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SummaryEpilepsy, intellectual and cortical sensory deficits and psychiatric manifestations are among the most frequent manifestations of mitochondrial diseases. Yet, how mitochondrial dysfunction affects neural structure and function remains largely elusive. This is mostly due to the lack of a properin vitrotranslational neuronal model system(s) with impaired energy metabolism. Leveraging the induced pluripotent stem cell technology, from a cohort of patients with the common pathogenic m.3243A>G variant of mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS), we differentiated excitatory cortical neurons (iNeurons) with normal (low heteroplasmy) and impaired (high heteroplasmy) mitochondrial function on an isogenic nuclear DNA background. iNeurons with high levels of heteroplasmy exhibited mitochondrial dysfunction, delayed neural maturation, reduced dendritic complexity and fewer functional excitatory synapses. Micro-electrode array recordings of neuronal networks with high heteroplasmy displayed reduced network activity and decreased synchronous network bursting. The impaired neural energy metabolism of iNeurons compromising the structural and functional integrity of neurons and neural networks, could be the primary driver of increased susceptibility to neuropsychiatric manifestations of mitochondrial disease.

Defects in histone methyltransferases (HMTs) are major contributing factors in neurodevelopmental disorders (NDDs). Heterozygous variants of SETD1A involved in histone H3 lysine 4 (H3K4) methylation were previously identified in individuals with schizophrenia. Here, we define the clinical features of the Mendelian syndrome associated with haploinsufficiency of SETD1A by investigating 15 predominantly pediatric individuals who all have de novo SETD1A variants. These individuals present with a core set of symptoms comprising global developmental delay and/or intellectual disability, subtle facial dysmorphisms, behavioral and psychiatric problems. We examined cellular phenotypes in three patient derived lymphoblastoid cell lines with three variants: p.Gly535Alafs*12, c.4582-2_4582delAG, and p.Tyr1499Asp. These patient cell lines displayed DNA damage repair defects that were comparable to previously observed RNAi-mediated depletion of SETD1A. This suggested that these variants, including the p.Tyr1499Asp in the catalytic SET domain, behave as Loss-of-Function (LoF) alleles. Previous studies demonstrated a role for SETD1A in cell cycle control and differentiation. However, individuals with SETD1A variants do not show major structural brain defects or severe microcephaly, suggesting that defective proliferation and differentiation of neural progenitors is unlikely the single underlying cause of the disorder. We show here that the Drosophila Melanogaster SETD1A orthologue is required in postmitotic neurons of the fly brain for normal memory, suggesting a role in post development neuronal function. Together, this study defines a neurodevelopmental disorder caused by dominant de novo LoF variants in SETD1A and further supports a role for H3K4 methyltransferases in the regulation of neuronal processes underlying normal cognitive functioning.

Epigenetic regulation of gene transcription plays a critical role in neural network development and in the etiology of Intellectual Disability (ID) and Autism Spectrum Disorder (ASD). However, little is known about the mechanisms by which epigenetic dysregulation leads to neural network defects. Kleefstra syndrome (KS), caused by mutation in the histone methyltransferase EHMT1, is a neurodevelopmental disorder with the clinical features of both ID and ASD. To study the impact of decreased EHMT1 function in human cells, we generated excitatory cortical neurons from induced pluripotent stem (iPS) cells derived from KS patients. In addition, we created an isogenic set by genetically editing healthy iPS cells. Characterization of the neurons at the single-cell and neuronal network level revealed consistent discriminative properties that distinguished EHMT1-mutant from wildtype neurons. Mutant neuronal networks exhibited network bursting with a reduced rate, longer duration, and increased temporal irregularity compared to control networks. We show that these changes were mediated by the upregulation of the NMDA receptor (NMDAR) subunit 1 and correlate with reduced deposition of the repressive H3K9me2 mark, the catalytic product of EHMT1, at the GRIN1 promoter. Furthermore, we show that EHMT1 deficiency in mice leads to similar neuronal network impairments and increased NMDAR function. Finally, we could rescue the KS patient-derived neuronal network phenotypes by pharmacological inhibition of NMDARs. Together, our results demonstrate a direct link between EHMT1 deficiency in human neurons and NMDAR hyperfunction, providing the basis for a more targeted therapeutic approach to treating KS.

Kleefstra syndrome (KS) is a neurodevelopmental disorder caused by mutations in the histone methyltransferase EHMT1. To study the impact of decreased EHMT1 function in human cells, we generated excitatory cortical neurons from induced pluripotent stem (iPS) cells derived from KS patients. Neuronal networks of patient-derived cells exhibit network bursting with a reduced rate, longer duration, and increased temporal irregularity compared to control networks. We show that these changes are mediated by upregulation of NMDA receptor (NMDAR) subunit 1 correlating with reduced deposition of the repressive H3K9me2 mark, the catalytic product of EHMT1, at the GRIN1 promoter. In mice EHMT1 deficiency leads to similar neuronal network impairments with increased NMDAR function. Finally, we rescue the KS patient-derived neuronal network phenotypes by pharmacological inhibition of NMDARs. Summarized, we demonstrate a direct link between EHMT1 deficiency and NMDAR hyperfunction in human neurons, providing a potential basis for more targeted therapeutic approaches for KS., Kleefstra syndrome is a neurodevelopmental disorder associated with hapoinsufficiency of the histone methyltransferase EHMT1. Here the authors show using induced pluripotent cells-derived neurons from patients that network dysfunction occurs and is due to dysfunction of the NMDA receptor.

