Six networks on a universal neuromorphic computing substrate

In this study, we present a highly configurable neuromorphic computing substrate and use it for emulating several types of neural networks. At the heart of this system lies a mixed-signal chip, with analog implementations of neurons and synapses and digital transmission of action potentials. Major advantages of this emulation device, which has been explicitly designed as a universal neural network emulator, are its inherent parallelism and high acceleration factor compared to conventional computers. Its configurability allows the realization of almost arbitrary network topologies and the use of widely varied neuronal and synaptic parameters. Fixed-pattern noise inherent to analog circuitry is reduced by calibration routines. An integrated development environment allows neuroscientists to operate the device without any prior knowledge of neuromorphic circuit design. As a showcase for the capabilities of the system, we describe the successful emulation of six different neural networks which cover a broad spectrum of both structure and functionality

On microelectronic self-learning cognitive chip systems

After a brief review of machine learning techniques and applications, this Ph.D. thesis examines several approaches for implementing machine learning architectures and algorithms into hardware within our laboratory. From this interdisciplinary background support, we have motivations for novel approaches that we intend to follow as an objective of innovative hardware implementations of dynamically self-reconfigurable logic for enhanced self-adaptive, self-(re)organizing and eventually self-assembling machine learning systems, while developing this new particular area of research. And after reviewing some relevant background of robotic control methods followed by most recent advanced cognitive controllers, this Ph.D. thesis suggests that amongst many well-known ways of designing operational technologies, the design methodologies of those leading-edge high-tech devices such as cognitive chips that may well lead to intelligent machines exhibiting conscious phenomena should crucially be restricted to extremely well defined constraints. Roboticists also need those as specifications to help decide upfront on otherwise infinitely free hardware/software design details. In addition and most importantly, we propose these specifications as methodological guidelines tightly related to ethics and the nowadays well-identified workings of the human body and of its psyche

Functional genomics of brain development and developmentally related brain disease in "Drosophila"

One of the fundamental challenges in basic neuroscience is to understand the molecular genetic networks associated with building the brain. As malfunction in these genetic pathways can lead to disorders like cancer, brain development is also a crucial research area for clinical neuroscience. In the course of this thesis, different molecular aspects of Drosophila brain development and related neoplastic disease were analyzed using high-density oligonucleotide arrays. The homeotic selector gene labial (lab) plays an important role in specification of neuronal identity in the embryonic brain of Drosophila. In labial mutants presumptive neurons in the posterior tritocerebrum fail to differentiate. This leads to severe defects in tritocerebral axon pathways. Using high density oligonucleotide arrays we identified downstream target genes of Labial and showed that only a limited and distinct set of genes expressed in the embryo is regulated by this homeoprotein. Furthermore, we performed genetic rescue experiments to analyze the functional equivalence of Drosophila Hox gene products in specification of the tritocerebral neuromere. Surprisingly, all tested homeotic proteins, with the exception of Abd-B, were able to rescue the labial mutant phenotype in the tritocerebrum. These results indicate that the specificity of homeotic gene action in embryonic brain development has to be modulated by cis-acting regulatory elements. Another study circled around the homeobox transcription factor otd and its human homolog Otx2. Cross-phylum rescue experiments have shown that these genes are functionally equivalent. We used quantitative transcript imaging to analyze otd and Otx gene action in the Drosophila embryo at a genomic level. Our experiments suggest that about one third of the Otd-regulated transcripts in Drosophila can also be controlled by the human Otx2. These common otd/Otx2 downstream genes are likely to represent the molecular basis for the functional equivalence of otd and Otx2 gene action in Drosophila. glial cells missing (gcm) is a key control gene of gliogenesis. gcm loss-of-function leads to a transformation of glial cells into neurons and, conversely, when gcm is ectopically misexpressed, presumptive neurons become glia. Since gcm encodes a transcription factor it is supposed that a set of downstream genes are regulated by GCM that in turn execute the glial differentiation program. Again, a set of full-genome transcript profiling experiments was conducted to identify gcm downstream genes in a comprehensive manner. A set of several hundred candidate gcm target genes were identified in this screen, giving new insights into neuroglial fate specification in Drosophila. Brain tumors have been extensively studied by looking at genetic alterations and mutations that lead to malignant growth. Still, the causes of brain tumorigenesis are largely unknown. Model systems like Drosophila can be of great help to shed light on altered transcriptional activity in brain tumor phenotypes. To investigate the in vivo transcriptional activity associated with a brain tumor, we conducted genome-wide microarray expression analyses of an adult brain tumor in Drosophila caused by homozygous mutation in the tumor suppressor gene brain tumor (brat). Two independent gene expression studies using two different oligonucleotide microarray platforms were used to compare the transcriptome of adult wildtype flies with mutants displaying the adult bratk06028 mutant brain tumor. Cross-validation and stringent statistical criteria identified a core transcriptional signature of bratk06028 neoplastic tissue. We found highly significant expression level changes for 321 annotated genes associated with the adult neoplastic bratk06028 tissue indicating elevated and aberrant metabolic and cell cycle activity, upregulation of the basal transcriptional machinery, as well as elevated and aberrant activity of ribosome synthesis and translation control. One fifth of these genes show homology to known mammalian genes involved in cancer formation. These results identify for the first time the genome-wide transcriptional alterations associated with an adult brain tumor in Drosophila and reveal insights into the possible mechanisms of tumor formation caused by homozygous mutation of the translational repressor brat

