Optogenetic techniques are described as “revolutionary” for the unprecedented causal control they allow neuroscientists to exert over neural activity in awake behaving animals. In this paper, I demonstrate by means of a case study that optogenetic techniques will only illuminate causal links between the brain and behavior to the extent that their error characteristics are known and, further, that determining these error characteristics requires comparison of optogenetic techniques with techniques having well known error characteristics and consideration of the broader neural (...) and behavioral context in which the targets of optogenetic interventions are situated. (shrink)

Constructivists about memory argue that memory is a capacity for building representations of past events from a generalized information store. The view is motivated by the memory errors discovered in cognitive psychology. Little has been known about the neural mechanisms by which false memories are produced. Recently, using a method I call the Optogenetic False Memory Technique, neuroscientists have created false memories in mice. In this paper, I examine how Constructivism fares in light of O-FaMe results. My aims are two-fold. (...) First, I argue that errors found in O-FaMe and cognitive psychology are similar behaviorally. Second, Constructivists should be able to explain the former since they purport to explain the latter, but they cannot. I conclude that O-FaMe studies reveal details about the mechanism by which false memories are produced that are incompatible with the explanatory approach to false memories favored by Constructivism. (shrink)

Optogenetics makes possible the control of neural activity with light. In this article, I explore how the development of this experimental tool has brought about methodological and theoretical advances in the neurobiological study of memory. I begin with Semon’s distinction between the engram and the ecphory, explaining how these concepts present a methodological challenge to investigating memory. Optogenetics provides a way to intervene into the engram without the ecphory that, in turn, opens up new means for testing theories (...) of memory error. I focus on a series of experiments where optogenetics is used to study false memory and forgetting. (shrink)

Open Peer Commentary on P. Zawadzki and A. K. Adamczyk's target article in AJOB Neuroscience on the potential of optogenetics for memory modification. I argue for a radically pluralistic understanding of the notion of authenticity, and highlight the need to further clarify the specific nature of the authors' concern about authenticity, as well as its policy implications.

Optogenetics is being optimistically presented in contemporary media for its unprecedented capacity to control cell behavior through the application of light to genetically modified target cells. As such, optogenetics holds obvious potential for application in a new generation of invasive medical devices by which to potentially provide treatment for neurological and psychiatric conditions such as Parkinson's disease, addiction, schizophrenia, autism and depression. Design of a first-in-human optogenetics experimental trial has already begun for the treatment of blindness. (...) class='Hi'>Optogenetics trials involve a combination of highly invasive genetic and electronic interventions that results in irreversible and permanent modifications of an individual's nervous system. Given its novelty, its uncertain benefit to patients, and its unique risk profile of irreversible physiological alteration, optogenetics requires a reassessment of the ethical challenges for protecting human participants in clinical trials, particularly at formative stages of clinical evaluation. This study explores the evolving ethical issues surrounding optogenetics’ potential harm to participants within trial design, especially focusing on whether Phase 1 trials should incorporate efficacy as well as safety endpoints in ways that are fair and respectful to research trial participants. (shrink)

I introduce two new tools in experimental neurobiology, optogenetics and DREADDs. These tools permit unprecedented control over activity in specific neurons in behaving animals. In addition to their inherent scientific interest, these tools make an important contribution to philosophy of science. They illustrate the very premises of Ian Hacking’s “microscope” argument for the relative independence of experiment from theory. This new example is important for generalizing Hacking’s argument because the background sciences and the fields of engineering producing these tools (...) differ significantly. (shrink)

Optogenetics is an invasive neuromodulation technology involving the use of light to control the activity of individual neurons. Even though optogenetics is a relatively new neuromodulation tool whose various implications have not yet been scrutinized, it has already been approved for its first clinical trials in humans. As optogenetics is being intensively investigated in animal models with the aim of developing novel brain stimulation treatments for various neurological and psychiatric disorders, it appears crucial to consider both the (...) opportunities and dangers such therapies may offer. In this review, we focus on the memory-modifying potential of optogenetics, investigating what it is capable of and how it differs from other memory modification technologies. We then outline the safety challenges that need to be addressed before optogenetics can be used in humans. Finally, we re-examine crucial neuroethical concerns expressed in regard to other MMTs in the light of optogenetics and address those that appear to be unique to the memory-modifying potential of optogenetic technology. (shrink)

