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Abstracts Rockefeller University (RU) -Karolinska Institutet (KI) Joint Symposium in Neuroscience and Immunology

Welcome to the Rockefeller University (RU) -Karolinska Institutet (KI) Joint Symposium in Neuroscience and Immunology. Here you can find the abstracts from all speakers.

Day 1, Session 1, Neuroscience - Chairs: Dr. Per Svenningsson, (KI) and Dr. Thomas Sakmar (RU)

Genes controlling sleep duration in Drosophila - Keynote lecture by Dr. Michael W. Young (RU)

The permeability of Drosophila’s blood-brain- barrier, the organ required for maintenance of homeostatic levels of nutrients, ions, and other molecules in the brain, displays clock-dependent circadian rhythmicity reflecting sleep need. Acute and chronic sleep deprivation open the barrier, while rebound sleep and administration of the sleeping aid Gabaxadol close it. We also found that the sleep gene inc is expressed in barrier-forming subperineurial glia (“glia”) and required cell-autonomously in glia for barrier development and function, and for homeostatic control of sleep. inc is thought to be a substrate adapter in the proteasomal degradation pathway. Knockdown of pathway components cullin3 and nedd8 only in glia phenocopied inc, suggesting that inc influences glial function through its role in the proteasomal pathway. Glia-specific modulation of lachesin, gao, or loco, each a well-studied, classical regulator of barrier function, also produced robust sleep phenotypes, supporting a central role for blood-brain barrier activity in the regulation of sleep in Drosophila.

A mouse model to evaluate treatment of mtDNA mutation diseases - Dr. Nils Göran Larsson (KI)

Mitochondrial diseases are caused by dysfunction of the oxidative phosphorylation (OXPHOS) system due to mutations in either mtDNA or nuclear genes. Pathogenic mtDNA mutations are typically maternally inherited and present only in a fraction of the thousands of mtDNA copies in a cell, a condition denoted heteroplasmy. The vast majority of heteroplasmic mtDNA mutations are functionally recessive, meaning that the OXPHOS system will only be impaired if the levels of mutated mtDNA exceeds a critical threshold. Patients with mitochondrial diseases often have neuromuscular manifestations and symptoms also from other organs, such as heart, kidney and endocrine glands. The great heterogeneity in clinical manifestations is a challenge in diagnosis and development of treatments for mitochondrial diseases. As mammalian mitochondria cannot be stably transfected, it has proven very difficult to generate mouse models harboring pathogenic mtDNA mutations. As an alternative approach, we have targeted the nucleus-encoded catalytic subunit of mtDNA polymerase to generate an mtDNA mutator mouse that transmits random mtDNA mutations through the maternal germline. By using this strategy, we have been able to generate mouse models that maternally transmit single pathogenic mtDNA mutations. One of these mouse lines, harboring a heteroplasmic mutation in the tRNAAla gene of mtDNA, recapitulates important features of human mitochondrial disease. Two different research groups have used this mouse model to decrease the mutant load of mtDNA in heart and skeletal muscle by using AAV-mediated expression of mitochondrially targeted TALENs and Zn-finger nucleases. As an alternate approach, we have used mouse genetics to manipulate mtDNA copy in the tRNAAla mouse model and report that a general increase of mtDNA copy number ameliorates a variety of phenotypes although the proportion of mutated mtDNA remains the same. This finding suggests that pharmacological or gene therapy approaches to increase mtDNA copy number is a potential new treatment strategy for a variety of heteroplasmic mtDNA mutation diseases.

Prefrontal Contributions to Memory Processing - Dr. Priya Rajasethupathy (RU)

Working memory, the ability to temporarily store and process task-relevant information on the time-scale of seconds to minutes, is important to daily life functions, since it enables a variety of cognitive abilities including attention, learning, and executive control. Deficits in working memory, therefore, are a prominent component of aging as well as many neuropsychiatric diseases including Alzheimers, Schizophrenia, Bipolar Disorder, ADHD, and Chronic Stress. Despite decades of intense study, many of the basic genetic mechanisms underlying working memory performance in humans appears elusive, preventing us from successfully understanding or treating deficits therein. Here, we used a genetically diverse outbred mouse population to identify a novel genetic loci linked to working memory performance. We further characterize the locus, the resulting genetic and neural-circuit consequences, that directly drive adaptive and maladaptive working memory function. We hope these results will provide more mechanistic insight, and potential therapeutic possibilities, for understanding cognitive disturbances in neuropsychiatric disease.

