalizes the reduction in neurogenesis after chronic stress
Authors: Oomen Charlotte A. , Mayer Joseph L. , De Kloet E. Ronald , Joëls Marian , Lucassen Paul J.
Published: July 2010

In rodents, stress suppresses adult neurogenesis. This is thought to involve activation of glucocorticoid receptors in the brain. In the present study, we therefore questioned whether glucocorticoid receptor blockade by mifepristone can normalize the effects of chronic stress on adult neurogenesis. Rats received mifepristone on the last 4 days of a 21‐day chronic unpredictable and inescapable stress regimen. Neurogenesis was analysed by stereological quantification of adult‐generated cell survival (bromodeoxyuridine), young neuronal survival (doublecortin) and cell proliferation (Ki‐67). The results show that only 4 days of mifepristone treatment normalized the stress‐induced reductions in neurogenesis. Importantly, mifepristone by itself had no effect on neurogenesis. We conclude that, contrary to other compounds interfering with the effects of chronic stress on neurogenesis, like antidepressants, the normalizing effects of mifepristone on neurogenesis are rapid and particularly potent in a high stress environment. This neurogenic action of mifepristone could potentially contribute to its clinical mechanism of action.
Differences in intermale aggression are accompanied by opposite vasopressin release patterns within the septum in rats bred for low and high anxiety
Authors: Beiderbeck Daniela I. , Neumann Inga D. , Veenema Alexa H.
Published: July 2010

Several studies suggest a role for arginine vasopressin (AVP), particularly in the lateral septum, in the regulation of intermale aggression. We used intracerebral microdialysis to monitor the local in vivo AVP release within the mediolateral septum of adult male Wistar rats bred for low (LAB) or high (HAB) anxiety‐related behaviour during exposure to the resident‐intruder test. LAB residents showed a significantly higher level of aggression than HAB residents, as reflected by more time spent with lateral threat, offensive upright and total aggressive behaviour as well as by more attacks and a shorter attack latency. Septal AVP release was significantly decreased in high‐aggressive LAB males, while septal AVP release tended to increase in HAB males during resident‐intruder test exposure. Moreover, LAB residents showed reduced neuronal activation of the lateral septum, as indicated by fewer c‐Fos‐positive cells, 1 h after the resident‐intruder test. Pharmacological manipulation of the septal AVP system by local application of either synthetic AVP to LAB residents or the selective V1a receptor antagonist d(CH2)5Tyr(Me)AVP to HAB residents did not change the level of aggression. However, application of AVP into the septum enhanced anxiety‐related behaviour on the elevated plus‐maze in LAB males, while local administration of the V1a receptor antagonist reduced social investigation in HAB males during the resident‐intruder test. In conclusion, although AVP release patterns within the septum are dependent on the level of aggression, locally released AVP does not seem to be directly involved in the regulation of aggression, but rather modulates non‐aggressive social and anxiety‐related behaviours.
Neural correlates of movement preparation in healthy ageing
Authors: Sterr Annette , Dean Philip
Published: July 2010

Motor disorders increase dramatically with age; however, little is known about non‐clinical ageing of motor control mechanisms and their respective neural correlates. With the present experiment we aimed to study age effects on advance movement preparation, a key characteristic of motor behaviour that is known to involve premotor and primary motor circuits. The respective brain regions are subject to age‐related brain atrophy of grey and white matter, and we therefore hypothesized that motor preparation mechanisms may be altered in older persons.

Using a motor priming paradigm, performance data and event‐related potentials were recorded in older (68–83 years) and younger (21–25 years) participants. The effect pattern observed for the younger group fully replicated previous findings, showing significant reaction time benefits and greater foreperiod activity for valid trials, as well as lateralized activation over motor regions. In older participants, the validity effect was insignificant, which corresponded to markedly reduced foreperiod amplitudes and the absence of lateralized activity. At the same time, the event‐related potential showed a frontocentrally distributed positive component peaking in the P300 latency range after presentation of the prime. The amplitude of this potential was enhanced in elderly compared with young participants.