There has been a growing interest in research concerning memory modification technologies (MMTs) in recent years. Neuroscientists and psychologists are beginning to explore the prospect of controllable and intentional modification of human memory. One of the technologies with the greatest potential to this end is optogenetics—an invasive neuromodulation technique involving the use of light to control the activity of individual brain cells. It has recently shown the potential to modify specific long-term memories in animal models in ways not yet (...) possible with other MMTs. As the therapeutic potential of optogenetics has already prompted approval of the first human trials, it is especially important and timely to consider the opportunities and dangers this technology may entail. In this article, we focus on possible consequences of optogenetics as an MMT by analyzing fundamental threats potentially associated with memory modifications: the potential disruption of personality and authenticity. (shrink)

Neuroscience communication is increasingly taking place on multidirectional social media platforms, creating new opportunities but also calling for critical ethical considerations. Twitter, one of the most popular social media applications in the world, is a leading platform for the dissemination of all information types, including emerging areas of neuroscience such as optogenetics, a technique aimed at the control of specific neurons. Since its discovery in 2005, optogenetics has been featured in the public eye and discussed extensively on social (...) media, but little is known about how this new technique is portrayed and who the users participating in the conversation are. To address this gap, we conducted content analysis of a sample of 1000 tweets mentioning “optogenetics” over a one-year period between 2014 and 2015. We found that academic researchers are the largest group contributing to the conversation, that the tweets often contain links to third-party websites from news organizations and peer-reviewed journals, and that common thematic motifs include the applications of optogenetics specifically for the control of brain activity and the treatment of disease. We also found that the majority of the tweets are neutral in their tone regarding optogenetics. As Twitter serves as a current and dynamic forum for exchange about advances in neuroscience, the conversation about optogenetics on this engaging platform can inform socially-responsive knowledge dissemination efforts in this area. (shrink)

We estimate that 208,000 deep brain stimulation (DBS) devices have been implanted to address neurological and neuropsychiatric disorders worldwide. DBS Think Tank presenters pooled data and determined that DBS expanded in its scope and has been applied to multiple brain disorders in an effort to modulate neural circuitry. The DBS Think Tank was founded in 2012 providing a space where clinicians, engineers, researchers from industry and academia discuss current and emerging DBS technologies and logistical and ethical issues facing the field. (...) The emphasis is on cutting edge research and collaboration aimed to advance the DBS field. The Eighth Annual DBS Think Tank was held virtually on September 1 and 2, 2020 (Zoom Video Communications) due to restrictions related to the COVID-19 pandemic. The meeting focused on advances in: (1) optogenetics as a tool for comprehending neurobiology of diseases and on optogenetically-inspired DBS, (2) cutting edge of emerging DBS technologies, (3) ethical issues affecting DBS research and access to care, (4) neuromodulatory approaches for depression, (5) advancing novel hardware, software and imaging methodologies, (6) use of neurophysiological signals in adaptive neurostimulation, and (7) use of more advanced technologies to improve DBS clinical outcomes. There were 178 attendees who participated in a DBS Think Tank survey, which revealed the expansion of DBS into several indications such as obesity, post-traumatic stress disorder, addiction and Alzheimer’s disease. This proceedings summarizes the advances discussed at the Eighth Annual DBS Think Tank. (shrink)

In our article (Zawadzki and Adamczyk 2021), we analyzed threats that novel memory modifying interventions may pose in the future. More specifically, we discussed how optogenetics’ potential for reversible erasure/deactivation of memory “may impact authenticity by producing changes at different levels of personality.” Our article has received many thoughtful open peer commentaries for which we would like to express our great appreciation. We have identified two main threads of objections. They are related to the potential applicability of optogenetics (...) as a therapeutic memory modification technology (MMT) in humans—applicability thread, and the normative value of authenticity, that is, the assumption that preserving authenticity is valuable (either in general or in the particular approach we adopted)—normative thread. Both of these threads concern fundamental issues: The former deals with the scientific credibility of the case vignette on which our discussion is based, and the latter deals with the normative weight of our considerations. We think that addressing both of them can be instructive in a broader context as they reflect a more general disagreement among neuroethicists about the very purpose and method of our discipline. (shrink)

