Organic Fluorophore Coated Polycrystalline Ceramic LSO:Ce Scintillators for X-ray Bioimaging

Burdette, Mary K.; Bandera, Yuriy; Zhang, Eric; Trofimov, Artem A.; Dickey, Ashley; Foulger, Isabell; Kolis, Joseph W.; Cannon, Kelli E.; Bartley, Aundrea F.; Dobrunz, Lynn E.; Bolding, Mark; McMahon, Lori L.; Foulger, Stephen H.

doi:10.1021/acs.langmuir.8b03129

Cited by 17 publications

(19 citation statements)

References 49 publications

(70 reference statements)

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“…We observed no toxicity in primary neuronal cultures following 24 h of LSO:Ce microparticle exposure, consistent with another study using coated LSO:Ce nanoparticles (Burdette et al, 2019). In acute hippocampal slices, there was no reactivity of the astrocytes as assessed by GFAP staining or decrease in the maximal strength of basal transmission assessed by I/O curves at CA3-CA1 synapses.…”

Section: Discussionsupporting

confidence: 92%

LSO:Ce Inorganic Scintillators Are Biocompatible With Neuronal and Circuit Function

Bartley

Abiraman

Stewart

et al. 2019

Front. Synaptic Neurosci.

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Optogenetics is widely used in neuroscience to control neural circuits. However, non-invasive methods for light delivery in brain are needed to avoid physical damage caused by current methods. One potential strategy could employ x-ray activation of radioluminescent particles (RPLs), enabling localized light generation within the brain. RPLs composed of inorganic scintillators can emit light at various wavelengths depending upon composition. Cerium doped lutetium oxyorthosilicate (LSO:Ce), an inorganic scintillator that emits blue light in response to x-ray or ultraviolet (UV) stimulation, could potentially be used to control neural circuits through activation of channelrhodopsin-2 (ChR2), a light-gated cation channel. Whether inorganic scintillators themselves negatively impact neuronal processes and synaptic function is unknown, and was investigated here using cellular, molecular, and electrophysiological approaches. As proof of principle, we applied UV stimulation to 4 μm LSO:Ce particles during whole-cell recording of CA1 pyramidal cells in acute hippocampal slices from mice that expressed ChR2 in glutamatergic neurons. We observed an increase in frequency and amplitude of spontaneous excitatory postsynaptic currents (sEPSCs), indicating activation of ChR2 and excitation of neurons. Importantly, LSO:Ce particles did not affect survival of primary mouse cortical neurons, even after 24 h of exposure. In extracellular dendritic field potential recordings, no change in the strength of basal glutamatergic transmission was observed during exposure to LSO:Ce microparticles. However, the amplitude of the fiber volley was slightly reduced with high stimulation. Additionally, there was a slight decrease in the frequency of sEPSCs in whole-cell voltage-clamp recordings from CA1 pyramidal cells, with no change in current amplitudes. The amplitude and frequency of spontaneous inhibitory postsynaptic currents were unchanged. Finally, long term potentiation (LTP), a synaptic modification believed to underlie learning and memory and a robust measure of synaptic integrity, was successfully induced, although the magnitude was slightly reduced. Together, these results show LSO:Ce particles are biocompatible even though there are modest effects on baseline synaptic function and long-term synaptic plasticity. Importantly, we show that light emitted from LSO:Ce particles is able to activate ChR2 and modify synaptic function. Therefore, LSO:Ce inorganic scintillators are potentially viable for use as a new light delivery system for optogenetics.

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Section: Discussionsupporting

confidence: 92%

LSO:Ce Inorganic Scintillators Are Biocompatible With Neuronal and Circuit Function

Bartley

Abiraman

Stewart

et al. 2019

Front. Synaptic Neurosci.

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“…However, in order to demonstrate that this noninvasive delivery method produced working opsin proteins Wang et al needed to implant an optical fiber for light activation. RLPs provide an alternative to implanted optic fibers and light emitting diodes (LEDs) and have been shown to be nontoxic to neurons [27], [28]. Here, we confirm that we are able to noninvasively deliver RLPs to the rat hippocampus using FUS BBB opening (Figure 1).…”

Section: Discussionsupporting

confidence: 71%

“…In order to overcome these limitations, we are working to replace fibers with novel lightemitting core-shell nanoparticles that can be activated noninvasively with X-ray exposure and can be strategically deposited such that they provide a more uniform distribution of light [27], [28]. Though further testing is still needed, these radioluminescent particle (RLPs) do not appear to interfere with neuronal functioning [29].…”

Section: Introductionmentioning

confidence: 99%

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

Rich

Zhang

Dickey

et al. 2020

Preprint

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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.

