Research on the Application of Optogenetic Tools in Learning and Memory

doi:10.12211/2096-8280.2024-042

Abstract

Abstract:

Optogenetics represents an advanced technology that facilitates precise control of gene expression and neuronal activity in living cells through light. Introduced by neuroscientist Karl Deisseroth in 2005, this methodology has transformed neuroscience research, empowering researchers to modulate excitable tissues and neural circuits with exceptional spatiotemporal accuracy. Optogenetics necessitates the expression of light-sensitive proteins, including channelrhodopsins, halorhodopsins, and various microbial opsins, within specific cells. Employing viral vectors and tissue-specific promoters, these proteins ensure targeted expression. Exposure to designated wavelengths of light permits these proteins to activate or inhibit cellular activity, thereby modulating neuronal behavior.The implementation of optogenetics has significantly enhanced comprehension of learning, memory, and neural plasticity. This technology enables the examination of the molecular dynamics associated with synaptic plasticity, long-term potentiation (LTP), and long-term depression (LTD), which are pivotal in the formation of memory. Manipulating specific neuronal populations in real-time elucidates the intricate neural circuits involved in these phenomena. Additionally, optogenetics has facilitated the exploration of potential therapeutic approaches for neurological conditions such as Alzheimer's disease by meticulously controlling memory-associated circuits.The utility of optogenetics transcends fundamental research, yielding promising prospects in addiction studies and motor function enhancement. By modulating distinct neural circuits, it is possible to alter addiction-related behaviors and augment motor functions in animal models. Furthermore, the amalgamation of optogenetics with cutting-edge technologies like artificial intelligence and deep learning is anticipated to refine stimulation protocols, resulting in more precise and efficacious experimental outcomes.Notwithstanding its transformative capacity, the clinical application of optogenetics encounters significant obstacles, including the requisites for safe and effective gene delivery mechanisms and the formulation of light-sensitive proteins with optimal characteristics for human application. Future investigations should concentrate on surmounting these hurdles while expanding the applications of optogenetics in neuroscience and related fields. The integration of optogenetics with multidisciplinary approaches is poised to unveil new realms in brain research, yielding profound insights into the mechanisms governing memory, learning, and neural plasticity.

Key words: optogenetics, photosensitive proteins, memory, ion channels, neural plasticity

摘要：

光遗传学技术是一种结合光学和遗传学的新型细胞生物学工具。通过引入光激活通道（光敏感蛋白基因）到特定的神经元群体，光遗传学能够以毫秒级精度对这些神经元进行非侵入性光学控制。这一技术的进步为研究学习和记忆的神经生物学基础提供了强大支持。通过在活体动物中精确操控神经元活动，研究人员可以更详细地分析神经网络的功能，探索学习和记忆过程中的分子、细胞和神经回路机制。光遗传学不仅揭示了突触可塑性在记忆形成中的关键作用，还通过特定波长的光激活或抑制神经元，实现记忆的生成、消除和恢复。本文综述了光遗传学工具在学习和记忆研究中的应用，包括不同波长光照对受体的影响、光学刺激对记忆的激活和抑制，以及基于光遗传学的神经功能增强研究方法。然而，在光遗传学的应用过程中仍存在一些挑战，例如开发安全且高效的基因传递载体、优化光敏蛋白的性能、探索其在临床环境中转化的可行性等。解决这些问题对于光遗传学技术的进一步发展至关重要。未来，随着光遗传学工具的持续优化和跨学科技术的融合应用，这项技术有望在治疗神经系统疾病、增强认知功能与成瘾研究等领域提供新的理论基础和实践方法。

关键词: 光遗传学, 光敏感蛋白质, 记忆, 离子通道, 神经可塑性

CLC Number:

Yikun ZHENG, Jie ZHENG, Guopeng HU. Research on the Application of Optogenetic Tools in Learning and Memory[J]. Synthetic Biology Journal, DOI: 10.12211/2096-8280.2024-042.

郑益坤, 郑婕, 胡国鹏. 光遗传学工具在学习记忆中的应用研究[J]. 合成生物学, DOI: 10.12211/2096-8280.2024-042.

