Quantifying the behavioural relevance of hippocampal neurogenesis

Few studies that examine the neurogenesis--behaviour relationship formally establish covariation between neurogenesis and behaviour or rule out competing explanations. The behavioural relevance of neurogenesis might therefore be overestimated if other mechanisms account for some, or even all, of the experimental effects. A systematic review of the literature was conducted and the data reanalysed using causal mediation analysis, which can estimate the behavioural contribution of new hippocampal neurons separately from other mechanisms that might be operating. Results from eleven eligible individual studies were then combined in a meta-analysis to increase precision (representing data from 215 animals) and showed that neurogenesis made a negligible contribution to behaviour (standarised effect = 0.15; 95% CI = -0.04 to 0.34; p = 0.128); other mechanisms accounted for the majority of experimental effects (standardised effect = 1.06; 95% CI = 0.74 to 1.38; p = 1.7 $\times 10^{-11}$).Comment: To be published in PLoS ON

Long-term course of brain-derived neurotrophic factor serum levels in a patient treated with deep brain stimulation of the lateral habenula

Introduction: According to the neurotrophin hypothesis, a brain-derived neurotrophic factor (BDNF) decrease has been postulated as a pivotal pathomechanism in affective disorder, and the treatment-associated increase in peripheral BDNF has been linked to therapeutic efficacy of antidepressant drugs and electroconvulsive therapy. However, in deep brain stimulation (DBS), a still experimental antidepressant treatment approach, this issue has not yet been investigated. Methods: We examine the long-term course of serum BDNF levels in a 64-year-old woman who is being treated with DBS of the lateral habenula for severe major depressive disorder. Results: Our main findings are a significant increase in BDNF serum levels following DBS of the lateral habenula and an inverse U-shaped correlation of depression scores and BDNF levels. Discussion: The data indicate that DBS, like other effective antidepressant treatments, may contribute to an increase in peripheral BDNF levels, which are thought to reflect central nervous DBS-induced neuroplastic changes. Moreover, our observations underscore the complex nature of disease-associated BDNF alterations. Their identification as either state or trait marker remains controversial and requires larger-scale longitudinal studies. Copyright (C) 2012 S. Karger AG, Base

Phenotyping Young GluA1 Deficient Mice – A Behavioral Characterization in a Genetic Loss-of-Function Model

Alterations of glutamatergic neurotransmission have been implicated in neurodevelopmental and neuropsychiatric disorders. Mice lacking the GluA1 AMPA receptor subunit, encoded by the Gria1 gene, display multiple phenotypical features associated with glutamatergic dysfunction. While the phenotype of adult GluA1 deficient (Gria1-/- ) mice has been studied comprehensively, there are relevant gaps in knowledge about the course and the onset of behavioral alterations in the Gria1 knockout mouse model during post-weaning development. Based on former investigations in young wild-type mice, we exposed female and male adolescent Gria1-/- mice to a behavioral home-cage based testing battery designed for the purpose of severity assessment. Data obtained from mice with a constitutive loss of GluA1 were compared with those from wild-type littermates. We identified several genotype-dependent behavioral alterations in young Gria1-/- mice. While the preference for sweetness was not affected by genotype during adolescence, Gria1-/- mice displayed limited burrowing performance, and reached lower nest complexity scores. Analysis of home-cage based voluntary wheel running performance failed to confirm genotype-dependent differences. In contrast, when exposed to the open field test, Gria1-/- mice showed pronounced hyperlocomotion in early and late adolescence, and female Gria1 -/- mice exhibited thigmotaxis when prepubescent. We found increased corticosterone metabolite levels in fecal samples of adolescent Gria1-/- mice with females exhibiting increased adrenocortical activity already in prepubescence. Considering the course of behavioral modifications in early and late adolescence, the results do not support a persistent level of distress associated with GluA1 deficiency in the line. In contrast, the laboratory-specific readouts indicate transient, mild impairments of behavioral patterns relevant to animal welfare, and suggest a mild overall burden of the line

Hysteretic thermal spin-crossover in heteroleptic Fe(II) complexes using alkyl chain substituted 2,2’-dipyridylamine ligands

