Scientific Understanding of Consciousness
Consciousness as an Emergent Property of Thalamocortical Activity

Embryonic Development -- Recent Research


Nature 449, 223-227 (13 September 2007)

Dscam diversity is essential for neuronal wiring and self-recognition

Daisuke Hattori, Ebru Demir, Ho Won Kim, Erika Viragh, S. Lawrence Zipursky & Barry J. Dickson

Department of Biological Chemistry, Howard Hughes Medical Institute, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California 90049, USA

Institute of Molecular Pathology, Dr. Bohr-gasse 7, Vienna A-1030, Austria

The complexity and specificity of neuronal wiring implies the existence of a cellular recognition code that allows neurons to distinguish between one another. It has been speculated that families of highly diverse cell-surface molecules could provide this function, such as the vertebrate neurexins, cadherins and cadherin-related neuronal receptors, and the insect Dscams. However, it remains unclear to what extent the molecular diversity of such proteins is essential for wiring specificity, and how their diversity contributes to neuronal recognition. In Drosophila melanogaster, as many as 38,016 Dscam isoforms are generated by alternative splicing. Each isoform consists of an ectodomain containing a unique combination of three different variable immunoglobulin-like domains linked to one of two alternative transmembrane segments. The variable ectodomain segments are encoded by 12, 48 and 33 alternatives for exons 4, 6 and 9, respectively, whereas the transmembrane domain is encoded by two versions of alternative exon 17. A given ectodomain isoform binds strongly to itself, but only weakly, if at all, to other isoforms. Thus, Dscam diversity could provide a molecular mechanism for selective recognition among neurons.

Neurons are thought to use diverse families of cell-surface molecules for cell recognition during circuit assembly. In Drosophila, alternative splicing of the Down syndrome cell adhesion molecule (Dscam) gene potentially generates 38,016 closely related transmembrane proteins of the immunoglobulin superfamily, each comprising one of 19,008 alternative ectodomains linked to one of two alternative transmembrane segments. These ectodomains show isoform-specific homophilic binding. We conclude that Dscam diversity provides each neuron with a unique identity by which it can distinguish its own processes from those of other neurons, and that this self-recognition is essential for wiring the Drosophila brain.



Science 8 September 2006: Vol. 313. no. 5792, pp. 1408 - 1413
Hoxa2- and Rhombomere-Dependent Development of the Mouse Facial Somatosensory Map

Franck Oury,1 asunori Murakami,1 ean-Sebastien Renaud,2 Massimo Pasqualetti,1 atrick Charnay,3 Shu-Yue Ren,1 ilippo M. Rijli1

1 Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/Université Louis Pasteur, UMR 7104, BP 10142, Communauté Urbaine de Strasbourg, 67404 Illkirch Cedex, France.
2 Department of Physiology, Institute of Basic Medical Science, University of Oslo, 0317 Oslo, Norway.
3 INSERM, U784, Ecole Normale Supérieure, 46 rue d'Ulm, 75230 Paris Cedex 05, France.

In the mouse trigeminal pathway, sensory inputs from distinct facial structures, such as whiskers or lower jaw and lip, are topographically mapped onto the somatosensory cortex through relay stations in the thalamus and hindbrain. In the developing hindbrain, the mechanisms generating such maps remain elusive. We found that in the principal sensory nucleus, the whisker-related map is contributed by rhombomere 3–derived neurons, whereas the rhombomere 2–derived progeny supply the lower jaw and lip representation. Moreover, early Hoxa2 expression in neuroepithelium prevents the trigeminal nerve from ectopically projecting to the cerebellum, whereas late expression in the principal sensory nucleus promotes selective arborization of whisker-related afferents and topographic connectivity to the thalamus. Hoxa2 inactivation further results in the absence of whisker-related maps in the postnatal brain. Thus, Hoxa2- and rhombomere 3–dependent cues determine the whisker area map and are required for the assembly of the whisker-to-barrel somatosensory circuit.



