Neural stem-progenitor cells in the embryonic, early postnatal, and adult mammalian brain
Significant advances have been made in our understanding of the regulation of neural stem-progenitor cell (NSC) fate during development of the mammalian brain as well as in adulthood. Embryonic NSCs divide frequently and generate a wide variety of neuronal and glial cell types that constitute the mature brain. In contrast to the widespread production of glial cells that continues in the postnatal brain, the production of neurons ceases by the completion of brain development—with the exception of that in two neurogenic niches, the subventricular zone of the lateral ventricles and the subgranular zone of the hippocampal dentate gyrus. This session focuses on regulation of the fate of embryonic, early postnatal, and adult NSCs through intrinsic and extrinsic mechanisms.
Cell lineage and neural diversity in the cerebral cortex
The cerebral cortex is responsible for all higher-order brain functions, such as sensory perception, motor control, and cognition. It contains a vast number of cells that exhibit an extraordinary diversity in molecular, cellular, and functional features. Since the ground-breaking work of Ramon y Cajal, cortical cell types have been increasingly defined by their location, neurotransmitter type, morphology, gene expression, and synaptic connectivity. The ability to observe accurately and manipulate precisely cortical activity depends on greater knowledge of diverse neural types. While extensive efforts such as single cell transcriptome analysis have been taken to provide an accurate census of cell types in the cortex, the origins of neural diversity in the cortex remain poorly understood. It is likely, at least to a certain degree, that cortical neural diversity is rooted in the process of neurogenesis and gliogenesis during early development. For example, it is well-established that excitatory glutamatergic principal neurons and inhibitory GABAergic interneurons in the cortex are originated from distinct progenitors. However, the intricate relationship between cell lineage and neural diversity is only beginning to come into focus. In this symposium, the speakers will present and discuss ongoing researches related to cell lineage and neural diversity in the cerebral cortex.
This session focuses on the interactions of oligodendrocytes and neurons during CNS development. The issues of axonal signaling to differentiating oligodendrocytes and signaling from myelinating oligodendrocytes to neurons will be presented. Dr. Kazuhiro Ikenaka will discuss the mechanisms of myelination by a single oligodendrocyte, when in the presence of active axons and inactive axons. Thus, will a single oligodendrocyte preferentially myelinate active axons over inactive ones? It is known that myelin sheath length is longer on active axons. Will a single oligodendrocyte form longer internodes on active axons and shorter internodes on inactive ones? Dr. Wendy Macklin will discuss the signaling between oligodendrocytes and axons that enhance myelination, studying a model in which gene expression in cortical neurons is altered. These studies address what changes occur in the axons and in the oligodendrocytes, which start to differentiate and then die. Dr. Kelly Monk will discuss studies on a recently completed large-scale, three-generation forward genetic screen in zebrafish to discover mutants with defects in myelinated axon development. This highly successful screen uncovered 28 new mutants, many of which identify genes with no previously defined functions in glial cells. One of the most interesting oligodendrocyte mutants will be discussed. Dr. Eva-Maria Albers will discuss activity-dependent transfer of extracellular vesicles termed exosomes from oligodendrocytes to neurons, and its relevance for neuronal homeostasis and glial support. A transgenic reporter model to study exosome transfer in vivo allows investigation of the functional competence of exosomes released from proteolipid protein- or 2’,3’ cyclic nucleotide phosphodiesterase-deficient oligodendrocytes.
