A receptor-based analysis of local ecosystems in the human brain.

BackgroundAs a complex system, the brain is a self-organizing entity that depends on local interactions among cells. Its regions (anatomically defined nuclei and areas) can be conceptualized as cellular ecosystems, but the similarity of their functional profiles is poorly understood. The study used the Allen Human Brain Atlas to classify 169 brain regions into hierarchically-organized environments based on their expression of 100 G protein-coupled neurotransmitter receptors, with no a priori reference to the regions' positions in the brain's anatomy or function. The analysis was based on hierarchical clustering, and multiscale bootstrap resampling was used to estimate the reliability of detected clusters.ResultsThe study presents the first unbiased, hierarchical tree of functional environments in the human brain. The similarity of brain regions was strongly influenced by their anatomical proximity, even when they belonged to different functional systems. Generally, spatial vicinity trumped long-range projections or network connectivity. The main cluster of brain regions excluded the dentate gyrus of the hippocampus. The nuclei of the amygdala formed a cluster irrespective of their striatal or pallial origin. In its receptor profile, the hypothalamus was more closely associated with the midbrain than with the thalamus. The cerebellar cortical areas formed a tight and exclusive cluster. Most of the neocortical areas (with the exception of some occipital areas) clustered in a large, statistically well supported group that included no other brain regions.ConclusionsThis study adds a new dimension to the established classifications of brain divisions. In a single framework, they are reconsidered at multiple scales-from individual nuclei and areas to their groups to the entire brain. The analysis provides support for predictive models of brain self-organization and adaptation

Evolving Synaptic Plasticity with an Evolutionary Cellular Development Model

Since synaptic plasticity is regarded as a potential mechanism for memory formation and learning, there is growing interest in the study of its underlying mechanisms. Recently several evolutionary models of cellular development have been presented, but none have been shown to be able to evolve a range of biological synaptic plasticity regimes. In this paper we present a biologically plausible evolutionary cellular development model and test its ability to evolve different biological synaptic plasticity regimes. The core of the model is a genomic and proteomic regulation network which controls cells and their neurites in a 2D environment. The model has previously been shown to successfully evolve behaving organisms, enable gene related phenomena, and produce biological neural mechanisms such as temporal representations. Several experiments are described in which the model evolves different synaptic plasticity regimes using a direct fitness function. Other experiments examine the ability of the model to evolve simple plasticity regimes in a task -based fitness function environment. These results suggest that such evolutionary cellular development models have the potential to be used as a research tool for investigating the evolutionary aspects of synaptic plasticity and at the same time can serve as the basis for novel artificial computational systems

Computational Evolutionary Embryogeny

Evolutionary and developmental processes are used to evolve the configurations of 3-D structures in silico to achieve desired performances. Natural systems utilize the combination of both evolution and development processes to produce remarkable performance and diversity. However, this approach has not yet been applied extensively to the design of continuous 3-D load-supporting structures. Beginning with a single artificial cell containing information analogous to a DNA sequence, a structure is grown according to the rules encoded in the sequence. Each artificial cell in the structure contains the same sequence of growth and development rules, and each artificial cell is an element in a finite element mesh representing the structure of the mature individual. Rule sequences are evolved over many generations through selection and survival of individuals in a population. Modularity and symmetry are visible in nearly every natural and engineered structure. An understanding of the evolution and expression of symmetry and modularity is emerging from recent biological research. Initial evidence of these attributes is present in the phenotypes that are developed from the artificial evolution, although neither characteristic is imposed nor selected-for directly. The computational evolutionary development approach presented here shows promise for synthesizing novel configurations of high-performance systems. The approach may advance the system design to a new paradigm, where current design strategies have difficulty producing useful solutions

