1991 — 1993 |
Devries, Steven H. |
F32Activity Code Description: To provide postdoctoral research training to individuals to broaden their scientific background and extend their potential for research in specified health-related areas. |
Signal Processing in the Vertebrate Retina |
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1999 — 2003 |
Devries, Steven H. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Function of Basal Synapses At Photoreceptors @ Northwestern University
The goal of this project is a quantitative description of the mechanism of signal transmission between cone photoreceptors and Off bipolar cells in the mammalian retina. Cones make two types of synapse: ribbon and basal. Ribbon synapses mediate transmission between cones and post- synaptic horizontal and On bipolar cells. The ribbon synapses have docked synaptic vesicles, and thus resemble conventional synapses made by other neurons in the brain. Basal synapses mediate transmission between cones and post-synaptic Off bipolar cells. At basal synapses, the membranes of pre- and post-synaptic cells come into close apposition, but there are no obvious docked vesicles and no active zones. Basal synapses are structurally different from conventional synapses, and little is known of their function. It is important to know how basal synapses function, since these synapses form a crucial link in the pathway that signals decreases in bright illumination. There are at least three hypotheses for how basal synapses operate: 1) Transmitter is released by Ca/2+-dependent exocytosis at basal junctions in the absence of morphological specialization (local vesicular release); 2) Exocytosis occurs only at ribbon synapses and basal synapses receive transmitter by overflow (remote vesicular release); and, 3) Transmitter release occurs at the basal synapse by a Ca/2+-independent, transporter-mediated mechanism. The function of basal synapses will be characterized in a mammalian retinal slice preparation in which the membrane voltage of both a cone (the pre-synaptic cell) and a hyperpolarizing bipolar cell (the post-synaptic cell) are controlled simultaneously with patch- pipette voltage clamps. Specific experiments have been designed to differentiated between three mechanisms. Experiments will first determine whether transmission at the basal synapse is vesicular by characterizing its Ca/2+ and voltage dependence. Experiments will then distinguish between local and remote release by characterizing the time- and voltage-dependent rate of vesicle fusion in a cone, the shape of the quantal response, the dwell-time of transmitter in the synaptic cleft, and the properties of the post-synaptic glutamate receptors.
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2004 — 2021 |
Devries, Steven H |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Function of Basal Synapses At Mammalian Photoreceptors @ Northwestern University At Chicago
The long-term objective of this project is to understand how the unique structure of the mammalian cone photoreceptor synapse determines its function in vision. The opsin proteins in the outer segments of cones convert absorbed light into a voltage signal. In a necessary step for visual perception, the voltage signal spreads to the photoreceptor synaptic terminal where it gates a Ca2+ channel that controls the release of the transmitter glutamate onto postsynaptic bipolar and horizontal cells. Parallel processing in the visual system begins at the cone synapse. Each cone terminal communicates with ~14 anatomically distinct bipolar cell types at two structurally unique contacts termed invaginating and basal. Transmitter is not released at basal contacts, but instead at sites near the top of each of a cone's 20-40 invaginations. Released glutamate must then diffuse over an extracellular path of 200 ? 500 nm to reach the dendrites of basally contacting bipolar cells. Recent results suggest that a long diffusion path can introduce a threshold that eliminates the low-amplitude noise associated with random fluctuations in cone transmitter release in the dark. At the same time, the threshold permits the cone to transmit signals resulting from larger release events coordinated by a change in illumination. Using electro- and opto-physiological techniques, this proposal addresses two mechanisms that increase the threshold nonlinearity at basal contacts: First, at least one type of Off bipolar cell expresses receptors with an unusually high EC50 for glutamate (~1.5 mM); and second, basally located glutamate transporters provide saturable binding sites that can deplete cleft glutamate under dark release conditions. Specific Aim 1 addresses the mechanisms and functions of the threshold nonlinearity at the cone to cb1a bipolar cell basal synapse. Experiments will determine how transporter glutamate binding and kainate receptor properties contribute to nonlinear signal transmission during a light stimulus. Specific Aim 2 focuses on the ?nano-scopic? spatial localization of the proteins that shape transmission at the cone synapse. This aim uses a newly developed ?thick slab? superresolution imaging technique to relate the cone synapse nanostructure to its response properties. Information about the properties of cone transmitter release, glutamate transporters, and postsynaptic receptors will be combined with localization information obtained from superresolution microscopy to create a functional model of the basal synapse. In addition to responding to membrane voltage, it is becoming increasingly clear that Ca2+ channels in the cone terminal integrate modulatory inputs from other sites in the retina including from horizontal cells. Blue or short wavelength-sensitive (S-) cones are unique among the photoreceptor types in expressing S-opsin both in the outer segment and at the synaptic terminal. Recent experiments show that when activated by light, terminal S-opsin enhances the Ca2+ current which in turn augments transmitter release. Specific Aim 3 uses electrophysiological techniques to address both the mechanisms of the S-opsin mediated Ca2+ current increase and the role of this enhancement in visual function.
