Improved expression of halorhodopsin for light-induced silencing of neuronal activity

Zhao, Shengli; Cunha, Catarina; Zhang, Feng; Liu, Qun; Gloss, Bernd; Deisseroth, Karl; Augustine, George J; Feng, Guoping

doi:10.1007/s11068-008-9034-7

Cited by 172 publications

(168 citation statements)

References 42 publications

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“…We also show that the inhibitory effect of optical stimulation on epileptiform activity (STIB) is mediated by hyperpolarization and suppression of PDS generation in principal hippocampal neurons, which are selectively targeted by the CaMKII␣ promoter driving NpHR expression. Our data suggest that expression of transgene NpHR per se does not lead to any major alterations in membrane or other intrinsic properties of the transduced neurons, although some aggregation of EYFP has been reported in transgenic animals expressing NpHR under EF1␣ promoter (15,16). In this study, we exclusively recorded from those cells that had no visible signs of such EYFP fragmentation.…”

Section: Discussionmentioning

confidence: 86%

Optogenetic control of epileptiform activity

Tønnesen

Sørensen

Deisseroth

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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219

174

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The optogenetic approach to gain control over neuronal excitability both in vitro and in vivo has emerged as a fascinating scientific tool to explore neuronal networks, but it also opens possibilities for developing novel treatment strategies for neurologic conditions. We have explored whether such an optogenetic approach using the light-driven halorhodopsin chloride pump from Natronomonas pharaonis (NpHR), modified for mammalian CNS expression to hyperpolarize central neurons, may inhibit excessive hyperexcitability and epileptiform activity. We show that a lentiviral vector containing the NpHR gene under the calcium/calmodulin-dependent protein kinase II␣ promoter transduces principal cells of the hippocampus and cortex and hyperpolarizes these cells, preventing generation of action potentials and epileptiform activity during optical stimulation. This study proves a principle, that selective hyperpolarization of principal cortical neurons by NpHR is sufficient to curtail paroxysmal activity in transduced neurons and can inhibit stimulation train-induced bursting in hippocampal organotypic slice cultures, which represents a model tissue of pharmacoresistant epilepsy. This study demonstrates that the optogenetic approach may prove useful for controlling epileptiform activity and opens a future perspective to develop it into a strategy to treat epilepsy.epilepsy ͉ hippocampus ͉ NpHR ͉ paroxysmal depolarizing shift (PDS) ͉ stimulation train-induced bursting (STIB)

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Section: Discussionmentioning

confidence: 86%

Optogenetic control of epileptiform activity

Tønnesen

Sørensen

Deisseroth

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

219

174

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“…Drosophila have expressed opsins under 20 copies of a conditional enhancer the upstream activating sequence (UAS), which may support a recent report of high light sensitivity of neurons in such flies for optogenetic activation . As another example, the Natronomonas pharaonis halorhodopsin first assessed in neurons as an optogenetic silencer candidate (Han and Boyden 2007;Zhang et al 2007a) has been efficacious in multiple Caenorhabditis elegans studies (e.g., Wen et al 2012), but in mammals appeared to form aggregates when expressed at high levels in cortical neurons (Zhang et al 2007a;Gradinaru et al 2008;Zhao et al 2008). As a result, other silencers have grown in popularity, including the archaerhodopsin-class silencers (Chow et al 2010), as well as halorhodopsins with appended trafficking-enhancement sequences Chuong et al 2014).…”

Section: Cell-autonomous Side Effects Protein Expressionmentioning

confidence: 99%

Principles of designing interpretable optogenetic behavior experiments

2015

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Over the last decade, there has been much excitement about the use of optogenetic tools to test whether specific cells, regions, and projection pathways are necessary or sufficient for initiating, sustaining, or altering behavior. However, the use of such tools can result in side effects that can complicate experimental design or interpretation. The presence of optogenetic proteins in cells, the effects of heat and light, and the activity of specific ions conducted by optogenetic proteins can result in cellular side effects. At the network level, activation or silencing of defined neural populations can alter the physiology of local or distant circuits, sometimes in undesired ways. We discuss how, in order to design interpretable behavioral experiments using optogenetics, one can understand, and control for, these potential confounds.