Contains fulltext : 200575.pdf (Publisher’s version ) (Open Access) Background: Active sensing is crucial for navigation. It is characterized by self-generated motor action controlling the accessibility and processing of sensory information. In rodents, active sensing is commonly studied in the whisker system. As rats and mice modulate their whisking contextually, they employ frequency and amplitude modulation. Understanding the development, mechanisms, and plasticity of adaptive motor control will require precise behavioral measurements of whisker position. Findings: Advances in high-speed videography and analytical methods now permit collection and systematic analysis of large datasets. Here, we provide 6,642 videos as freely moving juvenile (third to fourth postnatal week) and adult rodents explore a stationary object on the gap-crossing task. The dataset includes sensory exploration with single- or multi-whiskers in wild-type animals, serotonin transporter knockout rats, rats received pharmacological intervention targeting serotonergic signaling. The dataset includes varying background illumination conditions and signal-to-noise ratios (SNRs), ranging from homogenous/high contrast to non-homogenous/low contrast. A subset of videos has been whisker and nose tracked and are provided as reference for image processing algorithms. Conclusions: The recorded behavioral data can be directly used to study development of sensorimotor computation, top-down mechanisms that control sensory navigation and whisker position, and cross-species comparison of active sensing. It could also help to address contextual modulation of active sensing during touch-induced whisking in head-fixed vs freely behaving animals. Finally, it provides the necessary data for machine learning approaches for automated analysis of sensory and motion parameters across a wide variety of signal-to-noise ratios with accompanying human observer-determined ground-truth. 6 p.

Neuronal gene transcription through epigenetic modifications plays an important role in the etiology of intellectual disability (ID) and autism spectrum disorders (ASD). Haploinsufficiency of the Euchromatin Histone Methyltransferase 1 (EHMT1) gene causes Kleefstra syndrome, a neurodevelopmental disorder with the clinical features of both ID and ASD. Interestingly, patients with loss-of-function mutations in the functionally distinct epigenetic regulators MBD5, MLL3 or SMARCB1 also share the same core features, referred to as the Kleefstra syndrome spectrum (KSS). Currently, little is known about how variants in these different chromatin remodelers lead to the phenotypic convergence in KSS. To decipher the pathophysiology underlying KSS we here directly compared the effect of loss of function of four distinct KSS genes in developing rodent neuronal networks, using a combination of transcriptional analysis, immunocytochemistry, single-cell recordings and micro-electrode arrays. KSS gene-deficient neuronal networks all showed impaired neural network activity, resulting in hyperactive networks with altered network organization. At the single-cell level, we found genotype-specific changes in intrinsic excitability and in excitatory-inhibitory balance, all leading to increased excitability. These findings we could also recapitulate in a mouse model for Kleefstra syndrome. Transcriptional analysis further revealed distinct regulatory mechanisms. Nevertheless, KSS-target genes share similar functions in regulating neuronal excitability and synaptic function, several of which are associated with ID and ASD. Our results show that KSS genes mainly converge at the level of neuronal network development, providing new insights into the pathophysiology of KSS and to other phenotypically congruent disorders involving ID and autism.

Neurodevelopmental disorders (NDDs) are a collection of heterogeneous syndromes involving disruption of early neurobiological development. While the identification of disease genes has great benefits for diagnostic and prognostic purposes, for the vast majority of these genes there is little knowledge about neurobiological mechanisms that they control at the cellular and network level. Recent studies demonstrate that NDDs are "diseases of the synapse". Synaptic malfunction can severely affect network connectivity and dynamic. Understanding the neural circuit basis of NDDs is therefore imperial for a better understanding of these disorders. Kleefstra syndrome (KS) is a NDD characterized by moderate to severe intellectual disability, childhood hypotonia, and facial dysmorphism associated with genes deficiency. Here, we studied how KS genes-deficiency affects neuronal network maturation using dissociated neuronal cultures (i.e. from rodent or KS patient induced pluripotent stem cells). Using micro-electrode arrays technology we characterized the electrophysiological activity of control and KS genes-deficient neuronal networks. We showed that KS genes-deficient neuronal networks exhibited different pattern of synchronous activity compared to control condition. In particular, KS genes-deficiency induced an inappropriate network organization and irregular pattern of activity, indicating that KS genes are required for proper network formation. The neuronal network phenotype found here, provides for relevant future directions in the elucidation of pathophysiology in KS.