Thrombospondin receptor α2δ-1 promotes synaptogenesis and spinogenesis via postsynaptic Rac1

Astrocytes control excitatory synaptogenesis by secreting thrombospondins (TSPs), which function via their neuronal receptor, the calcium channel subunit α2δ-1. α2δ-1 is a drug target for epilepsy and neuropathic pain; thus the TSP–α2δ-1 interaction is implicated in both synaptic development and disease pathogenesis. However, the mechanism by which this interaction promotes synaptogenesis and the requirement for α2δ-1 for connectivity of the developing mammalian brain are unknown. In this study, we show that global or cell-specific loss of α2δ-1 yields profound deficits in excitatory synapse numbers, ultrastructure, and activity and severely stunts spinogenesis in the mouse cortex. Postsynaptic but not presynaptic α2δ-1 is required and sufficient for TSP-induced synaptogenesis in vitro and spine formation in vivo, but an α2δ-1 mutant linked to autism cannot rescue these synaptogenesis defects. Finally, we reveal that TSP–α2δ-1 interactions control synaptogenesis postsynaptically via Rac1, suggesting potential molecular mechanisms that underlie both synaptic development and pathology

Third CLIPS Conference Proceedings, volume 1

Expert systems are computed programs which emulate human expertise in well defined problem domains. The potential payoff from expert systems is high: valuable expertise can be captured and preserved, repetitive and/or mundane tasks requiring human expertise can be automated, and uniformity can be applied in decision making processes. The C Language Integrated Production Systems (CLIPS) is an expert system building tool, developed at the Johnson Space Center, which provides a complete environment for the development and delivery of rule and/or object based expert systems. CLIPS was specifically designed to provide a low cost option for developing and deploying expert system applications across a wide range of hardware platforms. The development of CLIPS has helped to improve the ability to deliver expert systems technology throughout the public and private sectors for a wide range of applications and diverse computing environments

Genetic targeting of NRXN2 in mice unveils role in excitatory cortical synapse function and social behaviors

Human genetics has identified rare copy number variations and deleterious mutations for all neurexin genes (NRXN1-3) in patients with neurodevelopmental diseases, and electrophysiological recordings in animal brains have shown that Nrxns are important for synaptic transmission. While several mouse models for Nrxn1α inactivation have previously been studied for behavioral changes, very little information is available for other variants. Here, we validate that mice lacking Nrxn2α exhibit behavioral abnormalities, characterized by social interaction deficits and increased anxiety-like behavior, which partially overlap, partially differ from Nrxn1α mutant behaviors. Using patch-clamp recordings in Nrxn2α knockout brains, we observe reduced spontaneous transmitter release at excitatory synapses in the neocortex. We also analyse at this cellular level a novel NRXN2 mouse model that carries a combined deletion of Nrxn2α and Nrxn2β. Electrophysiological analysis of this Nrxn2-mutant mouse shows surprisingly similar defects of excitatory release to Nrxn2α, indicating that the β-variant of Nrxn2 has no strong function in basic transmission at these synapses. Inhibitory transmission as well as synapse densities and ultrastructure remain unchanged in the neocortex of both models. Furthermore, at Nrxn2α and Nrxn2-mutant excitatory synapses we find an altered facilitation and N-methyl-D-aspartate receptor (NMDAR) function because NMDAR-dependent decay time and NMDAR-mediated responses are reduced. As Nrxn can indirectly be linked to NMDAR via neuroligin and PSD-95, the trans-synaptic nature of this complex may help to explain occurrence of presynaptic and postsynaptic effects. Since excitatory/inhibitory imbalances and impairment of NMDAR function are alledged to have a role in autism and schizophrenia, our results support the idea of a related pathomechanism in these disorders