Lineages and molecular heterogeneity in the developing nervous system

Information in the genome unfolds through a dynamic process leading to the molecular and anatomical organization of a physiologically functional organism. The nervous system is the most diverse and intricate architecture generated by this process. It is composed of hundreds of millions of cells of hundreds of different cell types, whose connectivity and interactions are the physiological underpinnings of our capacity to respond to stimuli, our ability to learn and our cognitive capabilities. In this thesis, I explore the formation of tissues in the nervous system during embryonic development. In particular, I focus on changes in molecular composition that lead progenitor cells to generate a complex mix of cell types. The specific aim of this work is to address the lack of complete and systematic knowledge of the heterogeneity of neural tissues and to describe the progression of a cell through different molecular states. To achieve this, I took advantage of the new opportunities offered by single-cell expression profiling technologies to gain a holistic view of a developing tissue. To contextualize the work, I review the relevant literature and conceptual framework. Starting with a historical perspective, I discuss the concept of cell type and how it relates to developmental dynamics and evolution. I then review different aspects of developmental neuroscience, starting with general principles and then focusing on the main areas of interest: the ventral midbrain, the sympathetic nervous system, and postnatal development. Then the technological advances instrumental for this thesis are reviewed, with a focus on analysis methods for single-cell RNA sequencing. Finally, I discuss the relationship between lineages and gene regulation, and I introduce the reader to the idea of a global time derivative of gene expression through traditional systems biology modeling. Then I present the results of three different studies. In paper I, we used single-cell RNA sequencing to describe the cell-type heterogeneity of sympathetic ganglia. We found seven distinct kinds of neurons, where only two had been previously described. Using lineage tracing, we shed light on the developmental origin of the new types. We linked their molecular profile to function and described how they innervate the erector muscles. Paper II describes the embryonic development of the ventral midbrain at the single-cell level. We characterized human and mouse embryonic tissues, identifying cell types and their homologies. We found an uncharacterized heterogeneity among radial glial cells and gained new insight into the timing of dopaminergic neurons specification. Finally, we presented a data-driven strategy to assess the quality of in vitro differentiation protocols. In paper III we addressed the major limitation of studying development with single-cell RNA sequencing: the absence of a temporal dimension. We described an analysis framework that uses the ratio of spliced to unspliced RNA abundance to estimate the time derivative of gene expression. The method was used to predict the future molecular states of cells and to determine their fate bias. In these studies, we produced a rich description of tissue heterogeneity and answered different biological questions. The results were achieved by harnessing the information contained in the data through analysis approaches inspired by developmental or physical principles. In summary, this thesis provides new insight into several aspects of mammalian nervous-system development, and it presents analytical approaches that I predict will inspire future investigation of the developmental dynamics of single-cells

Sensing risk, fearing uncertainty: systems science approach to change

Background: Medicine devotes its primary focus to understanding change, from cells to network relationships; observations of non-linearity are inescapable. Recent events provide extraordinary examples of major non-linear surprises within the societal system: human genome-from anticipated 100,000+ genes to only 20,000+; junk DNA-initially ignored but now proven to control genetic processes; economic reversals-bursting of bubbles in technology, housing, finance; foreign wars; relentless rise in obesity, neurodegenerative diseases. There are two attributes of systems science that are especially relevant to this research: One—it offers a method for creating a structural context with a guiding path to pragmatic knowledge; and, two—it gives pre-eminence to sensory input capable to register, evaluate, and react to change. Materials/Methods: Public domain records of change, during the last 50 years, have been studied in the context of systems science, the dynamic systems model, and various cycles. Results/Conclusions: Change is dynamic, ever-present, never isolated, and of variable impact; it reflects innumerable relationships among contextual systems; change can be perceived as risk or uncertainty depending upon how the assessment is made; risk is quantifiable by sensory input and generates a degree of rational optimism; uncertainty is not quantifiable and evokes fear; trust is key to sharing risk; the measurable financial credit can be a proxy for societal trust; expanding credit dilutes trust; when a credit bubble bursts, so will trust; absence of trust paralyzes systems' relationships leading to disorganized complexity which prevents value creation and heightens the probability of random events; disappearance of value, accompanied by chaos, threatens all systems. From personal health to economic sustainability and collective rationality, most examined components of the societal system were found not to be optimized and trust was not in evidence

Generative model of art

This work is a sort of set of notes I made while being both the experiment and the experimenter with the Master of Glass Art and Science. I’m not a scientist. At the beginning of my studying at Glass Art and Science program, my artistic voice longed to be made manifest, but I did not know how to find the right expression for it. Now I feel like I found the way, and it happened because here I had a possibility to be in art and science at once. I was lucky to find a lot of workable analogies in science that I could apply to my art making. I’ve looked at Biology, Morphogenesis and Fractal geometry and I learned about how objects take form in Nature. Thanks to the science I’ve got a rich soil of awareness, kind of strong base, from which I began to advance rapidly like an artist. Some of the facts from science I noticed, already exists in my art making, but the awareness of them still leads me somehow to the new levels of my work. The idea of “morphological fields” from evolutionary biologist Rupert Sheldrake’s is very much related to my art making. The heart of his idea is that if we look at how the cells multiply, how they reproduce themselves… if we look at Nature and try to break it down and to understand and read how things happen, if we try to explain why it looks like this or that, we fail to find enough information to explain the final forms. Sheldrake argues that there is not enough information available when we deconstruct cellular information to explain how larger scale forms occur. Something or some process appears to be happening outside of what we can see. We cannot see the force that makes thing take shape. As an artist, I understand that force very personally. I just open to it, I just give it to my hands, and there is no difference between me and the rest of natural processes