Coherent fiber bundles (CFB) are commonly used for endoscopic imaging, e.g. in biomedicine. Usually a CFB with several ten thousand cores is employed together with a lens system on its distal end. However, pixelation effects occur and the imaging plane can’t be scanned, limiting the field of application of CFBs. To circumvent these limitations, a spatial light modulator (SLM) is employed on the proximal side of a single-mode CFB. This enables creating arbitrary wave fronts at the distal fiber end, e.g. for instance for optical tweezers, endoscopes with tunable image plane or for exciting transgenetic nerve cells. However, of the shelf CFBs show phase distortions between individual cores (e.g. coupling between cores, speckle effect) which need to be calibrated and corrected at the proximal side. These distortions depend on the wavelength, temperature, polarization and most importantly on the bending of the CFB. Therefore an on-line calibration during bending variations is required. For this purpose a semitransparent mirror is employed at the distal fiber end, which allows to measure double the distortion at the proximal side by digital holography without the need for a guide star. For correcting the distortion the same SLM as above is employed. However, the distortion for a single transmission through the CFB commonly exceeds several 2 pi. Thus, an incremental phase measurement yields unambiguous results. To circumvent this problem, two approaches for on-line calibration are compared. 1st Multiple wavelength holography and 2nd initial calibration in transmission mode with subsequent tracking of distortion changes in reflecting mode.

Contains fulltext : 183010.pdf (Publisher’s version ) (Open Access) Depression during pregnancy is highly prevalent and has a multitude of potential risks of the offspring. Among confirmed consequences is a higher risk of psychopathology. However, it is unknown how maternal depression may impact the child's brain to mediate this vulnerability. Here we studied amygdala functioning, using task-based functional MRI, in children aged 6-9 years as a function of prenatal maternal depressive symptoms selected from a prospective population-based sample (The Generation R Study). We show that children exposed to clinically relevant maternal depressive symptoms during pregnancy (N = 19) have increased amygdala responses to negative emotional faces compared to control children (N = 20) [F(1,36) 7.02, p = 0.022]. Strikingly, postnatal maternal depressive symptoms, obtained at 3 years after birth, did not explain this relation. Our findings are in line with a model in which prenatal depressive symptoms of the mother are associated with amygdala hyperresponsivity in her offspring, which may represent a risk factor for later-life psychopathology. 8 p.

This chapter focuses on developments in democratic and pluralistic societies. Participation and community-driven planning were topics of debate after World War II, in light of increasing problems with housing and other issues in cities all over the world. Democratic rule is based on political equality and participation rights—although these are not about participation at the housing and building level, but at district and city level, and about having a say in the planning and design of the built environment. In representative democracies with legislative, executive, and judicial authorities, governments formed at various levels by elected politicians are responsible for political decisions, which include planning, land, and building laws. The social movements are the product and producers of modernization, and urban planning history is a victorious history of "successful" modernization processes. For urban planning history, it is important to contextualize stakeholders, projects, and plans before a socio-political background, and to integrate transdisciplinary and comparative approaches.

Contains fulltext : 168902.pdf (Publisher’s version ) (Open Access) Neurons derived from human induced Pluripotent Stem Cells (hiPSCs) provide a promising new tool for studying neurological disorders. In the past decade, many protocols for differentiating hiPSCs into neurons have been developed. However, these protocols are often slow with high variability, low reproducibility, and low efficiency. In addition, the neurons obtained with these protocols are often immature and lack adequate functional activity both at the single-cell and network levels unless the neurons are cultured for several months. Partially due to these limitations, the functional properties of hiPSC-derived neuronal networks are still not well characterized. Here, we adapt a recently published protocol that describes production of human neurons from hiPSCs by forced expression of the transcription factor neurogenin-212. This protocol is rapid (yielding mature neurons within 3 weeks) and efficient, with nearly 100% conversion efficiency of transduced cells (>95% of DAPI-positive cells are MAP2 positive). Furthermore, the protocol yields a homogeneous population of excitatory neurons that would allow the investigation of cell-type specific contributions to neurological disorders. We modified the original protocol by generating stably transduced hiPSC cells, giving us explicit control over the total number of neurons. These cells are then used to generate hiPSC-derived neuronal networks on micro-electrode arrays. In this way, the spontaneous electrophysiological activity of hiPSC-derived neuronal networks can be measured and characterized, while retaining interexperimental consistency in terms of cell density. The presented protocol is broadly applicable, especially for mechanistic and pharmacological studies on human neuronal networks. 10 p.

Item does not contain fulltext For studies of visual cortex organization, mouse is becoming an increasingly more often used model. In addition to its genetic tractability, the relatively small area of cortical surface devoted to visual processing simplifies efforts in relating the structure of visual cortex to visual function. However, the nature of this compact organization can make some comparisons to the much larger non-human primate visual cortex difficult. The squirrel, as a highly visual rodent offers a useful means for better understanding how mouse and monkey cortical organization compares. More in line with primates than their nocturnal rodent cousin, squirrels rely much more on sight and have evolved a larger expanse of cortex devoted to visual processing. To reveal the detailed organization of visual cortex in squirrels, we injected a highly sensitive monosynaptic retrograde tracer (glycoprotein deleted rabies virus) into several locations of primary visual cortex (V1) in California ground squirrels. The resulting pattern of connectivity revealed an organizational scheme in the squirrel that retains some of the basic features of the mouse visual cortex along the medial and posterior borders of V1, but unlike mouse has an elaborate and extensive pattern laterally that is more similar to the early visual cortex organization found in monkeys. In this way, we show that the squirrel can serve as a useful model for comparison to both mouse and primate visual systems, and may help facilitate comparisons between these two very different yet widely used animal models of visual processing. 13 p.

