As an emerging neuromodulation tool, optogenetics affords the capability of manipulating neuronal activities of genetically defined neurons using light. In principle, optogenetics offers scientific insights into deciphering the complexity of various behavioral states and the neural pathways that underpin normal and abnormal brain functions with therapeutic applications [1]. In fact, human clinical trials have been initiated in utilizing optogenetics to treat retinitis pigmentosa to restore vision, and animal models have been extensively used in optogenetics studies to develop therapies for a myriad of nervous system disorders as an alternative to deep brain stimulation (DBS) [2]. To understand the inner workings of this novel neurotechnology, the basic neurobiological basis of synaptic communication between neurons must be briefly elaborated. Fundamentally, Na+ions flow into neurons until the threshold potential is reached with sufficient voltage to elicit an action potential along the axons of successive depolarized neurons to transmit information by means of neurotransmitter release at the synapses. For ions to passively travel into the neurons across the cell membrane for activation or deactivation requires the gated ion channels to be opened or closed, respectively, which can be done by applying an external stimulus such as temperature and ligand molecules. Alternatively, protein pumps can also facilitate the inward flow of specific ions via active transport under similar stressors. Neurons eventually become hyperpolarized as K+ions begin to flow outward to inhibit the signal until the threshold is reached again from the resting potential, all of which are done iteratively [3].
The discovery of optogenetics has thus introduced light-gated channels and pumps as a new mechanism for controlling synaptic communication among neurons. Light-sensitive proteins called opsins are the genes responsible for encoding light-gated channels and pumps, which are typically found in microbial species of archaea, bacteria, and fungi—the source from which Type I opsin genes are derived [1]. Opsins are subsequently cloned to be expressed in a target population of neurons that lack light-gated channels and pumps via viral vectors (i.e., adeno-associated viruses (AAV) or lentiviruses (LV)), thereby enabling the control and regulation of neuronal activities of various neural circuits at the supramacroscopic scale in real time with light through the insertion of an optical fiber. Upon the illumination of light, neurons can either be excited or inhibited, depending on the nature of the optogenetic proteins that are neuronally expressed in accordance with the functions that the researcher intends to mediate for individual neurons [2]. Channelrhodopsin-2 (ChR2) is a light-gated cation channel protein that can excite neurons when illuminated with blue light at regular pulses, which causes the inward flow of cations (e.g., Na+, Ca2+, H+) to increase the rate of action potentials [4]. To inhibit the activity of neurons, the yellow-light sensitive proton pump archaerhodopsin-3 (AR3) is used, wherein protons are transported out of neurons to decrease the rate of action potentials. Similarly, wild-type halorhodopsin (NpHR) is a Cl ion pump that also engages in neuronal inhibition in response to the continuous illumination of yellow light to sustain neurons in a hyperpolarized state [5].
Given the bidirectional modality of optogenetics in controlling specific neuronal ensembles by means of regulating the movement of ions to facilitate or prevent synaptic communication, one application of optogenetics extends to its potential for modifying memories as a form of improved and versatile memory modification technology (MMT). Pre-existing MMTs include DBS along with pharmacological agents (i.e., propranolol or mifepristone), all of which can alter the brain via external means. However, due to the indiscriminate spread of electrical currents to neighboring nerve fibers of targeted cells in DBS and the poor temporal precision in the administration of pharmacological agents, optogenetics are fortunately capable of compensating these practical limitations [6]. The spatiotemporal selectivity and precision of optogenetics are best illustrated when considering the diversity of light-sensitive proteins that can be expressed in correspondence to the different cell types in the central nervous system (CNS), some of which are genetically defined such that they are restricted to limited optogenetic proteins based on the type of neurotransmitters they secrete or the direction of their axonal projections [2].
Therefore, optogenetics renders the ability for memory modification in such a manner that specific memories, whether they are newly formed or well-consolidated, can be activated or deactivated in their respective engrams by manipulating the activities of targeted neurons in the hippocampal region of the brain, primarily at the dentate gyrus (DG) where memories are initially formed from the merging of sensory modalities [7, 8]. For example, Liu et al. has demonstrated the implantation of de novo false memories into mice through optogenetic manipulation using ChR2 aided by contextual fear conditioning [9]. Another memory modification experiment using optogenetics conducted by Guskjolen et al. has surprisingly shown that lost, inaccessible memories in infant mice due to infantile amnesia can be recovered by optogenetically targeting hippocampal and cortical neurons responsible for encoding infant memories, ensued by reactivating the ChR2-labeled neuronal ensembles when the infant mice reached adulthood after a period of three months [10].