On the Neural Mechanisms of Face Recognition - Dr. Winrich Freiwald (RU)

Humans, like all primates, take great interest in faces. Faces, by structure and dynamics, display a plethora of social information for a visual system that can extract it. The primate visual system does so with specialized hardware: a network of tightly interconnected areas, each packed with face-selective cells and each tuned to a different dimension of facial information. The clarity and simplicity of the system’s functional organization provide us with a unique model to understand the neural mechanisms of face recognition and to extract the computational principles the system implements to achieve its goals. In my talk I will describe the functional organization of the primate face-processing system and how it supports face recognition. I will show how it encodes facial information and transforms these codes between network nodes. I will then discuss how we can understand why the system may be operating the way it does and what the computational principles are that it uses. The insights gathered from face processing are expected to generalize to object recognition in general. Yet among visual objects faces are special: faces are more than passive displays of social information, they are active agents: they evoke emotions, activate memories, invoke thoughts about others’ mental states, draw and direct attention, and elicit communicative reactions in the perceiver. At the end of my talk I will briefly describe the embedding of the face-processing system into the social brain and, by way of example, the circuits that support these high-level social cognitive functions.

Mapping brain circuits - Dr. Konstantinos Meletis (KI)

Brain maps form the basis for exploring the role of regions, circuits, and neuron types, in normal behavior and in uncovering the pathophysiology of brain disorders. We aimed to generate a formalized and systematic taxonomy of the adult mouse brain based on molecular information. For this purpose, we used spatial transcriptomics to capture the molecular code of brain subregions. We have mapped 76 coronal brain sections covering the whole adult mouse brain, and mapped the position of 34.000 spots and expression of more than 22.000 genes, in a common reference brain atlas. Using unbiased computational approaches, we have defined the spatial-molecular codes that form discrete spatial subdivisions of for example isocortex, thalamus, hippocampus and striatum. This molecular whole-brain atlas establishes a framework for the molecular classification of brain regions and comparative studies with other species, and provides a molecular code for genetic targeting to study structure-function relationships of brain circuits.

iPS cell models of human brain development - Dr. Anna Falk (KI)

We are taking advantage of the reprogramming technique to derive human induced pluripotent stem (iPS) cells for building in vitro models of the human brain. We use iPS cells and neural derivative thereof for modeling and studying neurodevelopmental and psychiatric disorders. We have developed cellular models of Lissencephaly, Autism, Schizophrenia, Down syndrome and are studying how neural stem cells and early neuronal differentiation is affected by the disease and the mutations identified in the patients from which we have taken skin biopsies for reprogramming. By studying these models, we have identified the importance of neuronal differentiation kinetics and precis neural fate choices for creating mature and functional neurons and how adhesion molecules direct the process. Mechanisms we have identified seem to be commonly deregulated in the various patient neural stem cells compared to healthy neural stem cells.

SESSION 2: Immunology - Chairs: Dr. Qiang Pan-Hammarström (KI) and Dr. Jean-Laurent Casanova (RU)

The HIV problem- Dr. Michel Nussenzweig (RU)

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Transcriptional delineation of human ILCs at the single-cell level - Dr. Jenny Mjösberg (KI)

Innate lymphoid cells (ILCs) are increasingly appreciated as important players in homeostasis and inflammation. Substantial plasticity and heterogeneity among ILC populations has been reported. We have recently delineated heterogeneity among human ILCs through single-cell RNA sequencing (scRNAseq) of human tonsil, blood and lung CD127+ ILCs and natural killer (NK) cells, revealing tissue-specific imprinting of human ILCs and molecular pathways expressed in particular ILC subsets. These efforts provide interesting targets for treatment of inflammatory conditions.