FOXP2 was the first gene shown to cause a Mendelian form of speech and language disorder. Although developmentally expressed in many organs, loss of a single copy of FOXP2 leads to a phenotype that is largely restricted to orofacial impairment during articulation and linguistic processing deficits. Why perturbed FOXP2 function affects specific aspects of the developing brain remains elusive. We investigated the role of FOXP2 in neuronal differentiation and found that FOXP2 drives molecular changes consistent with neuronal differentiation in a human model system. We identified a network of FOXP2 regulated genes related to retinoic acid signaling and neuronal differentiation. FOXP2 also produced phenotypic changes associated with neuronal differentiation including increased neurite outgrowth and reduced migration. Crucially, cells expressing FOXP2 displayed increased sensitivity to retinoic acid exposure. This suggests a mechanism by which FOXP2 may be able to increase the cellular differentiation response to environmental retinoic acid cues for specific subsets of neurons in the brain. These data demonstrate that FOXP2 promotes neuronal differentiation by interacting with the retinoic acid signaling pathway and regulates key processes required for normal circuit formation such as neuronal migration and neurite outgrowth. In this way, FOXP2, which is found only in specific subpopulations of neurons in the brain, may drive precise neuronal differentiation patterns and/or control localization and connectivity of these FOXP2 positive cells.

Visual Abstract, Brain research investigating electrical activity within neural tissue is producing an increasing amount of physiological data including local field potentials (LFPs) obtained via extracellular in vivo and in vitro recordings. In order to correctly interpret such electrophysiological data, it is vital to adequately understand the electrical properties of neural tissue itself. An ongoing controversy in the field of neuroscience is whether such frequency-dependent effects bias LFP recordings and affect the proper interpretation of the signal. On macroscopic scales and with large injected currents, previous studies have found various grades of frequency dependence of cortical tissue, ranging from negligible to strong, within the frequency band typically considered relevant for neuroscience (less than a few thousand hertz). Here, we performed a detailed investigation of the frequency dependence of the conductivity within cortical tissue at microscopic distances using small current amplitudes within the typical (neuro)physiological micrometer and sub-nanoampere range. We investigated the propagation of LFPs, induced by extracellular electrical current injections via patch-pipettes, in acute rat brain slice preparations containing the somatosensory cortex in vitro using multielectrode arrays. Based on our data, we determined the cortical tissue conductivity over a 100-fold increase in signal frequency (5–500 Hz). Our results imply at most very weak frequency-dependent effects within the frequency range of physiological LFPs. Using biophysical modeling, we estimated the impact of different putative impedance spectra. Our results indicate that frequency dependencies of the order measured here and in most other studies have negligible impact on the typical analysis and modeling of LFP signals from extracellular brain recordings.

Stadt und Sicherheit sind kein neues Thema. Uber viele Jahrhunderte hinweg bot die Stadt „innerhalb der Mauern“ relative „Sicherheit“ und Aufstiegs- und Wohlstandsperspektiven in okonomischer und sozialer Hinsicht. Im 19. Jahrhundert wurden im Kontext von Migration, Elendsvierteln und Wohnungsnot Themen von ethnischen Minderheiten, von abweichendem Verhalten und Kriminalitat in vielerlei Auspragungen Begleiterscheinungen des Urbanisierungsprozesses.

Vor dem Hintergrund wachsender sozialer Ungleichheit und sozialraumlicher Polarisierung in deutschen Grosstadten besteht an empirischen Studien zur Aufwertung, Gentrifizierung und sozialer Entmischung von Stadtquartieren kein Mangel und die Gefahren einer soziookonomischen Polarisierung der Stadte sind in Forschung und Politik hinreichend bekannt (vgl. BMVBS, 2009). Die Untersuchungen eint, dass aktuelle Veranderungsprozesse der Wohnbedingungen und des Einzelhandels detailliert beschrieben – praziser beklagt – werden, aber keine Studien bestehen, welche die Ausgangssituation eines (noch) nicht aufgewertet Viertels analysieren und mittels einer Langsschnittstudie mit gleichen Daten eine fundierte Ex-post-Analyse ermoglichen wurden. Sicher wurde die Immobilienwirtschaft derartige Identifizierungen von „Truffelschweinen der Stadtentwicklung“ fur „Gentrifizierungsgebiete im Wartezustand“ zu gerne aufgreifen, waren doch damit erhebliche Gewinnspannen zu erzielen.

Schizophrenia is a complex disorder that affects cognitive function and has been linked, both in patients and animal models, to dysfunction of the GABAergic system. However, the pathophysiological consequences of this dysfunction are not well understood. Here, we examined the GABAergic system in an animal model displaying schizophrenia-relevant features, the apomorphine-susceptible (APO-SUS) rat and its phenotypic counterpart, the apomorphine-unsusceptible (APO-UNSUS) rat at postnatal day 20–22. We found changes in the expression of the GABA-synthesizing enzyme GAD67 specifically in the prelimbic- but not the infralimbic region of the medial prefrontal cortex (mPFC), indicative of reduced inhibitory function in this region in APO-SUS rats. While we did not observe changes in basal synaptic transmission onto LII/III pyramidal cells in the mPFC of APO-SUS compared to APO-UNSUS rats, we report reduced paired-pulse ratios at longer inter-stimulus intervals. The GABAB receptor antagonist CGP 55845 abolished this reduction, indicating that the decreased paired-pulse ratio was caused by increased GABAB signaling. Consistently, we find an increased expression of the GABAB1 receptor subunit in APO-SUS rats. Our data provide physiological evidence for increased presynaptic GABAB signaling in the mPFC of APO-SUS rats, further supporting an important role for the GABAergic system in the pathophysiology of schizophrenia.