Additional applications of optogenetics in the context of memory modification includes enhancing the cognitive capacity for memory, changing the valence of a memory (from negative to positive, and vice versa) without distorting the content, and treating memory impairments that are characteristic of conditions such as Alzheimer’s disease (AD) and post-traumatic stress disorder (PTSD) in clinical patients [6]. Notwithstanding the futuristic promise of optogenetics, the apparent harm of manipulating select memories in humans to various extents on demand is of equal relevance when considering the collective ramifications of this novel yet ambivalent neurotechnology. The neuroethical flaws of using optogenetics for memory modification are thus worthy of being discussed in detail.
Of similar nature to many revolutionary technologies such as the CRISPR/Cas9 system for genome editing, safety risks present a limitation to the use of optogenetics for memory modification applications given its invasive nature—requiring the injection of viral vectors into the brains of experimental subjects for the in vivo delivery of optogenetic proteins [11]. Furthermore, deep brain optogenetic photostimulation also requires tethered optical fibers or other forms of implants to be surgically inserted into the brain to provide a light source, which may cause tissue damage, ischemia, and infections as with many invasive neurosurgeries [12]. A non-invasive approach in the utilization of optogenetics, interestingly, has been developed by Lin et al. using an engineered red-shifted variant of ChR known as red-activable ChR (ReaChR) that was expressed in the vibrissa motor cortex of mice. With the penetration of red light through the external auditory canal, neurons can subsequently be optically activated to drive spiking and vibrissa motion in mice to enable transcranial optogenetic excitations with an intact skull [13].
Nevertheless, safety risks cannot be easily dismissed in a premature manner in the event that optogenetic manipulations lead to off-target behavioral or emotional effects, wherein unpredictable network changes may occur in areas outside of the targeted optogenetic activation or deactivation zone [14]. For example, episodic memories are not solely distributed in the hippocampus; the entire system also consists of surrounding brain structures of the medial temporal lobe including the perirhinal and entorhinal cortices in conjunction with structurally connected sites (e.g., thalamic nuclei, mammillary bodies, retrosplenial cortex). Targeting a set of hippocampal neurons that is known to encode a specific memory may also induce unforeseeable changes, for it is presumed that their function is not solely exclusive to memory encoding. Moreover, since the off-target effects pertaining to the optogenetic modification of memory have not been heavily analyzed in the neuroethical literature, it adds the weight of uncertainties regarding safety issues. The level of uncertainties is further elevated by the risk of long-term expression of optogenetic proteins in the mammalian brain with unknown consequences [6].
Beyond safety issues and technical limitations of optogenetics, attention is now shifted toward issues unique to optogenetics that may or may not be shared among pre-existing MMTs in the context of memory modification, notably in regard to erasing one’s unwanted memories which are reasonable targets for optogenetic interventions. The first argument concerns the problem of abandoning one’s moral obligations in hypothetical scenarios where the witnesses of a crime wish to erase their memories of the event through optogenetics [15]. While doing so is aligned with one’s right to personal choice if the witnesses find the crime to be far too upsetting to remember, it is not within the interests of society to erase such memories which are useful as testimonies during criminal prosecutions, even if the memories prove to be unreliable. Therefore, it is a moral obligation for witnesses to retain their memories for consequentialist reasons (i.e., preventing future crimes and exploitation) and withholding justice, and the same idea is applicable to the victims of a crime. From the perspective of criminal offenders, furthermore, it is also their moral obligation to retain the memories of their unlawful actions without optogenetic interventions even if they develop a guilty conscience. Otherwise, it would be deemed as an inappropriate moral reaction and responsibility needs to be held nevertheless on the part of the criminal offender if their memories are erased [6, 7].
Retaining memories sustained from traumatic experiences such as discrimination or abuse is also justified in the sense that traumatic memories may have a subtle influence on cultivating one’s personality and values [6]. Children who experienced childhood trauma are found to exhibit elevated levels of empathy as adults relative to children who did not have such experiences, as shown by Greenberg et al. [16]. In turn, having undergone traumatic experiences will ultimately motivate affected individuals to seek and initiate systemic changes in society by means of activism, for instance, to mitigate the root cause of their experienced trauma [6]. To further justify the means of relying on the traumatic memories of individuals to achieve the ends of society’s welfare in the absence of optogenetic interventions, it ought to be reiterated that without such means, social relations among members of society will remain in an oppressive and unspontaneous condition, such that individuals will not be inured to the sufferings of others but live in a continuous state of mass oblivion [15]. Using optogenetics to erase traumatic memories will thus nullify the motivational impulses and humaneness that are shared among affected individuals and most significantly, it has the potential to distort the trajectory of one's personality and values to a certain extent, especially when the valence of the memories is significantly altered to affect one’s dispositions [6].
