Michael Friedlander - US grants

A laser scanning confocal microscope will be acquired to allow structural analysis of: 1) The development of and cellular communication in the central nervous system and 2) chromosome movement and partitioning within cell nuclei. Specific projects include analysis of synaptic transmission, analysis of 3-D neuronal structure, cellular and molecular responses glia to immunoegulatory molecules and molecules that regulate regeneration, and analysis of the interaction of the centromere/Kinetochore with microtubules in mitotic cells.

20 faculty from 3 Departments (Cell Biology, Physiology and Biophysics, Psychology) are collaborating to provide a training program in cellular and molecular neuroscience. Over its course, this award will provide support for about 12 students. A major innovation in the training program is an intensive, 12 week summer laboratory course for students at the end of their first year of graduate school. The course consists of six 2-week modules in electrophysiology, developmental neurobiology, microscopy and imaging, second messengers and neurotransmitters, protein biochemistry, and molecular biology.

DESCRIPTION (provided by applicant): This application requests continuing support for Predoctoral Training in Systems and Integrative Biology with specific emphasis on Graduate Training in Neuroscience. The training program proposed encompasses Neuroscience from the study of such complex systems as the cortical processing of visual information to the molecular biology of synaptic transmission and neurotransmitter regulation of gene expression. The goal of the program is to prepare students for research careers in Neuroscience with an emphasis on a multi-dimensional approach to the problem. With this goal in mind we have assembled a faculty able to direct research projects in behavior, development, biochemistry, cellular electrophysiology, biophysics, molecular biology, photonics, psychophysics, cortical function, computational neuroscience and the molecular genetics of diseases of the brain. These faculty members are brought together in this goal by their common interests in Neuroscience and in their commitment to providing both didactic teaching and laboratory training to graduate students. We have implemented a new integrated core curriculum in Integrative Neuroscience that provides students with a broad foundation in Neuroscience that we hope will carry them forward in their work even as their specific research in Neuroscience may change over the course of their careers. We have prepared a series of exams that will test our progress in this endeavor, and have a number of mechanisms in place to promote collaborative interactions between the students and the faculty in different departments. We believe that Predoctoral Training in Neuroscience meets an important need in modern neurobiology research, the training of a cadre of broadly trained students with an integrated understanding across the tremendously broad spectrum of contemporary molecular, cellular and systems neuroscience. Ph.D. students also need to gain a clear appreciation of the many timely disease-related opportunities in Neuroscience research. This program in Graduate Training in Neuroscience at Baylor College of Medicine makes an important contribution to this endeavor through the recruitment and education of young scientists able to execute this mission.

DESCRIPTION (provided by applicant): Synapses in the cerebral cortex undergo dynamic alterations in their efficiency throughout life. In particular, the neurons of the primary visual cortex can use such synaptic plasticity to perform parallel computations on aspects of visual processing. Such activity-dependent changes in synaptic signaling have been suggested to contribute to visual perception, cognitive performance, skill-learning, developmental re-organization and refinement of functional visual cortical synaptic networks and adaptive responses after injury. These forms of plasticity undergo dramatic changes in their robustness, modulation by intrinsic and extrinsic factors and underlying molecular processes during postnatal development. However, the developmental regulation of these forms of functional synaptic plasticity has received less attention. We utilize an experimental model of neocortical synaptic plasticity that is based on serial correlations of synaptic input with activation of the postsynaptic neuron to characterize the initial intracellular calcium triggering events that generally lead to long term synaptic potentiation (LTP). Interestingly, in the neonatal visual cortex, when the identical serial correlations are applied to neurons of the same class (layer 2/3 pyramidal neurons), the synaptic plasticity that occurs (LTP or long term synaptic depression - LTD) varies between individual cells. A variety of sources of calcium including NMDA receptors, metabotropic glutamate receptors, inositide trisphosphate receptors (IPaRs), ryanodine receptors and voltage activated calcium channels all contribute to this process in these neonatal visual cortical neurons. The outcome of LTP or LTD in the neonatal cortex is predicted by the intracellular dendritic calcium transient's kinetic profile that occurs during the individual correlations and the kinetics of the cumulative calcium wave that spreads to the cell body. This protocol offers a unique window into the initial underlying calcium signaling processes that determines polarity of synaptic changes in the visual cortex during postnatal development and provides a new provocative view of how kinetics and amplitude of the very first calcium signals may be critical in the subsequent downstream activation of plasticity. This project also provides the first comprehensive analysis of unitary synaptic connections between individual layer 4 and layer 2/3 neurons with dual patch recording from synaptically coupled pairs with analysis of plasticity and calcium signaling at those connections. We determine the effects of intrinsic cellular differences, maturation, previous experience (metaplasticity) and calcium sources on the signaling and plasticity processes.