Human immune system development early in life - Dr. Petter Brodin (KI)

Epidemiological data suggests that early life exposures are key determinants of immune mediated disease later in life. Young children are also susceptible to infections, warranting more analyses of immune system development early in life. Such analyses have mostly been performed in mouse models or human cord blood samples, but these cannot account for the complex environmental exposures influencing human newborns after birth. We have performed a systems-level analysis of newborn immune system development and uncovered drastic developmental changes, triggered by environmental exposures, and following a shared stereotypic pattern. Here I will describe our latest results in our pursuit of understanding how early-life environmental exposures shape human immune systems, and how this determines functional capacity and infectious disease susceptibility in human newborns.

Fc receptors - Drivers of Immunity - Dr. Jeffrey Ravetch (RU)

How do antibodies mediate diverse effector activities through an apparently invariant Fc domain? The solution to this paradox is to be found in the diversity of receptors that engage the Fc domain, collectively called the Fcg receptors. These cell surface receptors, selectively expressed on various immune cell populations, confer specificity on the IgG immune response by their selective engagement of Fcs that differ in subclass and glycan composition. The Fc domain thus displays a surprising degree of structural diversification enabling distinct structures to engage individual members of this extended family of receptors. Unique Fc structures and their cognate receptors have been defined that result in either pro-inflammatory, anti-inflammatory, or immunomodulatory activity of antibodies in vivo. These observations have provided a molecular explanation for the mechanisms by which antibodies can mediate their therapeutic or pathogenic activities and has resulted in in the development and approval of novel therapeutics for autoimmune, infectious and neoplastic diseases.

Pneumococcal interactions with the host - Dr. Birgitta Henriques Normark (KI)

Infections caused by pneumococci, gram positive bacteria, are major causes of morbidity and mortality world-wide. Pneumococci are the major cause of milder respiratory tract infections such as otitis and sinusitis, but also a major contributor to more severe diseases such as pneumonia, septicaemia and meningitis. Despite being a sometimes devastating pathogen, pneumococci are common colonizers of the upper respiratory tract of healthy children from where they may spread to susceptible individuals and cause disease. A major question is what determines whether these bacteria that normally are found in the nasopharynx of healthy individuals sometimes cause diseases with even lethal outcomes? Both bacterial and host factors are important and their interactions for disease progress. Symptoms during the infection are also mainly due to an inflammatory response evoked in the host. I will talk about our recent data where we find that specific pneumococcal proteins can interact with the host and affect the immune response.

Day 2, Session 3: Neuroscience and Immunology - Chairs: Dr. Marianne Schultzberg (KI) and Dr. Michel Nussenzweig (RU)

Toward a genetic theory of childhood infectious diseases - Dr. Jean-Laurent Casanova (RU)

The hypothesis that inborn errors of immunity underlie infectious diseases is gaining experimental support. However, the apparent modes of inheritance of predisposition or resistance differ considerably between diseases and between studies. A coherent genetic architecture of infectious diseases is lacking. We suggest here that life-threatening infectious diseases in childhood, occurring in the course of primary infection, result mostly from individually rare but collectively diverse single-gene variations of variable clinical penetrance, whereas the genetic component of predisposition to secondary or reactivation infections in adults is more complex. This model is consistent with (i) the high incidence of most infectious diseases in early childhood, followed by a steady decline, (ii) theoretical modeling of the impact of monogenic or polygenic predisposition on the incidence distribution of infectious diseases before reproductive age, (iii) available molecular evidence from both monogenic and complex genetics of infectious diseases in children and adults, (iv) current knowledge of immunity to primary and secondary or latent infections, (v) the state of the art in the clinical genetics of non-infectious pediatric and adult diseases, and (vi) evolutionary data for the genes underlying single-gene and complex disease risk. With the recent advent of new-generation deep resequencing, this model of single-gene variations underlying severe pediatric infectious diseases is experimentally testable.