Traumatic experiences are also pivotal in partially formulating self-defining memories that are of equal importance, for they are the underlying constituents of a person’s fundamental character and their sense of self. This is reinforced by the ideas of John Locke on memory with support from contemporary empirical evidence in spite of critical objections that claim no relationships between memory and personal identity [17]. While dissenting views ought to be acknowledged, the premise of Lockean ideas and any experimental support acts as a vital presumption in the current argument, which asserts that erasing one’s self-defining memories may change an individual’s narrative identity—the integration of one’s internalized, evolving life stories to render the person’s life with unity and meaning [18]. For the reason that narrative identities are malleable to change in sync with individuals’ memories, this implies that the reactivation of previously erased self-defining memories or implanting false memories may fail to be reintegrated with the self [6]. In such circumstances, individuals become susceptible to betraying or self-deceiving their original self as their life deviates from their truthful identity in the event of having their memories manipulated by optogenetics [6].
Analyzing the effects of memory modification on personal identity further requires a discussion on the threat posed toward individual authenticity. While the idea of authenticity has multiple conceptualizations, it is beneficial to consider authenticity from a dual-basis framework that combines accounts from existentialism (self-creation) and essentialism (self-discovery) in prompting critical ethical inquiries regarding the use of optogenetics [6]. Existentialists outline authenticity as having the ability to act upon one’s honest choices and identity without the influence of external social pressure and norms, while essentialists add in the concomitant aspect of being faithful to one’s true self—meaning that the individual has a clear and accurate depiction of their own life narratives in both the past and present that culminated in who they are to drive their purpose in life upon realization. The interference of optogenetics in modifying individuals’ memories suggests the alteration of one’s identity and certain affiliated values, beliefs, and other characteristics. Ultimately, doing so leads to the consequences as described above as one’s authenticity and intrinsic character becomes prone to diminishment and misrepresentation, respectively, thus leading the acts of self-creation and self-discovery into disarray [19, 20].
Note that the act of becoming inauthentic is generally deemed as morally permissible, however, under the circumstance that the choice of undergoing optogenetic intervention to modify one’s memory is made without ambivalence but rather it is derived from one’s higher-order desires that may lead to greater benefits relative to the potential harms, such as PTSD patients with severe symptoms in which conventional treatment methods are ineffective. These cases are important to be considered when formulating effective frameworks for regulating the use of optogenetics, yet questions such as to what extent is one’s external freedom compromised or is the essence of the individual resulted from optogenetic memory modification different than their original self are equally noteworthy for ethical examination. As a result, the dynamic and relational narrative construction of individuals’ identities (i.e., discovering oneself and acknowledging one’s identity) becomes subjugated to conformity in the sense that individual choices are no longer established on the basis of adhering to one’s true self; instead, they stem from the altering effects of optogenetic memory modification that violates the pillars of authenticity at the expense of favoring one’s local autonomy over authenticity. One familiar example is for a naturally shy individual to behave in an outgoing manner when interviewing for jobs that prefer extroverted attributes in its applicants [19, 20, 21].
The authenticity argument in relation to one’s identity nevertheless suffers from criticisms regarding the practical utility of the dual-basis framework in assessing memory modification and its implications given the individual-focused and idealistic framing of ideas. Despite everything, the dual-basis framework offers a well-balanced account of the complexity of neuroscience and psychology by presenting both the possibilities and constraints of creating one’s narrative identity [20]. Though interestingly, Kostick and Lázaro-Muñoz have argued that the brain has neural safeguards against inauthenticity caused by optogenetics that relies on neuroplasticity [22]. Of note that the discussion above only entails the worst-case scenarios of memory modification, however, to help guide future directions in the neuroethics of optogenetic applications since the degree of optogenetic effects on memory has yet to be demarcated. Therefore, it is worthwhile to be reliant upon the possible outcomes of hypotheticals to gauge reality, for it is currently difficult to translate optogenetic findings in animal models to humans in conjunction with the lack of a comprehensive neurobiological understanding of memory’s unpredictable nature.
As with any novel neurotechnology with an undefined impact, optogenetics imposes its own risks and benefits for the purpose of memory modification that requires a neuroethical evaluation of its ramifications in changing the properties and dimensions of memory. The arguments that have been presented herein is reminiscent of the events that unfolded in the 2004 romance and science fiction film Eternal Sunshine of the Spotless Mind, where the two protagonists both decided to undergo the procedure of having their memories of each other removed following a breakup, only to found remorse in the aftermath as they tried to reconcile their relationship despite the loss of their memories. Therefore, memory is what keeps the stories of our lives in a continuous state of progression as what oxygen is to fire; it is the gate that reveals our identities, values, ambitions, struggles, and relations to one another to empower us to live happily in a dreadful world in remembrance of who we are and those who we cherish.