In her article, Pascale Hess raises the issue of whether her proposed model may be extrapolated and applied to clinical research fields other than stem cell-based interventions in the brain (SCBI-B) (Hess 2012). Broadly summarized, Hess’s model suggests prioritizing efficacy over safety in phase 1 trials involving irreversible interventions in the brain, when clinical criteria meet the appropriate population suffering from “degenerative brain diseases” (Hess 2012). Although there is a need to reconsider the traditional phase 1 model, especially with respect (...) to first-in-human clinical trials involving novel technologies, the question arises as to whether it is appropriate to advocate for a new model that prioritizes efficacy over safety across all phase 1 clinical research trials involving irreversible interventions in the brain. -/- . (shrink)

Optogenetics and DREADDs (Designer Receptors Exclusively Activated by Designer Drugs) are important research tools in recent neurobiology. These tools allow unprecedented control over activity in specifically targeted neurons in behaving animals. Two approaches in philosophy of neuroscience, mechanism and ruthless reductionism, provide explicit accounts of experiments and results using tools like these, but each offers a different picture about how levels of mechanisms relate. I argue here that the ruthless reductionist’s direct mind‐to‐cellular/molecular activities linkages “in a single bound” better (...) fits with both the experimental designs using these tools and some of the scientists’ own judgments about their results than does the mechanist’s “nested hierarchies of mechanisms‐within‐mechanisms.” So at least some important work in current neuroscience appears to be ruthlessly reductive. Mechanism may not correctly characterize all current work in neuroscience, despite its recent popularity. (shrink)

The discovery of the engram, the physical substrate of memory, is a central challenge for the sciences of memory. Following the application of optogenetics to the neurobiological study of memory, scientists and philosophers claim that the engram has been found. In this paper, I evaluate the implications of applying optogenetic tools to the localization of the engram. I argue that conceptions of engram localization need to be revised to be made consistent with optogenetic studies of the engram. I distinguish (...) between challenges to vehicle and content localization. First, I consider the silent engram hypothesis. According to this hypothesis, optogenetic studies indicate that synaptic efficacy, the traditional engram-bearing vehicle, is important merely for retrieval. I argue that this interpretation rests upon a misunderstanding of accessibility. Second, I argue that optogenetic-based strategies and findings conflict with preservationist and constructivist views on memory storage. There is an enduring trace, but stored content may change over time and experience, resulting in doubt about what constitutes a single engram. (shrink)

The origin of memories is thought to be found in sensory perception. This conception is central to how the memory sciences characterize encoding. This paper considers how novel memory traces can be formed independently of external sensory inputs. I present a case study in which memory traces are created without sensory perception using a technique I call optogenetic memory implantation. Comparing this artificial process with normal memory encoding, I consider its implications for rethinking the causal chain that leads to remembering.

Rhodopsins are one of the most studied photoreceptor protein families, and ion‐translocating rhodopsins, both pumps and channels, have recently attracted broad attention because of the development of optogenetics. Recently, a new functional class of ion‐pumping rhodopsins, an outward Na+ pump, was discovered, and following structural and functional studies enable us to compare three functionally different ion‐pumping rhodopsins: outward proton pump, inward Cl− pump, and outward Na+ pump. Here, we review the current knowledge on structure‐function relationships in these three light‐driven (...) pumps, mainly focusing on Na+ pumps. A structural and functional comparison reveals both unique and conserved features of these ion pumps, and enhances our understanding about how the structurally similar microbial rhodopsins acquired such diverse functions. We also discuss some unresolved questions and future perspectives in research of ion‐pumping rhodopsins, including optogenetics application and engineering of novel rhodopsins. (shrink)

Theory has a central place in the traditional accounts of scientific practice. It’s less clear, however, what role theory has, and should have, in contemporary neuroscience. John Bickle argues that we should appreciate the central role that the development and use of experiment tools have in neuroscientific practice and the notable lack of an apparent need for theory. Call this the tools first method. I use two cases to assess Bickle’s assertion that the tools first method is always used in (...) neuroscience. In the first—the use of gene targeting to investigate the relationship between memory and long-term potentiation—a well-defined theory did have a prominent role. In contrast, the second case, an optogenetic investigation of neurons in the extended amygdala, illustrates the application of Bickle’s tools first method. -/- The takeaway, then, is twofold. Although sometimes theory has a role, there are productive investigations in neurobiology that proceed without a theory as the starting point. This is, in part, a consequence of experiment tools that allow for ever more precise investigations of cellular and molecular processes. It is also a consequence of the explanatory goals in neurobiology, namely, the description of mechanisms. When these two consequences come together, there is no longer an apparent need for theories of the sort traditionally taken to be central to scientific practice. (shrink)