Genetic control of photoreceptor terminal differentiation in Drosophila melanogaster

Why do photoreceptors differentiate in the eye? Though simple, biologically this is an important question, and it may prove complex to answer. To present a bigger picture: animals have evolved a diversity of highly specialised sensory organs, which they use to obtain information from their environment and thus survive. These organs contain different types of receptor neurons. For example, there are chemoreceptors in the labellum and in the antennae of insects, or mechanoreceptors in the inner ear of vertebrates... and each of these types of receptor neurons specifically possesses the molecular machinery to detect and transduce stimuli from one particular sensory modality. In the case of the eye, it contains photoreceptor neurons, which are specialised in light detection. Neither photoreceptors nor most of the components of the phototransduction cascade appear commonly outside the eye. Therefore, what are mechanisms that ensure that photoreceptors differentiate correctly in the eye, and not in other body parts? To start answering this question, first it might be useful to understand the early-acting process of eye field specification. This depends on a group of transcription factors that are collectively called the ‘retinal determination network’ (RDN), and work in combination with each other to confer eye identity to the developing, multipotent tissue. RDN genes are both necessary and sufficient for eye formation in different animal species, from Drosophila to vertebrates, and they tend to act through an evolutionarily conserved sequence of transcriptional events. First in this sequence, following the Drosophila nomenclature, the transcription factor Eyeless activates the expression of sine oculis and eyes absent. Then, Sine oculis and Eyes absent form a heterodimer and direct eye formation. Despite the importance of the RDN, until recently, little was known about its targets, or about the molecular mechanisms by which it coordinates eye development. In particular, how does it instruct photoreceptor differentiation? Our work suggests that a key step in this process is coordinated by the zinc finger transcription factor glass, which is a direct target of Sine oculis. While previous literature has shown that the Glass protein is primarily expressed in photoreceptors, its role in these cells was not known because it was believed that glass mutant photoreceptor precursors died during metamorphosis. Contrary to former studies, we demonstrate that glass mutant photoreceptor precursors survive and are present in the adult retina, but fail to mature as functional photoreceptors. Importantly, we have found that Glass is required for the expression of virtually all the proteins that are involved in the phototransduction cascade, and thus glass mutant flies are blind. Consistent with this, ectopic expression of Glass is able to induce some phototransduction components in the brain. Another step in the formation of photoreceptors is regulated by the homeodomain transcription factor Hazy, which is a direct target of Glass. While we show that both Glass and Hazy act synergistically to induce the expression of phototransduction proteins, we have also found that Glass can initiate the expression of most of the components of the phototransduction machinery in a Hazy-independent manner, and that hazy mutant flies only fail to detect white light after they are older than five days. Glass seems to be both required and sufficient for the expression of Hazy, and inducing Hazy in the retina partly rescues the glass mutant phenotype. Taken together, our results show a transcriptional link between the RDN and the expression of the proteins that adult Drosophila photoreceptors need to sense light, placing Glass at a key position in this developmental process. Finally, we compare the expression pattern of Glass in Drosophila and in the annelid Platynereis, and discuss the possibility that Glass plays an evolutionarily conserved role across different phyla.Warum bilden sich Fotorezeptoren gerade im Auge aus? Obwohl diese Frage einfach erscheint, ist sie aus biologischer Sicht doch sehr bedeutend und bedarf eventuell einer komplexen