References
1. Josselyn, S. A. (2018). The past, present and future of light-gated ion channels and optogenetics. Elife, 7, e42367.
2. Felsen, G., & Blumenthal-Barby, J. (2022). 7 Ethical Issues Raised by Recent Developments in Neuroscience: The Case of Optogenetics. Neuroscience and Philosophy.
3. Alberts, B., Johnson, A., Lewis, J., Raff, M., Roberts, K., & Walter, P. (2002). Ion channels and the electrical properties of membranes. In Molecular Biology of the Cell. 4th edition. Garland Science.
4. Fenno, L., Yizhar, O., & Deisseroth, K. (2011). The development and application of optogenetics. Annual review of neuroscience, 34, 389-412.
5. Carter, M., & Shieh, J. C. (2015). Guide to research techniques in neuroscience. Academic Press.
6. Adamczyk, A. K., & Zawadzki, P. (2020). The memory-modifying potential of optogenetics and the need for neuroethics. NanoEthics, 14(3), 207-225. 7. Canli, T. (2015). Neurogenethics: An emerging discipline at the intersection of ethics, neuroscience, and genomics. Applied & translational genomics, 5, 18-22. 8. Hamilton, G. F., & Rhodes, J. S. (2015). Exercise regulation of cognitive function and neuroplasticity in the healthy and diseased brain. Progress in molecular biology and translational science, 135, 381-406.
9. Liu, X., Ramirez, S., & Tonegawa, S. (2014). Inception of a false memory by optogenetic manipulation of a hippocampal memory engram. Philosophical Transactions of the Royal Society B: Biological Sciences, 369(1633), 20130142.
10. Guskjolen, A., Kenney, J. W., de la Parra, J., Yeung, B. R. A., Josselyn, S. A., & Frankland, P. W. (2018). Recovery of “lost” infant memories in mice. Current Biology, 28(14), 2283-2290.
11. Rook, N., Tuff, J. M., Isparta, S., Masseck, O. A., Herlitze, S., Güntürkün, O., & Pusch, R. (2021). AAV1 is the optimal viral vector for optogenetic experiments in pigeons (Columba livia). Communications Biology, 4(1), 100.
12. Chen, R., Gore, F., Nguyen, Q. A., Ramakrishnan, C., Patel, S., Kim, S. H., ... & Deisseroth, K. (2021). Deep brain optogenetics without intracranial surgery. Nature biotechnology, 39(2), 161-164.
13. Lin, J. Y., Knutsen, P. M., Muller, A., Kleinfeld, D., & Tsien, R. Y. (2013). ReaChR: a red-shifted variant of channelrhodopsin enables deep transcranial optogenetic excitation. Nature neuroscience, 16(10), 1499-1508.
14. Andrei, A. R., Debes, S., Chelaru, M., Liu, X., Rodarte, E., Spudich, J. L., ... & Dragoi, V. (2021). Heterogeneous side effects of cortical inactivation in behaving animals. Elife, 10, e66400.
15. Kolber, A. J. (2006). Therapeutic forgetting: The legal and ethical implications of memory dampening. Vand. L. Rev., 59, 1559.
16. Greenberg, D. M., Baron-Cohen, S., Rosenberg, N., Fonagy, P., & Rentfrow, P. J. (2018). Elevated empathy in adults following childhood trauma. PLoS one, 13(10), e0203886.
17. Robillard, J. M., & Illes, J. (2016). Manipulating memories: The ethics of yesterday’s science fiction and today’s reality. AMA Journal of Ethics, 18(12), 1225-1231.
18. McAdams, D. P., & McLean, K. C. (2013). Narrative identity. Current directions in psychological science, 22(3), 233-238.
19. Tan, S. Z. K., & Lim, L. W. (2020). A practical approach to the ethical use of memory modulating technologies. BMC Medical Ethics, 21(1), 1-14. 20. Leuenberger, M. (2022). Memory modification and authenticity: a narrative approach. Neuroethics, 15(1), 10.
21. Zawadzki, P. (2023). The Ethics of Memory Modification: Personal Narratives, Relational Selves and Autonomy. Neuroethics, 16(1), 6.
22. Kostick, K. M., & Lázaro-Muñoz, G. (2021). Neural safeguards against global impacts of memory modification on identity: ethical and practical considerations. AJOB neuroscience, 12(1), 45-48.