One of the lessons of the financial crisis as of late was the inherent credit risk attached to the value of derivatives. Since not all derivatives can be cleared by central counterparties, a significant amount of OTC derivatives will be subject to increased regulatory capital charges. These charges cover both current and future unexpected losses; the capital costs for derivatives transactions can become substantial if not prohibitive. At the same time, capital optimization through CDS hedging of counterparty risks will result in a hedge position beyond the economic risk (“overhedging”) required to meet Basel II/III rules. In addition, IFRS accounting rules again differ from Basel, creating a mismatch when hedging CVA. Even worse, CVA hedging using CDS may introduce significant profit and loss volatility while satisfying the conditions for capital relief. An innovative approach to hedging CVA aims to solve these issues.

Item does not contain fulltext Current research supports the notion that the apparently innate trait Sensory Processing Sensitivity (SPS) may act as a modulator of development as function of the environment. Interestingly, the common serotonin transporter linked polymorphic region (5-HTTLPR) does the same. While neural mechanisms underlying SPS are largely unknown, those associated with the 5-HTTLPR have been extensively investigated. We perform a comparative analysis of research findings on sensory processing facets associated with the trait and polymorphism to: 1. detect shared phenotypes and frame a hypothesis towards neural mechanisms underlying SPS; 2. increase the understanding of 5-HTTLPR-associated behavioral patterns. Trait and polymorphism are both associated with differential susceptibility to environmental stimuli; additionally, both involve 1. having stronger emotional reactions, 2. processing of sensory information more deeply, 3. being more aware of environmental subtleties, and 4. being easily overstimulated. We discuss neural mechanisms and environmental conditions that may underlie these four facets. Besides urging the actual assessment of the link between the two, the conclusions of our analyses may guide and focus future research strategies.

Heterozygous mutations or deletions in the human Euchromatin histone methyltransferase 1 (EHMT1) gene cause Kleefstra syndrome, a neurodevelopmental disorder that is characterized by autistic-like features and severe intellectual disability (ID). Neurodevelopmental disorders including ID and autism may be related to deficits in activity-dependent wiring of brain circuits during development. Although Kleefstra syndrome has been associated with dendritic and synaptic defects in mice and Drosophila, little is known about the role of EHMT1 in the development of cortical neuronal networks. Here we used micro-electrode arrays and whole-cell patch-clamp recordings to investigate the impact of EHMT1 deficiency at the network and single cell level. We show that EHMT1 deficiency impaired neural network activity during the transition from uncorrelated background action potential firing to synchronized network bursting. Spontaneous bursting and excitatory synaptic currents were transiently reduced, whereas miniature excitatory postsynaptic currents were not affected. Finally, we show that loss of function of EHMT1 ultimately resulted in less regular network bursting patterns later in development. These data suggest that the developmental impairments observed in EHMT1-deficient networks may result in a temporal misalignment between activity-dependent developmental processes thereby contributing to the pathophysiology of Kleefstra syndrome.

Fluoxetine (ProzacA (R)) is the most frequently prescribed drug to battle depression in pregnant women, but its safety in the unborn child has not yet been established. Fluoxetine, a selective serotonin reuptake inhibitor, crosses the placenta, leading to increased extracellular serotonin levels and potentially neurodevelopmental changes in the fetus. The purpose of this study was to elucidate the long-term consequences of prenatal fluoxetine in rats. Pregnant rats were injected daily with 12 mg/kg fluoxetine or vehicle from gestational day 11 until birth, and the behavior of the offspring was monitored. Plasma fluoxetine transfer from mother to pup was 83%, and high levels of fluoxetine (13.0 mu g/g) were detected in the pup brain 5 h after the last injection. Fluoxetine-treated dams gave birth to litters 15% smaller than usual and to pups of reduced weight (until postnatal day 7). Furthermore, prenatal fluoxetine exposure significantly increased anxiety in the novelty-suppressed feeding test, the footshock-induced conditioned place aversion test, and the elevated plus maze test (following footshock pre-exposure) during adulthood, and also significantly decreased components of social play behavior at 4 weeks of age, and a strong tendency for increased self-grooming and making less contact in adults. Behavioral despair, anhedonia, and sexual behavior were not different between treatment groups. Finally, the hypothermic response to the 5-HT1A agonist flesinoxan was observed at a lower dose in prenatally fluoxetine-exposed rats than in controls. Prenatal fluoxetine exposure in rats leads to detrimental behavioral outcomes in later life, which may partly be due to altered 5-HT1A receptor signaling.

