A Noninvasive Approach to Optogenetics Using Focused Ultrasound Blood Brain Barrier Disruption for the Delivery of Radioluminescent Particles

Abstract

Optogenetics, the genetic incorporation of light-sensitive proteins such as Channelrhodopsin-2 (ChR2) into target mammalian neurons, has enabled activation, silencing, and receptor subtype specific neuromodulation with high spatiotemporal resolution. However, the essential components of the ontogenetic system require invasive procedures with very few non-invasive alternatives preventing its use as a translational tool. The implantation of light emitting fibers deep within brain structures is both technically demanding and causes tissue scarring in target brain regions. To overcome these limitations, while maintaining the highly-tuned components of optogenetics we have developed a novel noninvasive alternative. Our approach replaces fibers with light-emitting radioluminescent particles (RLPs) that can be activated non-invasively with X-ray exposure. Here, we report successful noninvasive delivery of RLPs to target brain regions using MRI-guided focused ultrasound (FUS) blood brain barrier opening. In addition, FUS BBBO can be used to deliver viral vectors for light sensitive channel expression. Combined, these components can provide a completely non-invasive optogenetic system.

Feasibility of cerium-doped LSO particles as a scintillator for x-ray induced optogenetics

“…Radioluminescent nanoparticles have been shown to persist in brain tissue for at least 72 h after injection [54], enabling repeated experiments over multiple days. Radioluminescent nanoparticles can also be delivered into the brain using focused ultrasound to open the blood brain barrier [22], avoiding the damage of intracranial injection. X-ray activation of RLPs is therefore a potentially viable method for noninvasive optogenetics.…”

“…In addition, LSO:Ce is nonhygroscopic, biologically inert, and can be synthesized at the nanoscale level [76,77]. While we used microparticles in this study, LSO:Ce nanoparticles could be used to increase their likelihood of passing through the blood-brain barrier, especially if used together with focused ultrasound to increase BBB permeability [22]. We previously demonstrated that LSO:Ce microparticles are non-toxic to neurons and had very minor effects on synaptic transmission [21].…”

“…The use of RLPs would allow the light to be generated locally, overcoming the issue of light attenuation and the need for high power intensities. Additionally, inorganic scintillators can be noninvasively delivered to specific brain regions using focused ultrasound [22]. A common inorganic scintillator is Ceriumdoped lutetium oxyorthosilicate (LSO:Ce).…”

Personality and Authenticity in Light of the Memory-Modifying Potential of Optogenetics: A Reply to Objections about Potential Therapeutic Applicability of Optogenetics

“…Recently, Rich et al (2020) reported successful non-invasive delivery of light-emitting radio luminescent X-ray sensitive particles (RLPs) to the hippocampus of rats using magnetic resonance imaging (MRI)-guided focused ultrasound (FUS). Crucially, MRI-guided FUS can be used to deliver both RLPs and viral vectors for light-sensitive channel expression as demonstrated by Wang et al (2017).…”

The Ethics of Memory Modification: Personal Narratives, Relational Selves and Autonomy

“…In contrast, findings of recent years have shown that the prospect of providing measures to selectively deactivate the targeted memory can be actually realized with the use of an emerging MMT-optogenetics [35][36][37]. Although making optogenetic system operable to control neural activity underlying the memory still involves invasive manipulations, i.e., inserting opsin genes via viral infection and implanting optical fibers, less invasive optogenetic-systems are currently under development (see [38][39][40][41][42] for recent advancements in making optogenetics less or even non-invasive). While it may take years to make optogenetics or optogeneticlike technology a therapeutic memory-modifying measure, 2 if ever to be realized, 3 the fact that MMT has been shown to be effective in deactivating specific memories makes it timely and important to consider potential philosophical 4…”