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When these neurons are then illuminated with light of the correct frequency they will be transiently activated or inhibited or their signaling pathways will be modulated, depending on the particular kind of opsin that was chosen for expression. In brief, neurons are first genetically engineered (using a variety of mechanisms, described later) to express light-sensitive proteins (opsins). Genetic and optical methods applied together allow tight spatial and temporal control of the activity of specific kinds of neurons in the living brain, a revolutionary advance that will allow us to achieve an unprecedented understanding of neural circuit function in behaving animals. Optogenetics has ushered in a new era of potent and targeted control over multiple aspects of neural function. While powerful, intracranial lesions and electrical stimulation affect spatially defined brain regions without restricting their action to a particular kind of neuron, and cell type–specific pharmacology and transgenic or viral manipulation of gene expression have relatively low temporal resolution. Although substantial progress has been made towards understanding vertebrate neural circuits, there are significant limitations associated with the techniques classically used to probe and control brain function.
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The vertebrate brain, encompassing hundreds of millions of neurons in rodents and hundreds of billions of neurons in humans, contains many different cell types with distinct molecular expression patterns, physiological activity, and topological connectivity, which are intermingled in a highly heterogeneous network. Vertebrate animals (fish, mice, rats, birds, and primates), on the other hand, have a much larger, more complex, and highly variable nervous system that is not tractable using this kind of approach.
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Some model organisms (worm, sea slug, lobster, and crab, among others) have the significant advantage that their relatively small nervous systems permit experimental perturbation of individually identifiable single neurons, an approach that has given rise to a sophisticated understanding of the functional wiring diagram controlling behavior in these organisms. These techniques have allowed us to dissect the detailed workings of the neural circuits underlying natural behavior, and they have also enabled us to understand some facets of how neural circuits become dysfunctional in disease states. Progress towards understanding the neural circuits of the brain has historically relied on the development of new technologies that advance our ability to observe and control neuronal activity. It has revolutionized the field of neuroscience, and has enabled a new generation of experiments that probe the causal roles of specific neural circuit components. Optogenetics has been successfully employed to enhance our understanding of the neural circuit dysfunction underlying mood disorders, addiction, and Parkinson’s disease, and has enabled us to achieve a better understanding of the neural circuits mediating normal behavior. Since the advent of optogenetics, many different opsin variants have been discovered or engineered, and it is now possible to stimulate or inhibit neuronal activity or intracellular signaling pathways on fast or slow timescales with a variety of different wavelengths of light. When engineered cells are then illuminated with light of the correct frequency, opsin-bound retinal undergoes a conformational change that leads to channel opening or pump activation, cell depolarization or hyperpolarization, and neural activation or silencing. Cells are first genetically engineered to express a light-sensitive opsin, which is typically an ion channel, pump, or G protein–coupled receptor.
#Blue light ivia 2011b series
This review, one of a series of articles, tries to make sense of optogenetics, a recently developed technology that can be used to control the activity of genetically-defined neurons with light.