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“…LSO:Ce is a scintillator that has been extensively characterized (Melcher and Schweitzer, 1992;Roy et al, 2013) and used in multiple medical devices (Stratos et al, 2010;Roy et al, 2013;Burdette et al, 2019). Cerium forms the luminescence center in LSO, and the emission spectrum makes it well suited for optogenetics applications using ChR2 (Berndt et al, 2011;Lin, 2011).…”

Section: Discussionmentioning

confidence: 99%

“…Previously, we demonstrated that radioluminescent LSO:Ce microparticles are biocompatible with neuronal health and function (Bartley et al, 2019), and thus potentially useful for X-ray optogenetics. LSO:Ce has been widely studied as a scintillator, and has been shown to emit visible light in response to X-ray (Spurrier et al, 2007;Valais et al, 2008;Burdette et al, 2019). The LSO host lattice provides two potential Lu 3+ sites that Ce 3+ can substitute, with the Ce1 site surrounded by 7 oxygen neighbors while the Ce2 site has 6 oxygen neighbors.…”

Section: Lso:ce Radioluminescence Is Appropriate For Chr2mentioning

confidence: 99%

X-ray mediated scintillation increases synaptic activity via Cerium-doped LSO and Channelrhodopsin-2

Bartley

Fischer

Bagley

et al. 2020

Preprint

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Optogenetics is a widely used tool for studying neural circuits. However, non-invasive methods for light delivery in the brain are needed to avoid physical damage typically caused by intracranial insertion of light guides. An innovative strategy could employ X-ray activation of radioluminescent particles (RLPs) to emit localized light. We previously reported that RLPs composed of cerium doped lutetium oxyorthosilicate (LSO:Ce), an inorganic scintillator that emits blue light, are biocompatible with neuronal function and synaptic transmission. However, little is known about the consequences of acute X-ray exposure on synaptic function and long-term plasticity. Furthermore, modulation of neuronal or synaptic function by X-ray induced radioluminescence from RLPs has not yet been demonstrated. Here we show that 30 minutes of X-ray exposure at a rate of 0.042 Gy/second caused no change in the strength of basal glutamatergic transmission during extracellular dendritic field recordings in mouse hippocampal slices. Additionally, long-term potentiation (LTP), a robust measure of synaptic integrity, was able to be induced after X-ray exposure and expressed at a magnitude not different from control conditions (absence of X-rays). This is important as synaptic plasticity is critical to learning and memory. Next, we used molecular and electrophysiological approaches to determine if X-ray dependent radioluminescence emitted from RLPs can activate light sensitive proteins. We found that X-ray stimulation of RLPs elevated cAMP levels in HEK293T cells expressing OptoXR, a chimeric opsin receptor that combines the extracellular light-sensitive domain of channelrhodopsin-2 (ChR2) with an intracellular second messenger signaling cascade. This demonstrates that X-ray radioluminescence from LSO:Ce particles can activate OptoXR. Next, we tested whether X-ray activation of the RLPs can enhance synaptic activity in whole-cell recordings from hippocampal neurons expressing ChR2, both in cell culture and acute hippocampal slices. Importantly, X-ray radioluminescence caused an increase in the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) in both systems, indicating activation of ChR2 and excitation of neurons. Together, our results show that X-ray activation of LSO:Ce particles can heighten cellular and synaptic function. The combination of LSO:Ce inorganic scintillators and X-rays is therefore a viable method for optogenetics as an alternative to more invasive light delivery methods.

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Organic Fluorophore Coated Polycrystalline Ceramic LSO:Ce Scintillators for X-ray Bioimaging

Cited by 17 publications

References 49 publications

LSO:Ce Inorganic Scintillators Are Biocompatible With Neuronal and Circuit Function

LSO:Ce Inorganic Scintillators Are Biocompatible With Neuronal and Circuit Function

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

X-ray mediated scintillation increases synaptic activity via Cerium-doped LSO and Channelrhodopsin-2

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