The data suggest that the information processing related to the anticipation and preparation of an upcoming response changes substantially with age. In contrast to younger participants, older participants show no indication of effector‐specific activation and recruit frontal areas in anticipation of a response signal. It is therefore not only movement execution that changes with age but also motor cognition.
Computational significance of transient dynamics in cortical networks
Authors: Durstewitz Daniel , Deco Gustavo
Published: July 2010

Neural responses are most often characterized in terms of the sets of environmental or internal conditions or stimuli with which their firing rate are correlated increases or decreases. Their transient (nonstationary) temporal profiles of activity have received comparatively less attention. Similarly, the computational framework of attractor neural networks puts most emphasis on the representational or computational properties of the stable states of a neural system. Here we review a couple of neurophysiological observations and computational ideas that shift the focus to the transient dynamics of neural systems. We argue that there are many situations in which the transient neural behaviour, while hopping between different attractor states or moving along ‘attractor ruins’, carries most of the computational and/or behavioural significance, rather than the attractor states eventually reached. Such transients may be related to the computation of temporally precise predictions or the probabilistic transitions among choice options, accounting for Weber's law in decision‐making tasks. Finally, we conclude with a more general perspective on the role of transient dynamics in the brain, promoting the view that brain activity is characterized by a high‐dimensional chaotic ground state from which transient spatiotemporal patterns (metastable states) briefly emerge. Neural computation has to exploit the itinerant dynamics between these states.
Interaction between the glutamate transporter GLT1b and the synaptic PDZ domain protein PICK1
Authors: Bassan Merav , Liu Hongguang , Madsen Kenneth L. , Armsen Wencke , Zhou Jiayi , DeSilva Tara , Chen Weizhi , Paradise Allison , Brasch Michael A. , Staudinger Jeff , Gether Ulrik , Irwin Nina , Rosenberg Paul A.
Published: July 2010

Synaptic plasticity is implemented by the interaction of glutamate receptors with PDZ domain proteins. Glutamate transporters provide the only known mechanism of clearance of glutamate from excitatory synapses, and GLT1 is the major glutamate transporter. We show here that GLT1 interacts with the PDZ domain protein PICK1, which plays a critical role in regulating the expression of glutamate receptors at excitatory synapses. A yeast two‐hybrid screen of a neuronal library using the carboxyl tail of GLT1b yielded clones expressing PICK1. The GLT1b C‐terminal peptide bound to PICK1 with high affinity (Ki = 6.5 ± 0.4 µm) in anin vitrofluorescence polarization assay. We also tested peptides based on other variants of GLT1 and other glutamate transporters. GLT1b co‐immunoprecipitated with PICK1 from rat brain lysates and COS7 cell lysates derived from cells transfected with plasmids expressing PICK1 and GLT1b. In addition, expression of GLT1b in COS7 cells changed the distribution of PICK1, bringing it to the surface. GLT1b and PICK1 co‐localized with each other and with synaptic markers in hippocampal neurons in culture. Phorbol ester, an activator of protein kinase C (PKC), a known PICK1 interactor, had no effect on glutamate transport in rat forebrain neurons in culture. However, we found that exposure of neurons to a myristolated decoy peptide with sequence identical to the C‐terminal sequence of GLT1b designed to block the PICK1–GLT1b interaction rendered glutamate transport into neurons responsive to phorbol ester. These results suggest that the PICK1–GLT1b interaction regulates the modulation of GLT1 function by PKC.
Alcohol‐induced stress in painful alcoholic neuropathy
Authors: Dina Olayinka A. , Khasar Sachia G. , Alessandri‐Haber Nicole , Green Paul G. , Messing Robert O. , Levine Jon D.
Published: July 2010

Chronic alcohol consumption induces a painful small‐fiber peripheral neuropathy, the severity of which increases during alcohol withdrawal. Chronic alcohol consumption also produces a sustained increase in stress hormones, epinephrine and corticosterone, that is exacerbated during alcohol withdrawal. We report that adrenal medullectomy and administration of a glucocorticoid receptor antagonist, mifepristone (RU 38486), both prevented and reversed a model of painful peripheral neuropathy in alcohol binge‐drinking rats. Chronic administration of stress levels of epinephrine to rats that had undergone adrenal medullectomy and were being fed the alcohol diet reconstituted this phenotype. Intrathecal administration of oligodeoxynucleotides antisense to the β2‐adrenergic‐ or glucocorticoid‐receptor also prevented and reversed the pro‐nociceptive effects of ethanol. Our results suggest a convergence of the effects of mediators of the hypothalamic‐pituitary‐ and sympathoadrenal‐stress axes on sensory neurons in the induction and maintenance of alcohol‐induced painful peripheral neuropathy.
Neurokinins robustly activate the majority of septohippocampal cholinergic neurons
Authors: Morozova Elena , Wu Min , Dumalska Iryna , Alreja Meenakshi
Published: July 2010