Contains fulltext : 75307.pdf (Publisher’s version ) (Closed access) The bewildering complexity of cortical microcircuits at the single cell level gives rise to surprisingly robust emergent activity patterns at the level of laminar and columnar local field potentials (LFPs) in response to targeted local stimuli. Here we report the results of our multivariate data-analytic approach based on simultaneous multi-site recordings using micro-electrode-array chips for investigation of the microcircuitry of rat somatosensory (barrel) cortex. We find high repeatability of stimulus-induced responses, and typical spatial distributions of LFP responses to stimuli in supragranular, granular, and infragranular layers, where the last form a particularly distinct class. Population spikes appear to travel with about 33 cm/s from granular to infragranular layers. Responses within barrel related columns have different profiles than those in neighbouring columns to the left or interchangeably to the right. Variations between slices occur, but can be minimized by strictly obeying controlled experimental protocols. Cluster analysis on normalized recordings indicates specific spatial distributions of time series reflecting the location of sources and sinks independent of the stimulus layer. Although the precise correspondences between single cell activity and LFPs are still far from clear, a sophisticated neuroinformatics approach in combination with multi-site LFP recordings in the standardized slice preparation is suitable for comparing normal conditions to genetically or pharmacologically altered situations based on real cortical microcircuitry.

A topological approach to the analysis of isomeric dendrimers by considering their molecular graphs has been applied to correlate various properties of a series of new sulfonimide-based isomeric dendrimers with their structures. According to this approach isomeric dendrimers are referred to as either isographic, that is, having the same graph, or non-isographic, that is, having different graphs. Six sets of non-isographic isomeric dendrimers with four to ten peripheral groups and one set of three isographic isomers with eight peripheral groups have been designed, synthesized and investigated with regard to their melting, solubility, separation, NMR spectroscopic and mass spectrometric characteristics. The results are discussed in the light of the graph-dependent and-independent properties of the isomers. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

Systematic analysis of the persulfonylation of branched aromatic oligoamines with different arylsulfonyl chlorides allowed optimization of the repetitive steps involved in the synthesis of the sulfonimide-based dendrimers. The optimized procedures afforded the fourth generation N- and pentaphenylene-centered dendrimers with 16 and 32 peripheral groups, respectively. Analysis of products of incomplete substitution showed that the amino groups in aromatic oligoamines are persulfonylated consecutively.

Contains fulltext : 34492.pdf (Publisher’s version ) (Closed access) Synaptic circuits bind together functional modules of the neocortex. We aim to clarify in a rodent model how intra- and transcolumnar microcircuits in the barrel cortex are laid out to segregate and also integrate sensory information. The primary somatosensory (barrel) cortex of rodents is the ideal model system to study these issues because there, the tactile information derived from the large facial whiskers on the snout is mapped onto so called barrel-related columns which altogether form an isomorphic map of the sensory periphery. This allows to functionally interpret the synaptic microcircuits we have been analyzing in barrel-related columns by means of whole-cell recordings, biocytin filling and mapping of intracortical functional connectivity with sublaminar specificity by computer-controlled flash-release of glutamate. We find that excitatory spiny neurons (spiny stellate, star pyramidal, and pyramidal cells) show a layer-specific connectivity pattern on top of which further cell type-specific circuits can be distinguished. The main features are: (a) strong intralaminar, intracolumnar connections are established by all types of excitatory neurons with both, excitatory and (except for layer Vb- intrinsically burst-spiking-pyramidal cells) inhibitory cells; (b) effective translaminar, intracolumnar connections become more abundant along the three main layer compartments of the canonical microcircuit, and (c) extensive transcolumnar connectivity is preferentially found in specific cell types in each of the layer compartments of a barrel-related column. These multiple sequential and parallel circuits are likely to be suitable for specific cortical processing of "what" "where" and "when" aspects of tactile information acquired by the whiskers on the snout.

Cadherin-13 (CDH13), a unique glycosylphosphatidylinositol-anchored member of the cadherin family of cell adhesion molecules, has been identified as a risk gene for attention-deficit/hyperactivity disorder (ADHD) and various comorbid neurodevelopmental and psychiatric conditions, including depression, substance abuse, autism spectrum disorder and violent behavior, while the mechanism whereby CDH13 dysfunction influences pathogenesis of neuropsychiatric disorders remains elusive. Here we explored the potential role of CDH13 in the inhibitory modulation of brain activity by investigating synaptic function of GABAergic interneurons. Cellular and subcellular distribution of CDH13 was analyzed in the murine hippocampus and a mouse model with a targeted inactivation of Cdh13 was generated to evaluate how CDH13 modulates synaptic activity of hippocampal interneurons and behavioral domains related to psychopathologic (endo)phenotypes. We show that CDH13 expression in the cornu ammonis (CA) region of the hippocampus is confined to distinct classes of interneurons. Specifically, CDH13 is expressed by numerous parvalbumin and somatostatin-expressing interneurons located in the stratum oriens, where it localizes to both the soma and the presynaptic compartment. Cdh13−/− mice show an increase in basal inhibitory, but not excitatory, synaptic transmission in CA1 pyramidal neurons. Associated with these alterations in hippocampal function, Cdh13−/− mice display deficits in learning and memory. Taken together, our results indicate that CDH13 is a negative regulator of inhibitory synapses in the hippocampus, and provide insights into how CDH13 dysfunction may contribute to the excitatory/inhibitory imbalance observed in neurodevelopmental disorders, such as ADHD and autism.