Single-cell transcriptional and epigenomic states of oligodendroglia in multiple sclerosis - Dr. Gonçalo Castelo-Branco (KI)

Oligodendrocytes are glial cells that mediate myelination of neurons, a process that allows efficient electrical impulse transmission in the central nervous system (CNS). An autoimmune response against myelin triggers demyelination in multiple sclerosis (MS). Adult oligodendrocyte precursor cells (OPCs) in the CNS can initially differentiate and promote remyelination in MS, but this process eventually fails in progressive MS. In order to clearly define transcriptional states of oligodendrocyte lineage cells in MS, we performed single-cell RNA-Seq in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS and in different kinds of CNS lesions from MS patients. We identified disease-specific of oligodendrocytes and OPC populations in EAE, and altered heterogeneity of the oligodendrocyte lineage in MS patients. A subset of the identified populations expressed genes involved in antigen processing and presentation, and immunoprotection. Furthermore, we found that OPCs have immunomodulatory properties. Thus, our single cell transcriptomics analysis unveiled a transcriptional overhaul of oligodendroglia in multiple sclerosis.

CRISPR-Cas: acquired immunity in prokaryotes - Dr. Luciano Marraffini (RU)

Clustered, regularly interspaced, short palindromic repeat (CRISPR) loci and their associated (Cas) proteins provide adaptive immunity against viral and plasmid infection in prokaryotes. The CRISPR-Cas immune response can be divided into two phases. Upon infection, short phage or plasmid sequences known as spacers integrate between CRISPR repeats. This is known as the immunization stage. During the second phase, the targeting phase, spacers are transcribed into small RNA guides that identify the viral or plasmid targets of CRISPR immunity. The CRISPR RNA guides are loaded into Cas nucleases and direct them to complementary sequences in the invading genome. Cleavage of the target genome results in the end of the infection. I will discuss recent work in my lab which shows how these two phases of the CRISPR-Cas immune response are fundamentally linked.

Applied epigenomics: insights into the pathogenesis of Multiple Sclerosis

Multiple Sclerosis (MS) is a chronic inflammatory disease characterized by autoimmune destruction of myelin and neurons in the central nervous system. Today, MS is one of the leading causes of neurological disability in young adults. Current treatments act broadly on the immune system and they are effective in controlling the inflammatory stage of disease while there are no treatments that prevent sustained neuronal loss and disease progression. Although the cause of MS remains unknown, vast epidemiological data establish MS as a complex disease influenced by genetic and environmental factors. Epigenetic mechanisms, such as DNA methylation, orchestrate activity of the genome in response to environmental cues and may provide better understanding of disease pathogenesis. One of the main challenges with studying diseases such as MS is the limited access to the target tissue - the brain. Recent progress in development of methods to survey epigenetic modifications, and from them infer genome activity, opened up possibilities to study brain tissue and mechanisms that underlie neuronal loss in MS patients.

Neuro-immune interactions in the gut - Dr. Daniel Mucida (RU)

Enteric–associated neurons (EANs) are closely associated with immune cells and continuously monitor and modulate homeostatic intestinal functions, including motility. Bidirectional interactions between immune and neuronal cells are altered during disease processes such as neurodegeneration or irritable bowel syndrome. We investigated how infection-induced inflammation affects intrinsic EANs and the role of intestinal muscularis macrophages (MMs) in this process. Using murine model of bacterial infection, we observed long-term gastrointestinal symptoms including reduced motility and subtype-specific neuronal loss. Neuronal-specific translational–profiling uncovered a caspase 11–dependent EAN cell–death mechanism induced by enteric infections. MMs responded to luminal infection by upregulating a neuroprotective program; gain– and loss–of-function experiments indicated that b2-adrenergic receptor (β2-AR) signaling in MMs mediates neuronal protection during infection via an arginase 1-polyamine axis. Our results identify a mechanism of neuronal cell death post–infection and point to a role for tissue–resident MMs in limiting neuronal damage.