In the brain, tachykinins acting via the three cloned neurokinin (NK) receptors are implicated in stress‐related affective disorders. Hemokinin‐1 is a novel tachykinin that reportedly prefers NK1 to NK2 or NK3 receptors. Although NK1 and NK3 receptors are abundantly expressed in the brain, NK2‐receptor‐mediated electrophysiological effects have rarely been described as NK2 receptors are expressed only in a few brain regions such as the nucleus of the medial septum/diagonal band. Medial septal/diagonal band neurons that control hippocampal mnemonic functions also colocalize NK1 and NK3 receptors. Functionally, intraseptal activation of all three NK receptors increases hippocampal acetylcholine release and NK2 receptors have specifically been implicated in stress‐induced hippocampal acetylcholine release. Electrophysiological studies on the effects of NKs on septohippocampal cholinergic neurons are lacking and electrophysiological effects of hemokinin‐1 have thus far not been reported in brain neurons. In the present study we examined the electrophysiological and pharmacological effects of multiple NKs on fluorescently tagged septohippocampal cholinergic neurons using whole‐cell patch‐clamp recordings in a rat brain slice preparation. We demonstrate that a vast majority of septohippocampal cholinergic cells are activated by NK1, NK2 and NK3 receptor agonists as well as by hemokinin‐1 via direct post‐synaptic mechanisms. Pharmacologically, hemokinin‐1 recruits not only NK1 but also NK2 and NK3 receptors to activate septohippocampal cholinergic neurons that are the primary source of acetylcholine for the hippocampus.
Spatiotemporal loss of K+ transport proteins in the developing cochlear lateral wall of guinea pigs with hereditary deafness
Authors: Jin Zhe , Ulfendahl Mats , Järlebark Leif
Published: July 2010

Genetic deafness is one of the most common human genetic birth defects. To understand the molecular mechanisms underlying human hereditary deafness, deaf animal strains have proved to be invaluable models. The German waltzing guinea pig is a new strain of animals with unidentified gene mutation(s), displaying recessively inherited cochleovestibular impairment. Histological investigations of the homozygous animals (gw/gw) revealed a collapse of the endolymphatic compartment and malformation of stria vascularis. RT‐PCR showed a significant reduction in expression of the strial intermediate cell‐specific gene Dct and the tight‐junction gene Cldn11 in the embryonic day (E)40 and adult gw/gw cochlear lateral wall. Immunohistochemical analysis of the gw/gw cochlea showed loss of the tight junction protein CLDN11 in strial basal cells from E40, loss of the potassium channel subunit KCNJ10 in strial intermediate cells from E50, and loss of the Na–K–Cl cotransporter SLC12A2 in strial marginal cells from E50. In addition, a temporary loss of the gap junction protein GJB2 (connexin 26) between fibrocytes in the spiral ligament of the E50 gw/gw cochlea was observed. The barrier composed of tight junctions between strial basal cells was disrupted in the gw/gw cochlea as indicated by a biotin tracer permeability assay. In conclusion, spatiotemporal loss of K+ transport proteins in the cochlear lateral wall is caused by malformation of the stria vascularis in the developing German waltzing guinea pig inner ear. This new animal strain may serve as a good model for studying human genetic deafness due to disruption of inner ear ion homeostasis.
Overlapping representations of the neck and whiskers in the rat motor cortex revealed by mapping at different anaesthetic depths
Authors: Tandon Shashank , Kambi Niranjan , Jain Neeraj
Published: July 2010

The primary motor cortex of mammals has an orderly representation of different body parts. Within the representation of each body part the organization is more complex, with groups of neurons representing movements of a muscle or a group of muscles. In rats, uncertainties continue to exist regarding organization of the primary motor cortex in the whisker and the neck region. Using intracortical microstimulation (ICMS) we show that movements evoked in the whisker and the neck region of the rat motor cortex are highly sensitive to the depth of anaesthesia. At light anaesthetic depth, whisker movements are readily evoked from a large medial region of the motor cortex. Lateral to this is a small region where movements of the neck are evoked. However, in animals under deep anaesthesia whisker movements cannot be evoked. Instead, neck movements are evoked from this region. The neck movement region thus becomes greatly expanded. An analysis of the threshold currents required to evoke movements at different anaesthetic depths reveals that the caudal portion of the whisker region has dual representation, of both the whisker and the neck movements. The results also underline the importance of carefully controlling the depth of anaesthesia during ICMS experiments.
The leaner P/Q‐type calcium channel mutation renders cerebellar Purkinje neurons hyper‐excitable and eliminates Ca2+‐Na+ spike bursts
Authors: Ovsepian Saak V. , Friel David D.
Published: July 2010

