A Highly Sensitive A-Kinase Activity Reporter for Imaging Neuromodulatory Events in Awake Mice
Лей МаBart C. JongbloetsWei-Hong XiongJoshua B. MelanderMaozhen QinTess J. LameyerMadeleine F. HarrisonBoris V. ZemelmanTianyi MaoHaining Zhong
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Abstract Optogenetics enables temporally and spatially precise control of neuronal activity in vivo . One of the key advantages of optogenetics is that it can be used to control the activity of targeted neural pathways that connect specific brain regions. While such pathway-selective optogenetic control is a popular tool in rodents, attempts at modulating behaviour using pathway-selective optogenetics have not yet been successful in primates. Here we develop a methodology for pathway-selective optogenetics in macaque monkeys, focusing on the pathway from the frontal eye field (FEF) to the superior colliculus (SC), part of the complex oculomotor network. We find that the optogenetic stimulation of FEF projections to the SC modulates SC neuron activity and is sufficient to evoke saccadic eye movements towards the response field corresponding to the stimulation site. Thus, our results demonstrate the feasibility of using pathway-selective optogenetics to elucidate neural network function in primates.
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Magnetogenetics： remote non-invasive magnetic activation of neuronal activity with a magnetoreceptor
象 optogenetics 和深大脑的刺激那样的当前的 neuromodulation 技术正在转变基本、翻译的神经科学。然而，自从光纤维或电线电极的外科的培植被要求，这二条 neuromodulation 途径是侵略的。这里，我们发明了联合与遥远的磁性的刺激的 magnetoreceptor 的基因指向的非侵略的 magnetogenetics。神经原的非侵略的激活被外长的 magnetoreceptor 的 neuronal 表示完成，铁硫簇集会蛋白质 1 (Isca1 ) 。在 HEK-293 房间和表示这 magnetoreceptor 的有教养的海马趾的神经原，一个外部磁场的申请以一种可再现、可逆的方式导致了膜去极和钙流入，作为由 ultrasensitive 显示了荧光灯钙指示物 GCaMP6s。而且， neuronal 活动的 magnetogenetic 控制可能依赖于磁场和展览在反应上的方向，为外部磁场的离开反应模式适用。这 magnetoreceptor 的激活能动摇神经原并且得到行动潜力的火车，它能在记录的整个房间的补丁夹钳与一个遥远的磁场重复地被触发。在在 myo-3-specific 肌肉房间或 mec-4-specific 神经原表示这 magnetoreceptor 的转基因的 Caenorhabditis elegans，外部磁场的申请触发了蠕虫的肌肉收缩和退却行为，肌肉房间和触摸受体神经原的磁铁依赖者激活的陈述语气分别地。在 optogenetics 上的 magnetogenetics 的优点是它的独占的非侵略的、深穿入，长期的连续 dosing，无限的可接近性，空间一致性和相对安全。象通过了十年长的改进的 optogenetics 一样，与连续修正和成熟， magnetogenetics 将重塑 neuromodulation 工具箱的当前的风景并且将象另外的生物科学一样有大量应用到基本、翻译的神经科学。我们想象 magnetogenetics 的新年龄正在来。
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Summary Optogenetics is a novel technology that combines optics and genetics by optical control of microbial opsins, targeted to living cell membranes. The versatility and the electrophysiologic characteristics of the light‐sensitive ion‐channels channelrhodopsin‐2 (ChR2), halorhodopsin (Np HR ), and the light‐sensitive proton pump archaerhodopsin‐3 (Arch) make these optogenetic tools potent candidates in controlling neuronal firing in models of epilepsy and in providing insights into the physiology and pathology of neuronal network organization and synchronization. Opsins allow selective activation of excitatory neurons and inhibitory interneurons, or subclasses of interneurons, to study their activity patterns in distinct brain‐states in vivo and to dissect their role in generation of synchrony and seizures. The influence of gliotransmission on epileptic network function is another topic of great interest that can be further explored by using light‐activated Gq protein–coupled opsins for selective activation of astrocytes. The ever‐growing optogenetic toolbox can also be combined with emerging techniques that have greatly expanded our ability to record specific subtypes of cortical and hippocampal neurons in awake behaving animals such as juxtacellular recording and two‐photon guided whole‐cell recording, to identify the specific subtypes of neurons that are altered in epileptic networks. Finally, optogenetic tools allow rapid and reversible suppression of epileptic electroencephalography ( EEG ) activity upon photoactivation. This review outlines the most recent advances achieved with optogenetic techniques in the field of epilepsy by summarizing the presentations contributed to the 13th ILAE WONOEP meeting held in the Laurentian Mountains, Quebec, in June 2013.
