The Potential of Optogenetics to Implant, Modify and Erase Memories.

Figure 1: Simplified illustration of optogenetic control of cell activity. Optogenetic control of cellular activity the functional integration of light-responsive proteins (opsins), sophisticated optics and gene editing technologies. At its core, optogenetics enables targeted control of activity and more general effector functions in neural (and non-neural) cells following specific light-stimuli on millisecond timescales (1). This is mediated by delivery of light-sensitive ion-channels, pumps and enzymes into naturally non-light-sensitive cells (2). The most prominent optogenetic actuators of single-component optogenetic systems, as shown in this figure, which allow the bidirectional modulation (excitation & inhibition) of transmembrane currents in excitable cells, are channelrhodopsin (light-gated ion channels), halorhodopsins (light-gated ion-pump) and bacteriorhodopsin (light-gated proton pump), which can be delivered with spatial specificity to selected cellular subpopulations (e.g. specific neuron-types) by various genetic-targeting methods including in-utero electroporation, inserting of rhodopsin-genes behind cell-specific promoters and the usage of compatible viral vector such as adeno-associated viral vectors (see figure). Applying light (photons of a specific wavelength) induces conformational changes in the opsins, effectively opening them to ions they are selective for. Finally, behavioural observations, electrical recordings, calcium imaging or more sophisticated biosensing modalities allow a rapid read-out of the cellular activity (here, intracellular electrophysiological measurements of neuronal activity are depicted), which is crucial for appropriate modulation of the stimulus. Own figure.
Figure 2: The past, present and future of optogenetics. Rather than pledging to be an exhaustive chronology, this figure merely illustrates key advances and milestones from the early days of light-dependent neuromodulation to modern-day optogenetics. As postulated by Deitheroth in 2015 (3), optogenetics is a “three-body problem”, referring to opsin genomics, optics and engineering whose cross-integration, enabled by a large body of preceding literature (3,4,5,6,7,8), effectively paved the way for Boyden et al.’s paradigmatic research, which constituted a tipping point in the developmental trajectory of optogenetics. While in-vitro activation of ion-channels by light had been demonstrated (9) and the optical control of neurons had been intended before employing various strategies (10,11), Boyden et. al first successfully transduced opsins into neurons and activated them (1). Consequently, widespread scepticism tipped into enthusiasm and a multitude of studies followed up, not only replicating Boyden’s findings(12,13), but improving and sophisticating various parts of the optogenetic tool-box; Mentionable milestones were the first successful application to mammalian(14,15,16) and primate (17) behavioural control, multiple-feature targeting(18) the development and discovery of novel rhodopsin variants with modified properties like responding to different wavelengths, altered kinetics, and ion-conductances and permitting inhibitory control(19,20,21,22,23) and its application on non-neural cell types such as ES-cells(24, 25) and cardiomyocytes(26), corroborating its universality. Its potential in a therapeutic context has been demonstrated extensively (27), particularly regarding eye-related disorders(27, 28, 29) and first clinical trials for retinitis pigmentosa(30) and urinary bladder syndrome have been approved. More recent breakthroughs include the development of minimally invasive, wireless, and transdermal optoelectronic systems (31,32), single-cell resolution optogenetics(33) , highly specific viral targeting of neuron-subclasses(34) , multi-site targeting(35) and closed-loop optogenetics in which stimulation parameters are automatically modulated to match the desired stimulation based on near-real-time read-outs of neural activity resulting in enhanced temporal specificity(36,37). The widely shared vision of this technology’s future is of a minimal-invasive tool allowing the separate control of multiple cell types with an optimal spatial and temporal resolution allowing to mimic and, if needed, replace natural physiological mechanisms providing almost limitless opportunities to investigate and control biological systems. Own figure.

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Fynn Comerford

Fynn Comerford

BSc Neuroscience at The University of Edinburgh | Founder at Edinburgh’s first student-run accelerator | iGEM synthetic biology participant | Filmmaker