The leaner mouse mutation of the Cacna1a gene leads to a reduction in P‐type Ca2+ current, the dominant Ca2+ current in Purkinje cells (PCs). Here, we compare the electro‐responsiveness and structure of PCs from age‐matched leaner and wild‐type (WT) mice in pharmacological isolation from synaptic inputs in cerebellar slices. We report that compared with WT, leaner PCs exhibit lower current threshold for Na+ spike firing, larger subthreshold membrane depolarization, rapid adaptation followed by complete block of Na+ spikes upon strong depolarization, and fail to generate Ca2+‐Na+ spike bursts. The Na+ spike waveforms in leaner PCs have slower kinetics, reduced spike amplitude and afterhyperpolarization. We show that a deficit in the P‐type Ca2+ current caused by the leaner mutation accounts for most but not all of the changes in mutant PC electro‐responsiveness. The selective P‐type Ca2+ channel blocker, ω‐agatoxin‐IVA, eliminated differences in subthreshold membrane depolarization, adaptation of Na+ spikes upon strong current‐pulse stimuli, Na+ spike waveforms and Ca2+‐Na+ burst activity. In contrast, a lower current threshold for eliciting repetitive Na+ spikes in leaner PCs was still observed after blockade of the P‐type Ca2+ current, suggesting secondary effects of the mutation that render PCs hyper‐excitable. Higher input resistance, reduced whole‐cell capacitance and smaller dendritic size accompanied the enhanced excitability in leaner PCs, indicative of developmental retardation in these cells caused by P/Q‐type Ca2+ channel malfunction. Our data indicate that a deficit in P‐type Ca2+ current leads to complex functional and structural changes in PCs, impairing their intrinsic and integrative properties.
Evidence for a role of early oestrogens in the central processing of sexually relevant olfactory cues in female mice
Authors: Pierman Sylvie , Douhard Quentin , Bakker Julie
Published: July 2010

We previously found that female aromatase knockout (ArKO) mice showed less investigation of socially relevant odours as well as reduced sexual behaviour. We now ask whether these behavioural deficits might be due to an inadequate processing of odours in female ArKO mice. Therefore, we exposed female ArKO mice to same‐ and opposite‐sex urinary odours and determined the expression of the immediate early gene c‐Fos along the main and accessory olfactory projection pathways. We included ArKO males in the present study as we previously observed that they show female‐typical detection thresholds of urinary odours, suggesting a role for perinatal oestrogens in these behavioural responses. No sex or genotype differences were observed in the olfactory bulb after urine exposure. By contrast, sex differences in c‐Fos responses were observed in wild‐type (WT) mice following exposure to male urine in the more central regions of the olfactory pathway; only WT females showed a significant Fos induction in the amygdala, central medial pre‐optic area and ventromedial hypothalamus. However, ArKO females did not show a c‐Fos response to male odours in the ventromedial hypothalamus, suggesting that the processing of male odours is affected in ArKO females and thus that oestrogens may be necessary for the development of neural responses to sexually relevant odours in female mice. By contrast, c‐Fos responses to either male or oestrous female urine were very similar between ArKO and WT males, pointing to a central role of androgen vs. oestrogen signalling in the male circuits that control olfactory investigation and preferences.
Neuroprotective effects of novel phosphatidylglycerol‐based phospholipids in the 6‐hydroxydopamine model of Parkinson's disease
Authors: Crotty S. , Fitzgerald P. , Tuohy E. , Harris D. M. , Fisher A. , Mandel A. , Bolton A. E. , Sullivan A. M. , Nolan Y.
Published: July 2010

