Optogenetics and psychiatry: applications, challenges, and opportunities.

o a a A chieving circuit-level insight into the fundamental nature of psychiatric symptoms has long proven elusive. Technological limitations have traditionally prevented cell type-tareted and temporally precise interventions into intact mammalian eural circuitry to elicit or ameliorate expression of disease sympom-related phenotypes. However, recent years have seen a growng wave of applications of optogenetics to questions in neuropsyhiatric disease, with the deployment of millisecond-precision ptical excitation or inhibition of specific circuit elements within ehaving mammals. Indeed, optogenetic technology now exists in special relationship with psychiatry because one of the unique nd most versatile features of optogenetics (modulation of defined eural projections) is well aligned with what may be a core feature f psychiatric disease (altered function along pathways of neural ommunication). In this special issue, we collect perspectives from eading researchers at the convergence of psychiatry and optogeetics, highlighting the fundamental questions that have been adressed and many of the opportunities that remain. The convergence of optogenetics (1–3) and psychiatry has ocurred rapidly over the last few years, with enough complexity that review and update of the core technology is useful in this venue efore review of the psychiatry applications. Therefore, this special ssue opens with a detailed summary of optogenetic technology tself from an optogenetics pioneer. Mei and Zhang (4) lead with a etailed and concise introduction to the diversity of microbial opin-based optogenetic tools, the basic principles of operation, and he suite of enabling technologies that have been developed. Most important among the associated enabling technologies especially from the perspective of psychiatry) was the fiber optic eural interface, which overcame the depth limitation caused by ight scattering and allowed access to (and optogenetic control of) ny brain region even in freely moving mammals. This device deuted in 2007 (5) and was first applied (also in 2007) to address uestions relevant to narcolepsy and sleep-wake transitions (6). pecific activity patterns were played into targeted hypocretin neuons in the lateral hypothalamus in freely moving mice; certain atterns but not others were found to favor sleep-wake transitions, roviding the first casual understanding of specific activity patterns n well-defined cells underlying mammalian behaviors (6). Here damantidis et al. (7) provided a review and update from this field, describing not only the initial studies but also the rapid progression of the field since 2007, extending beyond sleep itself to questions of arousal and interactions among different relevant neuromodulatory systems in the brain. For the initial hypocretin work in 2007, a fragment of DNA called a cell type–specific promoter was fused to the opsin gene, and the resulting construct was packaged within an injected lentivirus that infected or transduced all the cells in the target brain region, but because of the promoter, the virus successfully manufactured opsin