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Optogenetic modulation of neuronal circuits in freely moving mice affects acute and long-term behavior. This method is able to perform manipulations of single neurons and region-specific transmitter release, up to whole neuronal circuitries in the central nervous system, and allows the direct measurement of behavioral outcomes. Neurons express optogenetic tools via an injection of viral vectors carrying the DNA of choice, such as Channelrhodopsin2 (ChR2). Light is brought into specific brain regions via chronic optical implants that terminate directly above the target region. After two weeks of recovery and proper tool-expression, mice can be repeatedly used for behavioral tests with optogenetic stimulation of the neurons of interest. Optogenetic modulation has a high temporal and spatial resolution that can be accomplished with high cell specificity, compared to the commonly used methods such as chemical or electrical stimulation. The light does not harm neuronal tissue and can therefore be used for long-term experiments as well as for multiple behavioral experiments in one mouse. The possibilities of optogenetic tools are nearly unlimited and enable the activation or silencing of whole neurons, or even the manipulation of a specific receptor type by light. The results of such behavioral experiments with integrated optogenetic stimulation directly visualizes changes in behavior caused by the manipulation. The behavior of the same animal without light stimulation as a baseline is a good control for induced changes. This allows a detailed overview of neuronal types or neurotransmitter systems involved in specific behaviors, such as anxiety. The plasticity of neuronal networks can also be investigated in great detail through long-term stimulation or behavioral observations after optical stimulation. Optogenetics will help to enlighten neuronal signaling in several kinds of neurological diseases.
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The striatum receives inputs from both cortical and subcortical structures, reflecting the role of the striatum as a limbic-motor interface. The relative simplicity of the cellular architecture of the striatum belies the complexity of the circuitry. Because synaptic inputs are intermingled, using classical methods to selectively activate or inhibit known populations of neurons has not been possible. The advent of optogenetics has enabled population-selective activation or inhibition in intact animals. In this review, I describe how optogenetic analysis can be used to study striatal circuits. First, I briefly introduce optogenetics and the widely used channelrhodopsin for excitation and halorhodopsin for inhibition. Next, I categorize optogenetic studies based on the approaches optogenetics have made possible, specifically (1) selective activation of identified synaptic inputs, (2) activation of convergent inputs to identify weak synaptic connections, (3) selective activation of identified neuronal populations in freely moving animals, and (4) cell identification for in vivo recording, and I discuss new insights into striatal circuits. Optogenetic approaches made impossible experiments possible and help to resolve the function of intact brain circuitry.
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Channelrhodopsin
Pyramidal cell
Local field potential
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Abstract Technology allowing genetically targeted cells to be modulated by light has revolutionized neuroscience in the past decade, and given rise to the field of optogenetic stimulation. For this, non‐native, light activated proteins (e.g., channelrhodopsin) are expressed in a specific cell phenotype (e.g., glutamatergic neurons) in a subset of central nervous system nuclei, and short pulses of light of a narrow wavelength (e.g., blue, 473 nm) are used to modulate cell activity. Cell activity can be increased or decreased depending on which light activated protein is used. We review how the greater precision provided by optogenetics has transformed the study of neural circuits, in terms of cognition and behavior, with a focus on learning and memory. We also explain how optogenetic modulation is facilitating a better understanding of the mechanistic underpinnings of some neurological and psychiatric conditions. Based on this research, we suggest that optogenetics may provide tools to improve memory in neurological conditions, particularly diencephalic amnesia and Alzheimer's disease.
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In neuroscience, the consequences of optogenetic manipulation are often studied using in vivo electrophysiology and by observing behavioral changes induced by light stimulation in genetically targeted rodents. In contrast, reports on the in vivo neurochemical effects of optogenetic stimulation are scarce despite the improving quality of analytical techniques available to monitor biochemical compounds involved in neurotransmission. This intriguing lack of neurochemical information suggests the existence of unknown or misunderstood factors hampering the expected rise of a novel specialty putatively be termed "neurochemical optogenetics".
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Optogenetic modulation of neuronal circuits in freely moving mice affects acute and long-term behavior. This method is able to perform manipulations of single neurons and region-specific transmitter release, up to whole neuronal circuitries in the central nervous system, and allows the direct measurement of behavioral outcomes. Neurons express optogenetic tools via an injection of viral vectors carrying the DNA of choice, such as Channelrhodopsin2 (ChR2). Light is brought into specific brain regions via chronic optical implants that terminate directly above the target region. After two weeks of recovery and proper tool-expression, mice can be repeatedly used for behavioral tests with optogenetic stimulation of the neurons of interest. Optogenetic modulation has a high temporal and spatial resolution that can be accomplished with high cell specificity, compared to the commonly used methods such as chemical or electrical stimulation. The light does not harm neuronal tissue and can therefore be used for long-term experiments as well as for multiple behavioral experiments in one mouse. The possibilities of optogenetic tools are nearly unlimited and enable the activation or silencing of whole neurons, or even the manipulation of a specific receptor type by light. The results of such behavioral experiments with integrated optogenetic stimulation directly visualizes changes in behavior caused by the manipulation. The behavior of the same animal without light stimulation as a baseline is a good control for induced changes. This allows a detailed overview of neuronal types or neurotransmitter systems involved in specific behaviors, such as anxiety. The plasticity of neuronal networks can also be investigated in great detail through long-term stimulation or behavioral observations after optical stimulation. Optogenetics will help to enlighten neuronal signaling in several kinds of neurological diseases.
Premovement neuronal activity
Biological neural network
Neuromodulation
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Neuronal Circuits
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