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“…A major advance in the ability to analyze learning-related neural circuitry in the intact behaving animal has come from the introduction of noninvasive ways of selectively activating or shutting off specific neurons in a learning circuit of the animal with beams of light or by expressing in these cells nonendogenous receptors or channels gated by light such as rhodopsin, halorhodopsin, or opto-XR (Zhang et al, 2007a,b;Zhao et al 2008;Airan et al, 2009). Also effective for turning neurons on or off are ligandgated variants with customized binding sites, such as the Drosophila allostatin receptor and the G 1 protein coupled designer receptor (Alexander et al, 2009), which are activated by an inert ligand (Arenkiel et al, 2007;Huber et al, 2008).…”

Section: New Ways Of Analyzing Neural Systems Involved In Learningmentioning

confidence: 99%

The Biology of Memory: A Forty-Year Perspective

Kandel¹

2009

J. Neurosci.

179

102

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In the forty years since the Society for Neuroscience was founded, our understanding of the biology of memory has progressed dramatically. From a historical perspective, one can discern four distinct periods of growth in neurobiological research during that time. Here I use that chronology to chart a personalized and selective course through forty years of extraordinary advances in our understanding of the biology of memory storage.Emergence of a cell biology of memory-related synaptic plasticity By 1969, we had already learned from the pioneering work of Brenda Milner that certain forms of memory were stored in the hippocampus and the medial temporal lobe. In addition, the work of Larry Squire revealed that there are two major memory systems in the brain: declarative (explicit) and procedural (implicit or nondeclarative). Declarative memory, a memory for facts and events-for people, places, and objects-requires the medial temporal lobe and the hippocampus (Scoville and Milner, 1957;Squire, 1992;Schacter and Tulving, 1994). In contrast, we knew less about procedural memory, a memory for perceptual and motor skills and other forms of nondeclarative memory that proved to involve not one but a number of brain systems: the cerebellum, the striatum, the amygdala, and in the most elementary instances, simple reflex pathways themselves. Moreover, we knew even less about the mechanisms of any form of memory storage; we did not even know whether the storage mechanisms were synaptic or nonsynaptic.In 1968, Alden Spencer and I were invited to write a perspective for Physiological Reviews, which we entitled "Cellular Neurophysiological Approaches in the Study of Learning." In it we pointed out that there was no frame of reference for studying memory because we could not yet distinguish between the two conflicting approaches to the biology of memory that had been advanced: the aggregate field approach advocated by Karl Lashley in the 1950s and Ross Adey in the 1960s, which assumed that information is stored in the bioelectric field generated by the aggregate activity of many neurons; and the cellular connectionist approach, which derived from Santiago Ramon y Cajal's idea (1894) that learning results from changes in the strength of the synapse. This idea was later renamed synaptic plasticity by Kornorski and incorporated into more refined models of learning by Hebb. We concluded our perspective by emphasizing the need to develop behavioral systems in which one could distinguish between these alternatives by relating, in a causal way, specific changes in the neuronal components of a behavior to modification of that behavior during learning and memory storage (Kandel and Spencer, 1968). Procedural memoryThe first behavioral systems to be analyzed in this manner were simple forms of learning in the context of procedural memory. From 1969 to 1979, several useful model systems emerged: the flexion reflex of cats, the eye-blink response of rabbits, and a variety of invertebrate systems: the gill-withdrawal reflex of Aplysia, olfac...

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Improved expression of halorhodopsin for light-induced silencing of neuronal activity

Cited by 172 publications

References 42 publications

Optogenetic control of epileptiform activity

Optogenetic control of epileptiform activity

Principles of designing interpretable optogenetic behavior experiments

The Biology of Memory: A Forty-Year Perspective

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