Mobius syndrome (MBS) is a neurological disorder that is characterized by paralysis of the facial nerves and variable other congenital anomalies. The aetiology of this syndrome has been enigmatic since the initial descriptions by von Graefe in 1880 and by Mobius in 1888, and it has been debated for decades whether MBS has a genetic or a non-genetic aetiology. Here, we report de novo mutations affecting two genes, PLXND1 and REV3L in MBS patients. PLXND1 and REV3L represent totally unrelated pathways involved in hindbrain development: neural migration and DNA translesion synthesis, essential for the replication of endogenously damaged DNA, respectively. Interestingly, analysis of Plxnd1 and Rev3l mutant mice shows that disruption of these separate pathways converge at the facial branchiomotor nucleus, affecting either motoneuron migration or proliferation. The finding that PLXND1 and REV3L mutations are responsible for a proportion of MBS patients suggests that de novo mutations in other genes might account for other MBS patients., Fundacion Seneca fellowship; EMBO short-term fellowship; IBRO Project InEurope grants programme; Fundacion Cultural Privada Esteban-Romero; European Union FP7 Large-Scale Integrating Project Genetic and Epigenetic Networks in Cognitive Dysfunction; Scientific and Technological Research Council of Turkey (TÜBİTAK); CRANIRARE consortia of the European Research Area Network (E-RARE); Italian Association of Mobius Syndrome (AISMO); Dutch Cancer Society; Netherlands Organization for Health Research and Development

State dependent changes in sensorimotor control are critical for interactions with the environment and are modulated by three principal monoaminergic neuromodulators: serotonin, dopamine and norepinephrine (noradrenaline). The neuromodulatory neurotransmitter release starts during embryonic development and transiently exerts neurotrophic actions that cease after the first 2–3 postnatal weeks in rodents. Particularly during these early postnatal weeks neuronal projections along sensorimotor circuits are most sensitive to experience-dependent development. This implies that early changes in neuromodulatory action will have long-lasting consequences, contributing to the normal range of individual differences in sensorimotor integration up to neurodevelopmental disorders like autism spectrum disorders. To delineate these neurodevelopmental processes we review herein (1) the basics of the three principal neuromodulators, (2) the organization of neuromodulatory innervation of sensorimotor circuits, (3) how targeted manipulation of neuromodulation during development affect the anatomical and functional organization of sensorimotor circuits and their behavioral correlates, and (4) how alterations in the anatomical and functional organization of these circuits contribute to sensorimotor deficits in adulthood, for example in brain disorders. Finally (5) we discuss the evidence for a developmental switch for neuromodulator neurotransmitter action in sensorimotor integration, and propose that neuromodulatory influences during early postnatal development is critical for sensorimotor function in adulthood.

The prefrontal cortex (PFC), seat of the highest-order cognitive functions, constitutes a conglomerate of highly specialized brain areas and has been implicated to have a role in the onset and installation of various neurodevelopmental disorders. The development of a properly functioning PFC is directed by transcription factors, guidance cues and other regulatory molecules and requires the intricate and temporal orchestration of a number of developmental processes. Disturbance or failure of any of these processes causing neurodevelopmental abnormalities within the PFC may contribute to several of the cognitive deficits seen in patients with neurodevelopmental disorders. In this review, we elaborate on the specific processes underlying prefrontal development, such as induction and patterning of the prefrontal area, proliferation, migration and axonal guidance of medial prefrontal progenitors, and their eventual efferent and afferent connections. We furthermore integrate for the first time the available knowledge from genome-wide studies that have revealed genes linked to neurodevelopmental disorders with experimental molecular evidence in rodents. The integrated data suggest that the pathogenic variants in the neurodevelopmental disorder-associated genes induce prefrontal cytoarchitectonical impairments. This enhances our understanding of the molecular mechanisms of prefrontal (mis)development underlying the four major neurodevelopmental disorders in humans, that is, intellectual disability, autism spectrum disorders, attention deficit hyperactivity disorder and schizophrenia, and may thus provide clues for the development of novel therapies.

This article presents a method for determining complex residual errors of calibrated two-port vector network analyzers. It utilizes the time-domain technique. Calibration residual errors are extracted from a distance-frequency system model using a special estimation algorithm based on the quasioptimal unscented Kalman filter. Because the method requires only three measurement conditions, it is in particular beneficial for on-wafer applications, as three test conditions can be obtained from using only one transmission line. Moreover, the length of the line can be relatively short. Experimental studies were performed and verified the proposed method.