GABA signaling in the thalamus

Inhibition of neuronal activity in networks of the mammalian central nervous system is essential for all fundamental brain functions, ranging from perception, to consciousness, to action. Both exacerbation and diminution of inhibition dramatically affect our behavioral capacities, indicating that, in the healthy brain, strength and dynamics of inhibition must be precisely balanced. Inhibitory functions are primarily accomplished by neurons releasing the neurotransmitter GABA. According to their wide variety of functions, GABAergic neurons show a tremendous diversity in morphological, biochemical and functional characteristics. The combination of these diverse properties allows the brain to generate interneurons acting as, for examples, filters, co-incidence detectors or contrast enhancers. GABAergic signaling in thalamus plays an essential role in controlling sensory information flow from the periphery to the cortical processing centers, and in generating sleep-related neuronal rhythms. Surprisingly, however, the diversity of GABAergic neurons is remarkably limited in thalamic networks. Both functions mentioned have been tightly associated with two homogeneous groups of GABAergic neurons arising within thalamic nuclei or within the nucleus reticularis, a shell of inhibitory nuclei surrounding the dorsal thalamus. The results arising from the present thesis challenge the view that the diversity of GABAergic signaling in thalamus is comparatively limited and proposes that, to fully understand GABAergic signaling in thalamus, at least two additional aspects have to be considered. First, it shows that GABAergic signaling arising from the nucleus reticularis can have a profound effect on the synthesis of second messenger compounds that are important in the control of neuronal rhythmicities and in the statedependent control of gene expression. Second, it demonstrates the functional relevance of a previously undescribed extrathalamic and extrareticular inhibitory pathway that arises within the anterior pretectal nuclei, indicating that the architecture of GABAergic signaling in thalamus has to be complemented by a conceptually novel, powerful afferent pathway. The first part investigates the modulation of cAMP synthesis by GABA in thalamocortical neurons through the activation of the Gi-coupled GABAB receptors. GABAB receptors can provide two different cAMP signals in the neurons. First, GABAB receptor activation depresses the level of cAMP inside thalamocortical neurons. However, a large and long cAMP signal is observed when GABAB receptors are activated concomitantly with b-adrenergic receptors, which are Gscoupled receptors. In the presence of GABAB receptor agonists, the moderate cAMP increase produced by b-adrenergic receptor activation is transformed into a large synthesis of cAMP. Remarkably, the activation of the GABAB receptors at the synapses between reticular neurons and thalamocortical neurons also potentiates the effects of b-adrenergic receptors. Thus, GABAB receptors modulate cAMP signals at synapses that are important for the regulation of the state of arousal. The second part provides the first electrophysiological description of synaptic connections between the anterior pretectum group and the thalamic higher-order nuclei. Electric stimulation in the anterior pretectum group evoked inhibitory postsynaptic responses (IPS) in the thalamocortical neurons of the higher-order nuclei. We showed that the IPS responses were mediated via the GABAA receptors activated through monosynaptic connections between the APT and the higher-order nuclei. Functionally, the anterior pretectum modulated the discharge properties of the thalamocortical neurons, suggesting an important role of this nucleus in the dialogue between the thalamus and the cortex