The alkyl chain carrying ligands N,N-di(pyridin-2-yl)butanamide (LC4) and N,N-di(pyridin-2-yl)decanamide (LC10) were combined with NCS− co-ligands to form the neutral heteroleptic Fe(II) complexes trans-[FeII(LC4)2(NCS)2] (1C4) and trans-[FeII(LC10)2(NCS)2] (1C10). Variable temperature crystallographic studies revealed that 1C4 is in the orthorhombic space group Pna21 between 85–200 K whereas 1C10 is in the monoclinic space group P21/c between 85–140 K. The average Fe–N bond lengths suggest that at 85 K 1C4 contains LS Fe(II) centres; however, the ca. 0.18 Å increase in the average Fe–N bond lengths between 85 and 120 K suggests a spin-transition to the HS state occurs within this temperature interval. 1C10 contains LS Fe(II) centres between 85 and 105 K. Upon warming from 105 to 140 K the average Fe–N bond lengths increase by ca. 0.19 Å, which suggests a spin-transition to the HS state. Solid-state magnetic susceptibility measurements showed that 1C4 undergoes semi-abrupt spin-crossover with T1/2 = 127.5 K and a thermal hysteresis of ca. 13 K whereas, 1C10 undergoes an abrupt spin-crossover with T1/2 = 119.0 K, and is also accompanied by thermal hysteresis of ca. 4 K. The crystallographic and magnetic data show that the length of the complex's alkyl chain substituents can have a large impact on the structure of the crystal lattice as well as a subtle effect on the T1/2 value for thermal spin-crossover

Spectroscopic and inclusion properties of G-series chemical warfare agents and their simulants: a DFT study

A computational protocol to predict the infrared spectra of chemical warfare agents (CWAs) tabun (GA), sarin (GB), soman (GD) and cyclosarin (GF) has been developed. Sarin was used to benchmark the method through gas phase simulations. DFT calculations using the EDF2 functional and diffuse 6-311++G** basis set was found to give the closest match to experimental infrared spectra. Using the same functional the 6-31G (2df, 2p) basis set was found to be superior when hydrated sarin was modelled. GA, GB, GD and GF, together with 11 commonly used simulants, were modelled in the gas and hydrated states. Complexes of GB and a number of CWA mimics with α-cyclodextrin were modelled to give insight into their different modes of inclusion

Inducible forebrain-specific ablation of the transcription factor Creb during adulthood induces anxiety but no spatial/contextual learning deficits

The cyclic AMP (cAMP)-response element binding protein (CREB) is an activity-dependent transcription factor playing a role in synaptic plasticity, learning and memory, and emotional behavior. However, the impact of Creb ablation on rodent behavior is vague as e.g. memory performance of different Creb mutant mice depends on the specific type of mutation per se but additionally on the background and learning protocol differences. Here we present the first targeted ablation of CREB induced during adulthood selectively in principal forebrain neurons in a pure background strain of C57BL/6 mice. All hippocampal principal neurons exhibited lack of CREB expression. Mutant mice showed a severe anxiety phenotype in the openfield and novel object exploration test as well as in the Dark-Light Box Test, but unaltered hippocampus-dependent long-term memory in the Morris water maze and in context dependent fear conditioning. On the molecular level, CREB ablation led to CREM up regulation in the hippocampus and frontal cortex which may at least in part compensate for the loss of CREB. BDNF, a postulated CREB target gene, was down regulated in the frontal lobe but not in the hippocampus; neurogenesis remained unaltered. Our data indicate that in the adult mouse forebrain the late onset of CREB ablation can, in case of memory functionality, be compensated for and is not essential for memory consolidation and retrieval during adulthood. In contrast, the presence of CREB protein during adulthood seems to be pivotal for the regulation of emotional behavior

Two Sides of the Same Coin: A Case Report of First-Episode Catatonic Syndrome in a High-Functioning Autism Patient

Background: Catatonic phenomena such as stupor, mutism, stereotypy, echolalia, echopraxia, affective flattening, psychomotor deficits, and social withdrawal are characteristic symptoms of both schizophrenia and autism spectrum disorders (ASD), suggesting overlapping pathophysiological similarities such as altered glutamatergic and dopaminergic synaptic transmission and common genetic mutations. In daily clinical practice, ASD can be masked by manifest catatonic or psychotic symptoms and represent a diagnostic challenge, especially in patients with unknown or empty medical history. Unclear diagnosis is one of the main factors for delayed treatment. However, we are still missing diagnostic recommendations when dealing with ASD patients suffering from catatonic syndrome.Case presentation: A 31-year-old male patient without history of psychiatric disease presented with a severe catatonic syndrome and was admitted to our closed psychiatric ward. After the treatment with high-dose lorazepam and intramuscular olanzapine, catatonic symptoms largely remitted, but autistic traits persisted. Following a detailed anamnesis and a thorough neuropsychological testing, we diagnosed the patient with high-functioning autism and catatonic schizophrenia. The patient was discharged in a remitted state with long-acting injectable olanzapine.Conclusion: This case represents an example of diagnostic and therapeutic challenges of catatonic schizophrenia in high-functioning autism due to clinical and neurobiological overlaps of these conditions. We discuss clinical features together with pathophysiological concepts of both conditions. Furthermore, we tackle social and legal hurdles in Germany that naturally arise in these patients. Finally, we present diagnostic “red flags” that can be used to rationally select and conduct current recommended diagnostic assessments if there is a suspicion of ASD in patients with catatonic syndrome in order to provide them with the most appropriate treatment