Previous analyses of the spiny layer IV neurons have almost exclusively focused on spiny stellate cells. Here we provide detailed morphological data characterizing three subpopulations of spiny neurons in slices of adolescent rats: (i) spiny stellate cells (58%), (ii) star pyramidal cells (25%) and (iii) pyramidal cells (17%), which can be distinguished objectively by the preferential orientation of their dendritic stems. Spiny stellate cells lacked an apical dendrite and frequently confined their dendritic and axonal arbors to the respective column. Star pyramidal and pyramidal cells possessed an apical dendrite, which reached the supragranular layers. Their axonal arbors were similar, showing both a columnar component and transcolumnar branches with direct transbarrel projections. However, a small fraction of star pyramidal cells possessed few or even no transcolumnar branches. Electrophysiologically, all three types of neurons were either regular-spiking or intrinsically burst-spiking without a significant relation to the morphological subtypes. The basic synaptic properties of thalamic inputs were also independent of the type of target layer IV spiny neuron. All remained subthreshold and showed paired-pulse depression. In conclusion, the columnar axonal arborization of spiny stellate cells is supplemented by a significant oblique to horizontal projection pattern in pyramidal-like neurons. This offers a structural basis for either segregation or early context-dependent integration of tactile information, in a cell-type specific manner.

The garden city is generally credited as being the brainchild of the English reformer and visionary, Ebenezer Howard, first published in 1898 in his book To‐morrow: A Peaceful Path to Real Reform. However a German contemporary, Theodor Fritsch (1852–1933), also claimed authorship of the idea in 1896 in his book Die Stadt der Zukunft. The second edition of this book, published in 1912, actually bears the subtitle Gartenstadt. Unlike Howard's progressive and humane reformism, Fritsch's vision reflected an extreme‐racist perspective that later contributed to National Socialist ideology and caused him to be revered as a prophet of Nazism. Unlike Howard, Fritsch was a prolific author whose other work included rabidly anti‐Semitic propaganda, often expressed in his journal, Hammer. His ideas were almost completely ignored by the German garden city association, founded in 1902, which embodied Howard's more liberal and humanistic perspectives. This article examines Fritsch's claims to authorship and considers the...

Cortical columns contain specific neuronal populations with characteristic sets of connections. This wiring forms the structural basis of dynamic information processing. However, at the single-cell level little is known about specific connectivity patterns. We performed experiments in infragranular layers (V and VI) of rat somatosensory cortex, to clarify further the input patterns of inhibitory interneurons immunoreactive (ir) for vasoactive intestinal polypeptide (VIP). Neurons in acute slices were electrophysiologically characterized using whole-cell recordings and filled with biocytin. This allowed us to determine their firing pattern as regular-spiking, intrinsically bursting and fast-spiking, respectively. Biocytin was revealed histochemically and VIP immunohistochemically. Sections were examined for contacts between the axons of the filled neurons and the VIP-ir targets. Twenty pyramidal cells and five nonpyramidal (inter)neurons were recovered and sufficiently stained for further analysis. Regular-spiking pyramidal cells displayed no axonal boutons in contact with VIP-ir targets. In contrast, intrinsically bursting layer V pyramidal cells showed four putative single contacts with a proximal dendrite of VIP neurons. Fast-spiking interneurons formed contacts with two to six VIP neurons, preferentially at their somata. Single as well as multiple contacts on individual target cells were found. Electron microscopic examinations showed that light-microscopically determined contacts represent sites of synaptic interactions. Our results suggest that, within infragranular local cortical circuits, (i) fast-spiking interneurons are more likely to influence VIP cells than are pyramidal cells and (ii) pyramidal cell input probably needs to be highly convergent to fire VIP target cells.

Recent experimental evidence suggests a finer genetic, structural and functional subdivision of the layers which form a cortical column. The classical layer II/III (LII/III) of rodent neocortex integrates ascending sensory information with contextual cortical information for behavioral read-out. We systematically investigated to which extent regular-spiking supragranular pyramidal neurons, located at different depths within the cortex, show different input-output connectivity patterns. Combining glutamate uncaging with whole-cell recordings and biocytin filling, we revealed a novel cellular organization of LII/III: (1) "Lower LII/III" pyramidal cells receive a very strong excitatory input from lemniscal LIV and much fewer inputs from paralemniscal LVa. They project to all layers of the home column, including a feedback projection to LIV, whereas transcolumnar projections are relatively sparse. (2) "Upper LII/III" pyramidal cells also receive their strongest input from LIV, but in addition, a very strong and dense excitatory input from LVa. They project extensively to LII/III as well as LVa and Vb of their home and neighboring columns. (3) "Middle LII/III" pyramidal cell shows an intermediate connectivity phenotype that stands in many ways in between the features described for lower versus upper LII/III. "Lower LII/III" intracolumnarly segregates and transcolumnarly integrates lemniscal information, whereas "upper LII/III" seems to integrate lemniscal with paralemniscal information. This suggests a fine-grained functional subdivision of the supragranular compartment containing multiple circuits without any obvious cytoarchitectonic, other structural or functional correlate of a laminar border in rodent barrel cortex. peerReviewed

Planning ideas after World War II were based on similar visions worldwide. Many of them were developed half a century before, and the war offered a unique chance to put them into practice. Although there were different political systems and a diversity of urban situations, the planning models seem to have been similar in this period. There was an almost universal agreement that reconstruction combined with slum clearances would be necessary and would need to be planned rather than be left to the free play of the market. Planning was seen as the key to postwar rebuilding—for slum clearance, optimized land use, new housing production, and restructuring dense urban area based on the neighborhood principle.