Hats Off (or on) for Optogenetic Neuropharmacology
Summary by Allison Saul: Qazi, R., Gomez, A.M., Castro, D.C., Zou, Z., Sim, J.Y., Xiong, Y., Abdo, J., Kim, C.Y., Anderson, A., Lohner, F., Byun, S.H., Chul Lee, B., Jang, K.I., Xiao, J., Bruchas, M.R., Jeong, J.W., 2019. Wireless optofluidic brain probes for chronic neuropharmacology and photostimulation. Nat Biomed Eng 3, 655-669.
Image credit: Midjourney
Neural circuits are characterized by highly dynamic spatiotemporal signaling, where populations of neurons carry out defined functions. Investigating and manipulating this circuitry can promote the development of new therapeutic strategies for brain disorders. Researchers have developed many methods of neuronal manipulation, including local pharmacology and optogenetics [1]. Ideally, experiments involving manipulation of neural activity would be spatiotemporally precise and minimally invasive. Optogenetically driven pharmacology (optopharmacology) leverages light as a tool to manipulate neuronal activity with greater specificity [2].
Localized pharmacological techniques in preclinical studies have conventionally delivered one drug via metal cannulas inserted into the brain that are connected to an external fluid delivery system. Rigid cannulas can induce significant brain damage and inflammation in implanted mice. Microfluidic probes, made of an elastomeric polymer (i.e., flexible silicon), are miniature fiber alternatives that significantly reduce damage [3]; however, both types of probes require tethering to external hardware, limiting natural animal movement. Qazi et. al. designed and characterized a wireless optofluidic brain probe that is minimally invasive and allows for simultaneous drug and light delivery at the touch of a smartphone button [4]. The hat-like device contains micro-LEDs for photo-stimulation, a microfluidic probe, four drug reservoirs, and microheaters to stimulate drug release. This system elegantly facilitates exchange of external drug cartridges using a “plug-n-play” system, allowing long-term multi-drug delivery without reimplantation.
To investigate chronic deep-brain implantation, they implanted the device into wild-type mice and observed local immune responses. One week post-surgery, the mice demonstrated immune responses similar to those caused by implanted metal cannulas, illustrated by an increase in microglial activity. However, microfluidic probes are smaller; only 1/3 of the tissue area typically impacted by a metal probe demonstrated damage response. Second, to establish the continuity of drug delivery between cartridge exchanges, implanted mice received a drug that induced locomotion defects. Following each cartridge exchange, locomotion defects persisted, establishing that the plug-n-play system is capable of chronic drug delivery.
Additionally, Qazi et. al. created a custom smartphone app and connected to the device via Bluetooth. This allows for long-range pairing to control light and drug release, enabling the animal to maintain normal, untethered movement. Electronically controlling these features enables pre-programmed experiments to run automatically on a population. To test in vivo optopharmacological capability, they used a “real-time place-preference” test (RTPT). Mice were allowed access to two rooms: one inducing photostimulation and one that doesn’t. A virus driving the lateral hypothalamus to express photosensitive ion channels [5] was injected into mice; when exposed to blue light, the channels open, inducing neuronal depolarization. Depolarization in this context induces reward-like behavior in mice. When injected mice entered the photostimulation room, they demonstrated a higher preference for this room than uninjected mice. A drug, gabazine, binds this channel and prevents depolarization; if the device is working, gabazine release will inhibit room preference. Injected, implanted mice that initially demonstrated room preference with photostimulation lost preference with concurrent gabazine release, demonstrating parallel application of Bluetooth controlled photostimulation and drug delivery in untethered, awake mice. This device provides an excellent tool for investigating neural circuitry.
1. Melonakos, E. D. et al. Manipulating Neural Circuits in Anesthesia Research. Anesthesia https://doi.org:10.1097/ALN.0000000000003279
2. Paoletti, P., Ellis-Davies, G. C. R. & Mourot, A. Optical control of neuronal ion channels and receptors. Nat Rev Neurosci 20, 514-532 (2019). https://doi.org:10.1038/s41583-019-0197-2
3. Sim, J. Y., Haney, M. P., Park, S. I., McCall, J. G. & Jeong, J. W. Microfluidic neural probes: in vivo tools for advancing neuroscience. Lab Chip 17, 1406-1435 (2017). https://doi.org:10.1039/c7lc00103g
4. Qazi, R. et al. Wireless optofluidic brain probes for chronic neuropharmacology and photostimulation. Nat Biomed Eng 3, 655-669 (2019). https://doi.org:10.1038/s41551-019-0432-1
5. Thomas, C. S. et al. Optogenetic stimulation of lateral hypothalamic orexin/dynorphin inputs in the ventral tegmental area potentiates mesolimbic dopamine neurotransmission and promotes reward-seeking behaviours. Neuropsychopharmacology 47, 728-740 (2022). https://doi.org:10.1038/s41386-021-01196-y