Antwort. Allgemein lässt sich sagen, dass Tiere eine Vielfalt von hoch spezialisierten Sinnesorganen entwickelt haben, durch die sie Informationen aus ihrer Umwelt aufnehmen und auf diese Weise ihr Überleben sichern. Diese Organe enthalten verschiedene Arten von Rezeptorneuronen. Zum Beispiel gibt es Chemorezeptoren im Labellum und in den Antennen der Insekten, oder Mechanorezeptoren im Innenohr von Wirbeltieren... und jedes dieser Rezeptorneuronen besitzt eine spezifische molekulare Maschinerie, um Reize einer bestimmten Sinnesmodalität wahrzunehmen und umzuwandeln. Beim Auge sind es Fotorezeptorneuronen, die auf die Wahrnehmung von Lichtreizen spezialisiert sind. Weder die Fotorezeptoren noch die meisten der Komponenten der Fototransduktionskaskade kommen außerhalb des Auges vor. Welche Mechanismen sind demzufolge ausschlaggebend, damit sich Fotorezeptoren im Auge und nicht in anderen Körperteilen entwickeln? Um diese Frage zu beantworten, ist es zunächst wichtig die frühen Mechanismen der Augenspezifizierung zu verstehen. Diese erfolgt unter Einfluss einer Gruppe von Transkriptionsfaktoren, die als „Retinales Determinations Netzwerk“ (RDN) bezeichnet werden. Diese Transkriptionsfaktoren interagieren, um aus dem sich entwickelnden multipotenten Gewebe ein Sehorgan zu bilden. RDN-Gene sind für die Augenentwicklung verschiedener Tierarten, von Drosophila bis zu Wirbeltieren, sowohl notwendig als auch ausreichend. Sie agieren durch eine evolutionär konservierte Sequenz transkriptioneller Mechanismen. An erster Stelle dieser Sequenz, nach der Drosophila Nomenklatur, aktiviert der Transkriptionsfaktor Eyeless die Expression von sine oculis und eyes absent. Anschließend bilden Sine Oculis und Eyes absent ein Heterodimer und induzieren die Entwicklung des Auges. Trotz der Bedeutung des RDNs war bis vor Kurzem nur sehr wenig über seinen Zweck oder die molekularen Mechanismen durch die es die Augenentwicklung koordiniert, bekannt. Vor allem stellt sich die Frage, wie es die Differenzierung der Fotorezeptoren reguliert? Unsere Arbeit legt nahe, dass ein wesentlicher Schritt in diesem Prozess durch den Zinkfinger-Transkriptionsfaktor glass koordiniert wird. Dabei handelt es sich um ein direktes Zielgen von Sine oculis. Obwohl in früheren wissenschaftlichen Arbeiten belegt wurde, dass das Glass-Protein in erster Linie in Fotorezeptoren exprimiert wird, war seine Rolle in diesen Zellen nicht bekannt, da angenommen wurde, dass Fotorezeptoren von glass Mutanten während der Metamorphose absterben. Im Gegensatz zu früheren Studien belegen wir das Überleben der Fotorezeptor-Vorläuferzellen von glass Mutanten und ihre Präsenz in der Retina adulter Fliegen, wobei sie jedoch nicht zu funktionsfähigen Fotorezeptoren heranreifen. Insbesondere konnten wir zeigen, dass Glass für die Expression fast aller Proteine, die in der Fototransduktionskaskade involviert sind, erforderlich ist. Daher sind glass Mutanten blind. In Übereinstimmung mit diesen Erkenntnissen bewirkt die ektopische Expression von Glass die Induktion einiger Komponenten der Fototransduktion im Gehirn. Ein weiterer Schritt in der Bildung von Fotorezeptoren wird reguliert durch den Homeodomänen-Transkriptionsfaktor Hazy, der ein direktes Ziel von Glass ist. Wir zeigen zum einen die synergetische Wirkung von Glass und Hazy bei der Expression von Fototransduktionsproteinen, zum anderen belegen wir, dass Glass die meisten Komponenten der Fototransduktionsmaschinerie unabhängig von Hazy induzieren kann, und dass hazy Mutanten ab dem Alter von fünf Tagen weißes Licht nicht mehr wahrnehmen können. Glass scheint notwendig und ausreichend für die Expression von Hazy zu sein und die Induktion von Hazy in der Retina rettet teilweise den Phänotyp von glass Mutanten. Insgesamt beweisen unsere Ergebnisse einen transkriptionellen Zusammenhang zwischen dem RDN und der Expression von Proteinen, die in Fotorezeptoren von adulten Drosophila Fliegen notwendig sind um Licht wahrzunehmen. Bei diesem Entwicklungsprozess hat Glass eine Schlüsselposition. Schließlich vergleichen wir die Expressionsmuster von Glass in Drosophila und im Anneliden Platynereis und diskutieren die Möglichkeit, dass Glass eine evolutionär konservierte Rolle über verschiedene Phyla hinweg spielt