Modeling neurodevelopment and developmental brain disorders: from Primate to human PSC-based 2D and 3D models
Recent advancement in deriving pluripotent stem cells from humans and genome engineering technology to genetically edit the primate and human genome made it possible to develop primate and human model systems to address biological questions. This session will provide the audience an updated view of how these state-of-the-art technologies are applied to understand organogenesis and to decipher the pathology and molecular mechanisms underlying disorders, with an emphasize in the brain development and neurological disorders. Dr. Pierre Vanderhaeghen, a Professor at University of Brussels will talk about species-specific mechanisms of human cortical neurogenesis. Dr. Orly Reiner, a professor at Weizmann Institute Israel will discuss her work using human brain organoids on a Chip to model brain development and disease. Dr. Ming, a Professor at University of Pennsylvania, will discuss the use of 2D and 3D organoid cultures systems from human iPSC to understand the cellular impact of Zika virus infection on neurogenesis, synapse formation and underlying molecular mechanism. And Dr. Yi Sun, a Professor at University of California, Los Angeles will discuss their effort of using TALEN-edited MECP2 mutant cynomolgus monkeys to model Rett Syndrome, a devastating neurodevelopmental disorder with no cure.
Mechanisms of circuit formation and degeneration
This symposium will explore mechanisms of neural circuit formation during development and genetic and molecular underpinnings of neurodevelopmental and neurodegenerative disease.
Shernaz Bamji, from the University of British Columbia (Canada) will present new data demonstrating that disrupting the X-linked intellectual disability gene, DHHC9, decreases dendritic arborization and the number of inhibitory inputs. Her results provide a plausible explanation why patients with X-linked intellectual disability associated with DHHC9 mutations have a significantly higher incidence of epilepsy.
Aaron Gitler, Stanford University (USA), will present results of genomewide CRISPR screens in human cells and rodent primary neurons to identify modifiers of human neurodegenerative disease proteins, with a focus on the ALS gene C9orf72. Additional data will be presented describing a role of the ataxin 2 gene as a genetic risk factor for ALS and also as a promising therapeutic target for ALS.
Zilong Qiu, from Institute of Neuroscience (China) will describe a genome editing approach as a therapy for autism-related phenotypes in a mouse model of MECP2 gene duplication. He will describe experiments using circuitry-specific genome editing methods to reverse autistic phenotypes even in adult mice. His data indicate that autism-related developmental defects could be corrected in late stage of life.
Yimin Zou, University of California San Diego (USA) will present results revealing signaling mechanisms mediating glutamatergic synapse assembly, which are fundamental to our understanding of neural circuit function, plasticity, and disorders, but have remained elusive. He will present direct evidence that two components of the conserved planar cell polarity signaling pathway, which assembles asymmetric cell–cell junctions, have opposing functions in glutamatergic synapse formation. Celsr3 promotes assembly whereas Vangl2 inhibits assembly, suggesting that this signaling mechanism is accessible for both positive and negative regulation and is also a candidate pathway for mediating synaptic plasticity.
Neurodevelopmental programming is a key area in population health research. The activity of non-genetic factors early in life that results in the permanent organization or imprinting of physiological systems is known as perinatal “programming”. In animal models, stress-related events that occur during early life have lifelong programming effects on the regulation of stress response, emotional behavior, metabolism and cerebral plasticity, with a considerable impact on the susceptibility to developing age-related disorders or to be transmitted to the following generations. This early programming has become a dominant theory for the origins of health and disease (Developmental Origins of Health and Disease). Knowledge of the mechanisms of neurodevelopmental programming will allow physicians to develop treatments that are best suited to each new born and adult patient. In adult humans, even if there is a large experimentation on the psycho-medication, mental illness is pathology of the human relationship that finds its origin after birth and during the first year of life. Indeed, for psychiatric disorders, postnatal programming plays a crucial role. In this symposium will thus take in account different aspects to understand mechanisms involved in the neurodevelopment of psychiatric disorders: 1) Psychodynamics and the critical role of the first year of life, based on the Human Birth Theory of Massimo Fagioli, psychiatrist recently died; 2) Epigenetics, based on evidence that stressors and /or maternal care alterations occurring during critical periods of development may change the phenotype of an individual; 3) Neuropharmacology, involving glutamate transmission and ketamine with a rapid antidepressant effect; 4) Neurobiology, focusing on the role of the Habenula on fear and social conflict related to the evolutionary conserved mechanisms as a link with depression.