Deep brain stimulation is a clinical intervention for the treatment of movement disorders. It has also been applied to the treatment of psychiatric disorders such as depression, anorexia nervosa, obsessive-compulsive disorder, and schizophrenia. Psychiatric disorders including schizophrenia, bipolar disorder, and major depression can lead to psychosis, which can cause patients to lose touch with reality. The ventral tegmental area, located near the midline of the midbrain, is an important region involved in psychosis. However, the clinical application of electrical stimulation of (...) the VTA to treat psychotic diseases has been limited, and related mechanisms have not been thoroughly studied. In the present study, hyperlocomotion and stereotyped behaviors of the mice were employed to mimic and evaluate the positive-psychotic-like behaviors. We attempted to treat positive psychotic-like behaviors by electrically stimulating the VTA in mice and exploring the neural mechanisms behind behavioral effects. Local field potential recording and in vivo fiber photometry to observe the behavioral effects and changes in neural activities caused by DBS in the VTA of mice. Optogenetic techniques were used to verify the neural mechanisms underlying the behavioral effects induced by DBS. Our results showed that electrical stimulation of the VTA activates local gamma-aminobutyric acid neurons, and dopamine neurons, reduces hyperlocomotion, and relieves stereotyped behaviors induced by MK-801 injection. The results of optogenetic manipulation showed that the activation of the VTA GABA neurons, but not DA neurons, is involved in the alleviation of hyperlocomotion and stereotyped behaviors. We visualized changes in the activity of specific types in specific brain areas induced by DBS, and explored the neural mechanism of DBS in alleviating positive psychotic-like behaviors. This preclinical study not only proposes new technical means of exploring the mechanism of DBS, but also provides experimental justification for the clinical treatment of psychotic diseases by electrical stimulation of the VTA. (shrink)

Deep brain stimulation of the subthalamic nucleus is an effective treatment for the motor symptoms of movement disorders including Parkinson's Disease. Despite its therapeutic benefits, STN-DBS has been associated with adverse effects on mood and cognition. Specifically, apathy, which is defined as a loss of motivation, has been reported to emerge or to worsen following STN-DBS. However, it is often challenging to disentangle the effects of STN-DBSper sefrom concurrent reduction of dopamine replacement therapy, from underlying PD pathology or from disease (...) progression. To this end, pre-clinical models allow for the dissociation of each of these factors, and to establish neural substrates underlying the emergence of motivational symptoms following STN-DBS. Here, we performed a systematic analysis of rodent studies assessing the effects of STN-DBS on reward seeking, reward motivation and reward consumption across a variety of behavioral paradigms. We find that STN-DBS decreases reward seeking in the majority of experiments, and we outline how design of the behavioral task and DBS parameters can influence experimental outcomes. While an early hypothesis posited that DBS acts as a “functional lesion,” an analysis of lesions and inhibition of the STN revealed no consistent pattern on reward-related behavior. Thus, we discuss alternative mechanisms that could contribute to the amotivational effects of STN-DBS. We also argue that optogenetic-assisted circuit dissection could yield important insight into the effects of the STN on motivated behavior in health and disease. Understanding the mechanisms underlying the effects of STN-DBS on motivated behavior-will be critical for optimizing the clinical application of STN-DBS. (shrink)

Memory modification technologies (MMTs)—interventions within the memory affecting its functions and contents in specific ways—raise great therapeutic hopes but also great fears. Ethicists have expressed concerns that developing and using MMTs may endanger the very fabric of who we are—our personal identity. This threat has been mainly considered in relation to two interrelated concerns: truthfulness and narrative self‐constitution. In this article, we propose that although this perspective brings up important matters concerning the potential aftermaths of MMT utilization, it fails to (...) tell the whole story. We suggest that capturing more tangible potential consequences of MMT use, namely, its psychological ramifications is crucial both in ethical considerations and in making decisions regarding the permissibility of such interventions. To this end, we first examine what current MMTs are capable of and what are the prospects of emerging MMTs. Subsequently, we outline the relationship between memory and personal identity; specifically, we indicate that concepts of self‐defining memories and narrative identity are crucial to considering how MMTs may influence one's psychological functioning. On this basis, we analyze potential consequences of narrative disruption that may be the result of the use of MMTs; more precisely, we consider its potential effects on mental health, well‐being, and personal agency, and outline the ethical dilemmas that decision‐makers face in this context. We conclude by considering the broader cultural context that may have influence on policymaking regarding permissibility of memory modification interventions. (shrink)