Administration of VP025 (Vasogen Inc.), a novel drug formulation based on phospholipid nanoparticles incorporating phosphatidylglycerol, has previously been shown to have a neuroprotective effect in the brain. We examined the effect of VP025 in a rat model of Parkinson's disease, the 6‐hydroxydopamine (6‐OHDA) lesion of the medial forebrain bundle. VP025 or phosphate‐buffered saline (PBS) was administered to rats 14 days, 13 days and 1 day before the unilateral 6‐OHDA lesion. Functional integrity of nigrostriatal dopaminergic neurons was assessed 7 and 21 days later by amphetamine‐induced rotational testing and we observed that rotational counts were significantly less in rats that were pretreated with VP025 compared with PBS‐pretreated 6‐OHDA‐lesioned rats. Neurochemical analysis at 10 and 28 days after lesion revealed that VP025 protected against a 6‐OHDA‐induced decrease in concentrations of striatal dopamine and its metabolites. Immunocytochemical studies of the ipsilateral substantia nigra showed that VP025 significantly inhibited 6‐OHDA‐induced loss of dopaminergic neurons. We also observed that increases in immunostaining for activated microglia and for activated p38 in dopaminergic neurons of 6‐OHDA‐lesioned rats were prevented by VP025. This study shows that VP025 has significant protective effects on the 6‐OHDA‐lesioned nigrostriatal pathway and may therefore have potential for the treatment of Parkinson's disease.
Characterization of GABAergic neurons in rapid‐eye‐movement sleep controlling regions of the brainstem reticular formation in GAD67–green fluorescent protein knock‐in mice
Authors: Brown Ritchie E. , McKenna James T. , Winston Stuart , Basheer Radhika , Yanagawa Yuchio , Thakkar Mahesh M. , McCarley Robert W.
Published: July 2010

Recent experiments suggest that brainstem GABAergic neurons may control rapid‐eye‐movement (REM) sleep. However, understanding their pharmacology/physiology has been hindered by difficulty in identification. Here we report that mice expressing green fluorescent protein (GFP) under the control of the GAD67 promoter (GAD67‐GFP knock‐in mice) exhibit numerous GFP‐positive neurons in the central gray and reticular formation, allowing on‐line identification in vitro. Small (10–15 µm) or medium‐sized (15–25 µm) GFP‐positive perikarya surrounded larger serotonergic, noradrenergic, cholinergic and reticular neurons, and > 96% of neurons were double‐labeled for GFP and GABA, confirming that GFP‐positive neurons are GABAergic. Whole‐cell recordings in brainstem regions important for promoting REM sleep [subcoeruleus (SubC) or pontine nucleus oralis (PnO) regions] revealed that GFP‐positive neurons were spontaneously active at 3–12 Hz, fired tonically, and possessed a medium‐sized depolarizing sag during hyperpolarizing steps. Many neurons also exhibited a small, low‐threshold calcium spike. GFP‐positive neurons were tested with pharmacological agents known to promote (carbachol) or inhibit (orexin A) REM sleep. SubC GFP‐positive neurons were excited by the cholinergic agonist carbachol, whereas those in the PnO were either inhibited or excited. GFP‐positive neurons in both areas were excited by orexins/hypocretins. These data are congruent with the hypothesis that carbachol‐inhibited GABAergic PnO neurons project to, and inhibit, REM‐on SubC reticular neurons during waking, whereas carbachol‐excited SubC and PnO GABAergic neurons are involved in silencing locus coeruleus and dorsal raphe aminergic neurons during REM sleep. Orexinergic suppression of REM during waking is probably mediated in part via excitation of acetylcholine‐inhibited GABAergic neurons.
Meningeal cells induce dopaminergic neurons from embryonic stem cells
Authors: Hayashi Hideki , Morizane Asuka , Koyanagi Masaomi , Ono Yuichi , Sasai Yoshiki , Hashimoto Nobuo , Takahashi Jun
Published: July 2010

Neural induction of midbrain dopaminergic (DA) neurons from embryonic stem (ES) cells can be achieved by culturing them on a bone marrow‐derived stromal cell line, PA6, which possesses stromal cell‐derived inducing activity (SDIA). The mechanism of SDIA is unknown, but clinical application of ES cell transplantation requires the use of defined factors for DA neuron induction. Here, we demonstrate that meningeal cells harvested from the developing dura can induce DA neuron differentiation from mouse and human ES cells, as assessed by midbrain DA marker expression and secretion of DA in response to potassium stimuli. Intriguingly, the inductive strength of meningeal cells depends on their developmental stage, with those harvested from embryonic day 18 embryos showing the highest activity. Among six soluble factors known to be involved in DA neuron differentiation, only Wnt‐5a and transforming growth factor‐β3 were expressed by both meningeal and PA6 cells, and the expression of Wnt‐5a correlated with the DA neuron induction activity of these cells. Furthermore, the induction of DA neuron differentiation by PA6 cell‐conditioned medium was reversed by addition of a Wnt‐5a neutralizing antibody, whereas recombinant Wnt‐5a promoted DA neuron induction when cells were cultured on Matrigel. These results indicate that meningeal cells can be used as feeders to induce DA neurons from ES cells, and that Wnt‐5a plays an important role in DA neuron induction by SDIA.