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2007 — 2021 |
Devries, Steven H |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Signal Processing in the Inner Retina @ Northwestern University At Chicago
DESCRIPTION (provided by applicant): The mammalian retina contains at least 15-20 types of retinal ganglion cells each tuned to respond best to different and sometimes complex features in a visual scene. Together, these diverse ganglion cell responses provide us with all of the information that we use to navigate in the visual world. Each type of retinal ganglion cell monitors a patch on the retinal surface, its receptive field, by collecting inputs from presynaptic bipolar and amacrine cells of which there are more than 12 and 30 types, respectively. While the general patterns of amacrine and bipolar cell connectivity that contribute to he ganglion cell light response are known, the daunting complexity of the IPL has impeded our understanding of the specific connections that underlie the tuning properties that distinguish the ganglion cell types. We have developed a toolbox of optogenetic and virally-based techniques that will enable us to trace and functionally characterize the connections between bipolar, amacrine, and ganglion cells in both the rod dominant mouse and cone dominant ground squirrel retinas. In three specific aims, our goals are to: 1) test the hypothesis that ganglio cells obtain different temporal light responses, in part, by summing the excitatory inputs of bipolar cells with different temporal responses. 2) test the hypothesis that ganglion cells obtain direct input from different types of amacrine cells with different temporal properties and, 3) determine the functional connections and the role in vision of a specific amacrine cell type that expresses cre recombinase under the control of the corticotropin releasing hormone (CRH) promoter. Our work will define the wiring and functions of specific inner retinal circuits i health, and provide the background for understanding circuit changes that are known to occur following photoreceptor degeneration, whether from genetic or age-onset disease.
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2015 — 2021 |
Devries, Steven H |
T32Activity Code Description: To enable institutions to make National Research Service Awards to individuals selected by them for predoctoral and postdoctoral research training in specified shortage areas. |
Multidisciplinary Visual Sciences Training Program @ Northwestern University At Chicago
? DESCRIPTION (provided by applicant): The past 10 years have witnessed a stunning convergence between basic and clinical visual science. Basic advances in optogenetics, retinal array fabrication, stem cell biology, angiogenesis pathways, and microscopy have all seen rapid application in the clinical setting. The ideal visual scientist of the future, today's trainee, nees to have a multidisciplinary background so as to be well-versed in both basic science and clinical applications. The objective of the Northwestern University Multidisciplinary Vision Training Program is to prepare pre- and postdoctoral trainees for independent careers in vision research broadly defined to include diseases and functions of the anterior eye, diseases and processing mechanisms of the retina, and central processing. The rationale for this proposal is to capitalize on the existing multidisciplinary research base at Northwestern University by integrating labs into a cohesive unit for the purposes of training. The 20 preceptors offer research training in cel and molecular biology, genetics, neurobiology of the visual system, advanced microscopy, stem cells, diseases of the anterior and posterior eye, and evidenced based analysis of treatment outcomes and healthcare delivery. Funding to support 2 predoctoral candidates, after they have begun full time thesis research, and 2 postdoctoral trainees, in the early or middle stages of training, is requested. The predoctoral trainees are recruited on the basis of course performance, rotation evaluations, and relevance of the proposed dissertation research from the Northwestern University Integrated Neuroscience (NUIN) program, the Interdepartmental Biological Sciences (IBiS) program, the Driskill Graduate Program in Life Sciences (DGP), and the Biomedical Engineering (BME) Graduate Program. Predocs are supported for three years. Postdoctoral trainees are selected for support for two years based on research record and preceptor recommendation. A Steering Committee evaluates and selects trainees from among the eligible pre- and postdocs. The training program also educates students in the ethics of science and responsible conduct of research. Major emphasis is placed on recruiting trainees from under-represented minority groups to vision research. The program for each trainee is determined by the trainee, preceptor, and Steering Committee who formulate an individual development plan. The Program Director is Steven H. DeVries, MD, PhD, Professor of Ophthalmology and Physiology and the co-Director is Jianhua Cang, PhD, Associate Professor of Neurobiology. In addition to research training, the program offers a curriculum that includes two formal courses (mandatory for pre-docs), a biweekly presentation series on advanced topics in vision, multiple journal clubs, invited lectures by nationally known researchers, and a Research Day. It is expected that the trainees will continue as independent, productive, and ethical investigators who will address national priorities in vision research.
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