Rational Design of Combination Enzyme Therapy for Celiac Sprue

SummaryCeliac sprue (also known as celiac disease) is an inheritable, gluten-induced enteropathy of the upper small intestine with an estimated prevalence of 0.5%–1% in most parts of the world. The ubiquitous nature of food gluten, coupled with inadequate labeling regulations in most countries, constantly poses a threat of disease exacerbation and relapse for patients. Here, we demonstrate that a two-enzyme cocktail comprised of a glutamine-specific cysteine protease (EP-B2) that functions under gastric conditions and a PEP, which acts in concert with pancreatic proteases under duodenal conditions, is a particularly potent candidate for celiac sprue therapy. At a gluten:EP-B2:PEP weight ratio of 75:3:1, grocery store gluten is fully detoxified within 10 min of simulated duodenal conditions, as judged by chromatographic analysis, biopsy-derived T cell proliferation assays, and a commercial antigluten antibody test

Geo-Biological Investigations on Azooxanthellate Cold-Water Coral Reefs on the Carbonate Mounds Along the Celtic Continental Slope

Northeast Atlantic 2004 Cruise No. 61, Leg 1 April 19 to May 4, 2004, Lisbon – Cor

A tale of two parasites:statistical modelling to support disease control programmes in Africa

Vector-borne diseases have long presented major challenges to the health of rural communities in the wet tropical regions of the world, but especially in sub-Saharan Africa. In this paper we describe the contribution that statistical modelling has made to the global elimination programme for one vector-borne disease, onchocerciasis. We explain why information on the spatial distribution of a second vector-borne disease, Loa loa, is needed before communities at high risk of onchocerciasis can be treated safely with mass distribution of ivermectin, an antifiarial medication. We show how a model-based geostatistical analysis of Loa loa prevalence survey data can be used to map the predictive probability that each location in the region of interest meets a WHO policy guideline for safe mass distribution of ivermectin and describe two applications: one is to data from Cameroon that assesses prevalence using traditional blood-smear microscopy; the other is to Africa-wide data that uses a low-cost questionnaire-based method. We describe how a recent technological development in image-based microscopy has resulted in a change of emphasis from prevalence alone to the bivariate spatial distribution of prevalence and the intensity of infection amongst infected individuals. We discuss how statistical modelling of the kind described here can contribute to health policy guidelines and decisionmaking in two ways. One is to ensure that, in a resource-limited setting, prevalence surveys are designed, and the resulting data analysed, as efficiently as possible. The other is to provide an honest quantification of the uncertainty attached to any binary decision by reporting predictive probabilities that a policy-defined condition for action is or is not met. Vector-borne diseases have long presented major challenges to the health of rural communities in the wet tropical regions of the world, but especially in sub-Saharan Africa. In this paper we describe the contribution that statistical modelling has made to the global elimination programme for one vector-borne disease, onchocerciasis. We explain why information on the spatial distribution of a second vector-borne disease, Loa loa, is needed before communities at high risk of onchocerciasis can be treated safely with mass distribuiton of ivermectin, an antiflarial medication. We show how a model-based geostatistical analysis of Loa loa prevalence survey data can be used to map the predictive probability that each location in the region of interest meets a WHO policy guideline for safe mass distribution of ivermectin and describe two applications: one to data from Cameroon that assesses prevalence using traditional blood-smear microscopy; one to Africa-wide data that uses a low-cost questionnaire-based method. We describe how a recent technological development in image-based microscopy has resulted in a change of emphasis from prevalence alone to the bivariate spatial distribution of prevalence and the intensity of infection amongst infected individuals. We discuss how statistical modelling of the kind described here can contribute to health policy guidelines and decision-making in two ways. One is to ensure that, in a resourcelimited setting, prevalece surveys are designed, and the resulting data analysed, as efficiently as possible. The other is to provide an honest quantification of the uncertainy attached to any binary decision by reporting predictive probabilities that a policy-defined condition for action is or is not met