Science 8 December 2006: vol. 314. no. 5805, pp. 1610 - 1613

Sequential Interplay of Nicotinic and GABAergic Signaling Guides Neuronal Development

Zhaoping Liu, Robert A. Neff, Darwin K. Berg

GABA ({gamma}-aminobutyric acid), the major inhibitory transmitter in the brain, goes through a transitory phase of excitation during development. The excitatory phase promotes neuronal growth and integration into circuits. We show here that spontaneous nicotinic cholinergic activity is responsible for terminating GABAergic excitation and initiating inhibition. It does so by changing chloride transporter levels, shifting the driving force on GABA-induced currents. The timing of the transition is critical, because the two phases of GABAergic signaling provide contrasting developmental instructions. Synergistic with nicotinic excitation, GABAergic inhibition constrains neuronal morphology and innervation. The results reveal a multitiered activity-dependent strategy controlling neuronal development.

Division of Biological Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093–0357, USA.



Nature 443, 210-213 (14 September 2006)

The tumour suppressor Hippo acts with the NDR kinases in dendritic tiling and maintenance

Kazuo Emoto1,2, Jay Z. Parrish1, Lily Yeh Jan1 and Yuh-Nung Jan1

Howard Hughes Medical Institute, Departments of Physiology, Biochemistry, and Biophysics, University of California San Francisco, San Francisco, California 94143-0725, USA

Precise patterning of dendritic fields is essential for neuronal circuit formation and function, but how neurons establish and maintain their dendritic fields during development is poorly understood. In Drosophila class IV dendritic arborization neurons, dendritic tiling, which allows for the complete but non-overlapping coverage of the dendritic fields, is established through a 'like-repels-like' behaviour of dendrites mediated by Tricornered (Trc), one of two NDR (nuclear Dbf2-related) family kinases in Drosophila. Here we report that the other NDR family kinase, the tumour suppressor Warts/Lats (Wts), regulates the maintenance of dendrites; in wts mutants, dendrites initially tile the body wall normally, but progressively lose branches at later larval stages, whereas the axon shows no obvious defects. We further provide biochemical and genetic evidence for the tumour suppressor kinase Hippo (Hpo) as an upstream regulator of Wts and Trc for dendrite maintenance and tiling, respectively, thereby revealing important functions of tumour suppressor genes of the Hpo signalling pathway in dendrite morphogenesis.


Science 17 July 2009: Vol. 325. no. 5938, pp. 284 - 288

Foundations for a New Science of Learning

Andrew N. Meltzoff,1,2,3 Patricia K. Kuhl,1,3,4 Javier Movellan,5,6 Terrence J. Sejnowski5,6,7,8

1 Institute for Learning and Brain Sciences, University of Washington, Seattle, WA 98195, USA.
2 Department of Psychology, University of Washington, Seattle, WA, 98195, USA.
3 Learning in Informal and Formal Environments (LIFE) Center, University of Washington, Seattle, WA 98195, USA.
4 Department of Speech and Hearing Sciences, University of Washington, Seattle, WA, 98195, USA.
5 Institute for Neural Computation, University of California at San Diego, La Jolla, CA 92093, USA.
6 Temporal Dynamics of Learning Center (TDLC), University of California at San Diego, La Jolla, CA 92093, USA.
7 Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
8 Division of Biological Sciences, University of California at San Diego, La Jolla, CA 92093, USA.

Neuroscientists are beginning to understand the brain mechanisms underlying learning and how shared brain systems for perception and action support social learning. New insights from many different fields are converging to create a new science of learning that may transform educational practices.

The brain continues to grow during childhood and reaches the adult size around puberty. The development of the cerebral cortex has "sensitive periods" during which connections between neurons are more plastic and susceptible to environmental influence: The sensitive periods for sensory processing areas occur early in development, higher cortical areas mature later, and the prefrontal cortex continues to develop into early adulthood.

Human children readily learn through social interactions with other people. Three social skills are foundational to human development and rare in other animals: imitation, shared attention, and empathic understanding.

Imitation. Learning by observing and imitating experts in the culture is a powerful social learning mechanism.

Shared attention. Social learning is facilitated when people share attention. Shared attention to the same object or event provides a common ground for communication and teaching. An early component of shared attention is gaze following. Infants in the first half year of life look more often in the direction of an adult’s head turn when peripheral targets are in the visual field.

Empathy and social emotions. The capacity to feel and regulate emotions is critical to understanding human intelligence. In humans, many affective processes are uniquely social.

Neural plasticity. In humans, a sensitive period exists between birth and 7 years of age when language is learned effortlessly; after puberty, new language learning is more difficult, and native-language levels are rarely achieved. At 6 months of age, listening to speech activates higher auditory brain areas (superior temporal), as expected, but also simultaneously activates Broca’s area, which controls speech production.