Figures/Tables 5

Fig.1 Diagram of Synaptic Connection StrengtheningThe diagram illustrates how synaptic connections between neurons A, R, and B are strengthened through repeated electrophysiological stimulation. This process simulates the mechanism of repeated encoding of information and reflects the fundamental principles of long-term memory formation. According to Hebb's rule, if two neurons frequently and closely act together, the associated synaptic connections will be strengthened, thereby improving the efficiency of information transmission and enhancing the postsynaptic response.

Fig.2 Specific neuronal synaptic connections enhanced by Hebbian ruleThe application of Hebb's rule in synaptic plasticity indicates that repeated activation of specific neurons can enhance synaptic connections, a mechanism that is a fundamental component in the processes of learning and memory formation.

Fig.3 Signal segregation and integration transmission processing architecture(a) Input-biased—separated output architecture, in which different input signals (represented by arrows of varying thickness indicating different input strengths) are processed separately and transmitted to different output targets. (b) Integration and transmission architecture, where all input signals are integrated at an intermediate layer and transmitted to multiple target neuronal groups[32].

Fig.4 Optogenetic tools and their mechanisms of action(a) The optogenetic toolkit includes the distribution of different optogenetic actuators and sensors across various wavelengths. Depolarizing actuators include CheRiff, BLINK-1, ChR2, PAC-K, with wavelengths ranging from blue to green light. Hyperpolarizing actuators include GtACR1, Arch, NpHR, ArchT, Halo, ReaChR, Crimson, Jaws, with wavelengths ranging from green to red light. Optogenetic sensors include voltage sensors (GEVI, VSFP2.3, ArcLight, ASAP, Voltron525, FlicR1) and calcium sensors (GECI, GCaMPs, R-CaMPs, R-GECOs, Quasars, Archon1, NIR-Butterfly, NIR-GECO)[40]. (b) Excitation spectra of three main optogenetic tools: ChR2 (blue, maximum excitation wavelength approximately 470 nm), NpHR (orange, maximum excitation wavelength approximately 589 nm), Arch (green, maximum excitation wavelength approximately 575 nm). (c) Specific activation and inhibition ion channels under different spectra: In blue light, ChR2 channels open, allowing potassium ions (K+) to enter the cell, along with sodium ions (Na+) and calcium ions (Ca2+) through other channels such as CheTA, SFO, and VChR1, leading to neuronal depolarization. Under yellow or yellow-green light, NpHR channels open, allowing chloride ions (Cl-) to enter the cell, causing neuronal hyperpolarization; Arch channels open, pumping protons (H+) out of the cell, also causing hyperpolarization. Other inhibition channels such as Mac, eNpHR2.0, eBR, eNpHR3.0, GtR3 inhibit neuronal activity through similar mechanisms. (d) Specific effects of activation and inhibition channels on neuronal voltage: Activation channels, when activated by blue light, cause the neuronal membrane potential to rise from -70 mV; inhibition channels, when activated by yellow or yellow-green light, cause the membrane potential to drop from -70 mV [42].

Fig.5 Artificially inserted memories and actual memories are encoded by the same neural circuitry(a)Experimental design illustration: Mice training patterns under two different memory formation conditions. The real memory group uses a traditional pairing of odor (acetophenone) and foot shock (CS + US), and acetophenone alone (CS only). The artificial memory group uses M72 light stimulation paired with LHb-VTA projection light stimulation (CS + US), and M72 light stimulation alone (CS only).(b) Neural circuit activation diagram: Shows the brain regions activated by the two training modalities, indicating similar neural circuits are activated by different training methods.(c) Brain structure activity schematic: Analyzes CS-induced Fos expression in the central olfactory system and regions associated with associative memory one day later. Demonstrates the changes in brain structure activity during the memory formation process.(d) & (e) Comparative analysis of Fos expression: Quantifies Fos expression under true memory and artificial memory for both CS and CS+US conditions. Shows enhancement of Fos expression in brain regions after different memory trainings. (f) & (h) Detailed observation of Fos induction: Significant enhancement of Fos expression in the basolateral amygdala (BLA) in mice with real and artificial memory formation. This enhancement reflects the learning-specific activation associated with specific memory formation.(g) & (i) Sagittal section diagrams: Displays Fos induction under different conditions. The white areas represent the expression of Fos, further confirming the critical role of the BLA region in learning and memory formation (The image is sourced from reference 114) [114].

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