A cellular model for human daily behaviour

All the biochemical, physiological or behavioural processes whose period is about 24 hours possess a circadian rhythm. In mammals circadian rhythms control almost all aspects of human daily behaviour and physiology. Dysregulation of circadian rhythms leads to several pathologies, such as depression, cancer and metabolic syndromes. Mammalian circadian system is organized in a hierarchic fashion: suprachiasmatic nucleus (SCN) is master clock and governs the circadian rhythms of all peripheral oscillators, virtually all the other cells of the body. The study of human circadian rhythms in subjects in vivo is expensive, time consuming and invading. However, since SCN and peripheral oscillators share the same circadian molecular machinery, it is possible to use peripheral oscillator as model to study molecular mechanisms of circadian rhythms. To visualize in real-time cellular circadian rhythms, fibroblasts were infected with a lentivirus coding for the circadian reporter firefly luciferase under a clock gene promoter (Bmal1). After the synchronization of circadian rhythms, the measurement of the light emitted by the cells gave a representation of fibroblast circadian oscillations. The aim of the thesis was to establish the use of human primary skin fibroblasts as a valuable model to study different aspects of human circadian rhythms. To address these questions three projects were designed. A first set of experiments aimed at validating human skin fibroblast model, ascertaining that this in vitro model parallels in vivo human circadian parameters. We found a very good correlation between the in vivo and the in vitro period length in the three groups of subjects (two sighted and one blind) recruited for this study. Interestingly, although the in vivo period obtained from the blind group was longer than the in vivo period obtained from the sighted groups, the in vitro period length from the three groups of subjects was similar, revealing that human skin fibroblasts are insensitive to the after-effects caused by light. In summary, human circadian period can be approximated by measurement in fibroblasts. In a second project human age-related circadian impairments were studied in the cellular skin fibroblasts model. Indeed sleep-wake cycle alterations and phase advancing of gene expression and behaviour can be found in elder individuals. To better understand the rebound of ageing on the circadian rhythms we characterized the period length of skin fibroblasts from young and elder persons. No differences in amplitude, phase and period length were found between cells from the two groups. However, in the presence of sera from older donors human fibroblasts showed a reduced period length and a shorter phase of entrainment compared to the same cells measured in the presence of sera from young donors. These differences are likely due to one or more thermolabile substances, since heat-inactivation of sera from older donors almost undid the reduction of the circadian period length. Thus, these results suggest that during ageing the molecular machinery of peripheral circadian clocks does not change per se, but some age-related circadian changes observed in vivo might be caused by circulating molecules. Human fibroblasts were also used to investigate the role of melatonin as zeitgeber on peripheral oscillators. Melatonin is secreted in a circadian fashion and was demonstrated to regulate the SCN firing rate and to entrain the sleep-wake cycle of most mammals and humans. The circadian presence of melatonin is well conserved in all biological fluids, suggesting that melatonin may be one of the molecules that the master clock uses to synchronize peripheral oscillators. This hypothesis was tested in damped fibroblasts, using a wide range of concentrations of melatonin to restore the amplitude of the rhythms. However, no increase of amplitude or phase shift of the rhythms was observed after treating cells with melatonin. Moreover, the application of the hormone to newly synchronized oscillators decreased their bioluminescence. In summary, the experiments demonstrated that melatonin does not play a direct role as peripheral oscillator zeitgeber. In conclusion, the studies of the present thesis succeeded in revealing three primary findings: first, fibroblast circadian rhythms parallel human circadian physiology, such as circadian period length. Second, apparently, during ageing the molecular components of peripheral circadian clocks in skin fibroblasts do not change per se, but some age-related circadian changes observed in vivo might be caused by one or more heat-sensitive substances present in the blood of older subjects. Finally, melatonin does not possess direct synchronizing properties on peripheral oscillators like fibroblasts. In total, the present thesis revealed that primary human skin fibroblasts are an easily accessible, cheap and reliable model to enlighten our understanding of human circadian mechanisms

Exploring the potential of brain-inspired computing

The gap between brains and computers regarding both their cognitive capability and power efficiency is remarkably huge. Brains process information massively in parallel and its constituents are intrinsically self-organizing, while in digital computers the execution of instructions is deterministic and rather serial. The recent progress in the development of dedicated hardware systems implementing physical models of neurons and synapses enables to efficiently emulate spiking neural networks. In this work, we verify the design and explore the potential for brain-inspired computing of such an analog neuromorphic system, called Spikey. We demonstrate the versatility of this highly configurable substrate by the implementation of a rich repertoire of network models, including models for signal propagation and enhancement, general purpose classifiers, cortical models and decorrelating feedback systems. Network emulations on Spikey are highly accelerated and consume less than 1 nJ per synaptic transmission. The Spikey system, hence, outperforms modern desktop computers in terms of fast and efficient network simulations closing the gap to brains. During this thesis the stability, performance and user-friendliness of the Spikey system was improved integrating it into the neuroscientific tool chain and making it available for the community. The implementation of networks suitable to solve everyday tasks, like object or speech recognition, qualifies this technology to be an alternative to conventional computers. Considering the compactness, computational capability and power efficiency, neuromorphic systems may qualify as a valuable complement to classical computation

Development of a diffusion kernel density estimator and application on marine carbon-13 isotope data

My work developed a kernel density estimator that well resolves typical structures of probability densities, which was demonstrated on a newly compiled marine data set of organic carbon-13 isotope ratios (δ13CPOC). All work was conducted within the emerging field of marine data science. I identified classical data science, a general understanding of ocean science, communication skills, and confidence as requirements for marine data scientists. In the beginning of my work, the existing δ13CPOC data consisted of about 500 data points in the global ocean. I expanded the existing data set to 4732 data points in a first version, and additionally to 6952 in a second. Both are published at PANGAEA along with meta information such as measurement location, time, and method, and interpolations. I have published a description of the temporal and geographic distribution of the first version at Earth System Science Data. I designed the development of the kernel density estimator algorithm on the existing concept of computing it as a solution of the diffusion equation. My algorithm uses finite differences in space and equidistant time steps with an implicit Euler method, and approximates the optimal smoothing parameter by two pilot steps. Compared to other well-known kernel density estimators, my algorithm produces reliable approximations of multimodal and boundary-close distributions on artificial and real marine data and is robust to noise. My implementation is published as a Python package on Zenodo, its description is submitted to Geoscientific Model Development. I was able to show that my kernel density estimator reliably evalu- ates ocean data and thus lays a foundation for calibrating Earth system models. At the same time, I was able to contribute to the definition and establishment of the field of Marine Data Science