Abstract: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 scintill… Show more
“…ChR2 has been shown to be activated by wavelengths between 350 to 525 nm, with a peak at 470 nm (Lin et al, 2009;Bartley et al, 2019). 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.…”
Section: Lso:ce Radioluminescence Is Appropriate For Chr2mentioning
confidence: 97%
“…ChR2 has been shown to be activated by wavelengths between 350 to 525 nm, with a peak at 470 nm (Lin et al, 2009;Bartley et al, 2019). 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).…”
Section: Lso:ce Radioluminescence Is Appropriate For Chr2mentioning
confidence: 97%
“…Several photosensitive proteins can be activated by X-rays exposure (Dawson and Wiederwohl, 1965;Pande et al, 2016), especially ones that respond to UV light (Cannon et al, 2019). Channelrhodopsin-2 (ChR2), a light-gated cation channel, can be activated by wavelengths in the UV range (Bartley et al, 2019), as well as visible light (Boyden et al, 2005). However, it is unknown if ChR2 can be directly activated by acute X-ray exposure.…”
Section: X-ray Exposure Does Not Directly Activate Chr2mentioning
confidence: 99%
“…One potential strategy for less invasive light delivery to the brain is the use of X-rays to activate radioluminescent materials (Shuba, 2014;French et al, 2018;Bartley et al, 2019;. Radioluminescence is produced by exposing scintillating material to ionizing radiation, thereby causing generation of visible light.…”
Section: Introductionmentioning
confidence: 99%
“…LSO:Ce material has a high light output (Melcher and Schweitzer, 1991;Roy et al, 2013), and its X-ray activation has been shown to emit wavelengths of light needed to activate channelrhodopsin-2 (ChR2) (Melcher and Schweitzer, 1991). Previously, we showed that LSO:Ce particles had minimal effects on neuronal function and synaptic transmission (Bartley et al, 2019). Together, this makes it an ideal material to determine if radioluminescence from RLPs generated by X-ray exposure can activate ChR2 to modulate synaptic circuits.…”
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 lightsensitive 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, Xray 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.
“…ChR2 has been shown to be activated by wavelengths between 350 to 525 nm, with a peak at 470 nm (Lin et al, 2009;Bartley et al, 2019). 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.…”
Section: Lso:ce Radioluminescence Is Appropriate For Chr2mentioning
confidence: 97%
“…ChR2 has been shown to be activated by wavelengths between 350 to 525 nm, with a peak at 470 nm (Lin et al, 2009;Bartley et al, 2019). 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).…”
Section: Lso:ce Radioluminescence Is Appropriate For Chr2mentioning
confidence: 97%
“…Several photosensitive proteins can be activated by X-rays exposure (Dawson and Wiederwohl, 1965;Pande et al, 2016), especially ones that respond to UV light (Cannon et al, 2019). Channelrhodopsin-2 (ChR2), a light-gated cation channel, can be activated by wavelengths in the UV range (Bartley et al, 2019), as well as visible light (Boyden et al, 2005). However, it is unknown if ChR2 can be directly activated by acute X-ray exposure.…”
Section: X-ray Exposure Does Not Directly Activate Chr2mentioning
confidence: 99%
“…One potential strategy for less invasive light delivery to the brain is the use of X-rays to activate radioluminescent materials (Shuba, 2014;French et al, 2018;Bartley et al, 2019;. Radioluminescence is produced by exposing scintillating material to ionizing radiation, thereby causing generation of visible light.…”
Section: Introductionmentioning
confidence: 99%
“…LSO:Ce material has a high light output (Melcher and Schweitzer, 1991;Roy et al, 2013), and its X-ray activation has been shown to emit wavelengths of light needed to activate channelrhodopsin-2 (ChR2) (Melcher and Schweitzer, 1991). Previously, we showed that LSO:Ce particles had minimal effects on neuronal function and synaptic transmission (Bartley et al, 2019). Together, this makes it an ideal material to determine if radioluminescence from RLPs generated by X-ray exposure can activate ChR2 to modulate synaptic circuits.…”
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 lightsensitive 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, Xray 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.
Scintillators emit visible luminescence when irradiated with X-rays. Given the unlimited tissue penetration of X-rays, the employment of scintillators could enable remote optogenetic control of neural functions at any depth of the brain. Here we show that a yellow-emitting inorganic scintillator, Ce-doped Gd3(Al,Ga)5O12 (Ce:GAGG), can effectively activate red-shifted excitatory and inhibitory opsins, ChRmine and GtACR1, respectively. Using injectable Ce:GAGG microparticles, we successfully activated and inhibited midbrain dopamine neurons in freely moving mice by X-ray irradiation, producing bidirectional modulation of place preference behavior. Ce:GAGG microparticles are non-cytotoxic and biocompatible, allowing for chronic implantation. Pulsed X-ray irradiation at a clinical dose level is sufficient to elicit behavioral changes without reducing the number of radiosensitive cells in the brain and bone marrow. Thus, scintillator-mediated optogenetics enables minimally invasive, wireless control of cellular functions at any tissue depth in living animals, expanding X-ray applications to functional studies of biology and medicine.
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