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• W2034375382 abstract "Electrical stimulation of neurons in the central nervous system of awake, behaving animals offers the ultimate test to determine whether the activation of specific neurons is sufficient to elicit perception, motor activity, or other behaviors. In this issue of Cell, Lima and Miesenböck (Lima and Miesenböck, 2005Lima S.Q. Miesenböck G. Cell. 2005; 121 (this issue): 141-152Abstract Full Text Full Text PDF PubMed Scopus (401) Google Scholar) dump the stimulating electrode in favor of a new remote control system to excite specific neurons—light activation of transgenically supplied ion channels. Electrical stimulation of neurons in the central nervous system of awake, behaving animals offers the ultimate test to determine whether the activation of specific neurons is sufficient to elicit perception, motor activity, or other behaviors. In this issue of Cell, Lima and Miesenböck (Lima and Miesenböck, 2005Lima S.Q. Miesenböck G. Cell. 2005; 121 (this issue): 141-152Abstract Full Text Full Text PDF PubMed Scopus (401) Google Scholar) dump the stimulating electrode in favor of a new remote control system to excite specific neurons—light activation of transgenically supplied ion channels. Most biology experiments can be classed as one of only three types. Biochemists will measure a biochemical activity, block it, or mimic it with a substitute. Geneticists measure phenotypic variables, block the activity of genes with loss-of-function mutations, and mimic endogenous gene function with transgenes. Neuroscientists also measure and block neural and behavioral processes using many different approaches. Neural activity is traditionally mimicked by electrical stimulation experiments. Powerful biological insights are provided by this latter type of experiment—the mimic—since these experiments test for sufficiency. In this issue of Cell, Susana Lima and Gero Miesenböck offer a creative new method for stimulating specific neurons in behaving Drosophila. Electrical stimulation experiments of the central nervous system using stimulating electrodes have been performed for decades on organisms as diverse as insects and humans. About 50 years ago, Wilder Penfield performed revolutionary electrical stimulation studies of different areas of the human cortex on neurosurgery patients under local anesthesia (see Squire, 1987Squire L.R. Memory and Brain. Oxford University Press, New York1987Google Scholar for a review). Patients reported hearing voices, seeing images, or experiencing a memory-like flashback. Franz Huber, 1967Huber F. Central control of movements and behavior in invertebrates.in: Wiersma C.A.G. Invertebrate Central Nervous Systems. Academic Press, Inc, New York1967: 333-354Google Scholar pioneered electrical stimulation to the brain of insects and showed that mushroom body stimulation elicits complex behaviors, including the inhibition of locomotion. More recently, monkey experiments have revealed that extracellular microstimulation of cortical cells in the middle temporal visual area alters the monkey’s perception of object motion in the visual field. In contrast, stimulation of somatosensory cortex neurons mimics the monkey’s perception of vibrations applied to its hand (Cohen and Newsome, 2004Cohen M.R. Newsome W.T. Curr. Opin. Neurobiol. 2004; 14: 169-177Crossref PubMed Scopus (120) Google Scholar). Neural stimulation experiments have thus provided an approach to determine whether the stimulation of selected neurons is sufficient to alter perception, cognition, or motor activity. With a new take on this old approach, Lima and Miesenböck have banished the stimulating electrode and replaced it with a tripartite remote control system that evokes action potentials in pre-specified Drosophila neurons. The central component of the remote is a ligand-gated ion channel, the ionotropic purinoceptor P2X2, which is gated by ATP. When ATP was applied to cultured Drosophila cells expressing P2X2, uptake of external calcium was induced. To test whether channel activation could depolarize neuronal membranes and stimulate action potentials, the investigators expressed the receptor in transgenic animals using a cholinergic neuron promoter and monitored the electrophysiological responses in larval muscles when the central nervous system was bathed in ATP. Robust excitatory junctional potentials were measured in the presence of ATP that were driven by action potentials in motor neurons, and these potentials were similar in magnitude to those observed in response to direct electrical stimulation of motor neurons. This confirmed that the expression of the P2X2 channel produced action potentials in the presence of ATP. The remaining two parts of the remote control system