Vocal communication is critical to survival and reproduction in a wide range of vertebrates and there is impressive diversity in the structure, complexity, and plasticity of vocal signals across species. Human language is a notable example: it is a learned, highly complex, referential signal that is dependent on sensory exposure and sensorimotor practice during development. While language is generally considered to be uniquely human, studies on vocal production and perception in other species have substantially informed our understanding of the mechanisms underlying the learning, development, and evolution of vocal communication in general and language in particular. In this panel, we will explore a range of factors that can influence vocal communication systems, and their learning and development. For example, social interactions and experience, genetic and molecular cascades, and auditory and motor abilities have each been shown to influence the neural mechanisms underlying the production and perception of vocal signals in developing individuals as well as in adults. The panel will discuss these multiple facets of vocal communication, surveying advances in research focused on different levels of analysis, from genetics to behavior, in a diversity of model organisms, including bats, primates and songbirds. By integrating these perspectives in a broad array of taxa we aim to gain insight into the general mechanisms underlying vocal communication.
The mammalian neocortex has a highly organized 6-layered structure of neurons, which serves as the fundamental basis of various higher brain functions. Neuronal migration plays an important role in the establishment of this layered structure. Cortical excitatory neurons are known to be generated near the ventricle (ventricular zone or subventricular zone) and migrate toward the brain surface, where they form a cortical plate. Within the cortical plate, neurons are basically aligned in a birthdate-dependent “inside-out” manner, in which late-born neurons are located more superficially than the early-born neurons. Inhibitory cortical interneurons are generated outside of the neocortex and colonize the different layers, thereby shaping the excitation/inhibition balance essential for proper cerebral functions.
The building of this layered architecture is regulated by several key players, including Cajal-Retzius neurons in the marginal zone/layer I and immune brain cells called microglia. Neuronal migration is also involved in the global morphogenesis of the brain such as cortical folding. The speakers in this session will present recent results related to these topics and discuss the significance of the control of cell migration and positioning in the developing cerebral cortex.
Recent advances in gene-editing have revolutionized biological research. In particular, the CRISPR/Cas9 system has had a profound impact in the development of the technique, because of its accessibility and adaptability. The capability to insert, delete and edit genome with high precision in specific sets of cells provided useful means to measuring and manipulating the function of the gene of interest in various cellular function as well as behavioral paradigms. The technology has been implemented for mutagenesis in various animal models including primates, for editing genome in single cells, for editing RNA, and for manipulating epi-genomic regulations. This symposium will focus on recent development of new genome editing techniques and their applications in neuroscience research.
Sensory pathways bring information into the brain and help wire circuits that process, transform and direct information to outputs that mediate goal-directed action. The development of brain pathways involves a wide range of molecules that influence, in serial as well as parallel stages, cellular specification, axonal targeting, cell-specific wiring, synaptic development, and activity-dependent synaptic plasticity that shapes circuits. This symposium will bring together leading investigators who use diverse model systems and approaches to study the development and plasticity of brain pathways and circuits. Patricia Gaspar will describe studies aimed at analyzing the effects of neural activity, mediated by early life stress, and serotonin transmission, mediated by early exposure to SSRI antidepressants, on cells and circuits of the prefrontal cortex. Shubha Tole will describe studies of cortical progenitor-specific mechanisms which control thalamocortical innervation of the subplate and cortical wiring. Artur Kania will describe genetic studies of nociceptive circuit development which reveal the specification and organization of ascending pain pathways and their functions. Mriganka Sur will describe studies using high resolution imaging of neurons, dendrites and synapses in awake mice to reveal rules by which Hebbian and homeostatic mechanisms of plasticity regulate visual cortex circuits. In addition, two oral presentations by young investigators will describe the role of patterned activity in wiring of olfactory sensory neurons, and the role of Otx2 homeoprotein in visual cortex plasticity.