include chemically caged ATP, which was injected into the central nervous system through the fly’s simple eye, and laser light capable of uncaging the injected ATP. The ability of this three-part system to remotely control fly behavior was then tested by constructing transgenic flies expressing P2X2 in the giant fiber system, a small neuronal system activated by physiological stimuli that induce an escape response. The giant fiber system in insects is comprised of a pair of large interneurons in the brain whose synaptic targets can excite the insect flight and jump muscles. Amazingly, a 200 ms pulse of laser light elicited jumping, wing flapping, or other flight movements in 60%–80% of the flies expressing P2X2 in the giant fiber system and injected with caged ATP! Although this frequency is lower than that observed with direct electrical stimulation of the giant fiber system, it is higher than that elicited by natural stimuli, such as a light-off stimulus. In addition, the investigators investigated a second neuronal system, the dopaminergic system, and showed that activation of P2X2 in dopaminergic neurons led to an increase in locomotor activity, which was attributed to fewer pauses during walking rather than an overall increase in the speed of walking. Thus, proof of concept of using the P2X2 receptor/caged ATP/laser light as a tripartite remote control system for eliciting behavior was thus established for two different neural systems within the Drosophila central nervous system. It is remarkable that the remote control system works so well given the constraints that must be met. Injected, caged ATP must be stable and must diffuse freely throughout the central nervous system, so that a sufficient titre is in the vicinity of the P2X2 channel at photostimulation. Laser light must efficiently penetrate cuticle and tissue to stimulate the uncaging reaction. The incomplete efficiency of the remote control system is probably due to variable concentrations of caged ATP near the expressed P2X2 channel, or to the incomplete uncaging of ATP. Incomplete uncaging could result from variability in cuticle pigmentation between animals or from the animal’s orientation relative to the light source during the uncaging reaction. Many different questions in Drosophila systems neuroscience and behavior can be approached using this new methodology, although there exist some constraints that will probably be circumvented with additional refinements. One constraint arises from basal activity of the P2X2 channel in the absence of uncaged ATP. When strong promoters are used to drive P2X2 expression, an observable increase in the frequency of miniature excitatory junctional potentials at the larval neuromuscular junction occurs. Basal channel activity was also revealed by the poor coordination that flies exhibit when the P2X2 channel is expressed with strong pan-neuronal promoters. Moreover, when the channel is expressed in cholinergic neurons, the transgenic animals have a life span reduced by more than 20-fold! Presumably, these phenotypes are due to leakage currents and possibly calcium toxicity to the neurons. These factors may potentially compromise the use of the system for some behavioral assays. In addition, injecting caged ATP into the animals can be time consuming and laborious, especially for those behavioral assays that required hundreds of flies at one time. The half-life of the injected and caged ATP was measured to be approximately 1 hr, so a rapid injection system might allow for the accumulation of a sufficient number of flies within this time period. It is unlikely that feeding the caged ATP to the transgenic animals would offer a solution since caged ATP is not likely to survive the digestive system, cross the blood-brain barrier, and accumulate to sufficient titres in the CNS. So it is likely that the new remote control system will initially be used for circuits controlling behavior that can be read with just a few animals. Nevertheless, these constraints are really quite minimal for this clever new technique that offers so much potential for defining the neural circuits that can drive behavior upon activation. The remote stimulation of neurons can now be added to several other methodologies developed in recent years that have transformed the fruit fly from an organism valued mostly for probing issues of molecular neuroscience into one that offers the wonderful potential to synthesize both molecular and systems neuroscience (Davis, 2005Davis R.L. Annu. Rev. Neurosci. 2005; 28: 275-302Crossref PubMed Scopus (443) Google Scholar)." @default.
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• W2034375382 title "Remote Control of Fruit Fly Behavior" @default.
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