A MEMS ultrasound stimulation system for modulation of neural circuits with high spatial resolution in vitro.

Neuromodulation by ultrasound has recently received attention due to its noninvasive stimulation capability for treating brain diseases. Although there have been several studies related to ultrasonic neuromodulation, these studies have suffered from poor spatial resolution of the ultrasound and low repeatability with a fixed condition caused by conventional and commercialized ultrasound transducers. In addition, the underlying physics and mechanisms of ultrasonic neuromodulation are still unknown. To determine these mechanisms and accurately modulate neural circuits, researchers must have a precisely controllable ultrasound transducer to conduct experiments at the cellular level. Herein, we introduce a new MEMS ultrasound stimulation system for modulating neurons or brain slices with high spatial resolution. The piezoelectric micromachined ultrasonic transducers (pMUTs) with small membranes (sub-mm membranes) generate enough power to stimulate neurons and enable precise modulation of neural circuits. We designed the ultrasound transducer as an array structure to enable localized modulation in the target region. In addition, we integrated a cell culture chamber with the system to make it compatible with conventional cell-based experiments, such as in vitro cell cultures and brain slices. In this work, we successfully demonstrated the functionality of the system by showing that the number of responding cells is proportional to the acoustic intensity of the applied ultrasound. We also demonstrated localized stimulation capability with high spatial resolution by conducting experiments in which cocultured cells responded only around a working transducer.

Wireless optofluidic brain probes for chronic neuropharmacology and photostimulation.

Both in vivo neuropharmacology and optogenetic stimulation can be used to decode neural circuitry, and can provide therapeutic strategies for brain disorders. However, current neuronal interfaces hinder long-term studies in awake and freely behaving animals, as they are limited in their ability to provide simultaneous and prolonged delivery of multiple drugs, are often bulky and lack multifunctionality, and employ custom control systems with insufficiently versatile selectivity for output mode, animal selection and target brain circuits. Here, we describe smartphone-controlled, minimally invasive, soft optofluidic probes with replaceable plug-like drug cartridges for chronic in vivo pharmacology and optogenetics with selective manipulation of brain circuits. We demonstrate the use of the probes for the control of the locomotor activity of mice for over four weeks via programmable wireless drug delivery and photostimulation. Owing to their ability to deliver both drugs and photopharmacology into the brain repeatedly over long time periods, the probes may contribute to uncovering the basis of neuropsychiatric diseases.

Synthesis and evaluation of novel potent TSPO PET ligands with 2-phenylpyrazolo[1,5-a]pyrimidin-3-yl acetamide.

Translocator protein (TSPO) expression is closely related with neuroinflammation and neuronal damage which might cause several central nervous system diseases. Herein, a series of TSPO ligands (11a-c and 13a-d) with a 2-phenylpyrazolo[1,5-a]pyrimidin-3-yl acetamide structure were prepared and evaluated via an in vitro binding assay. Most of the novel ligands exhibited a nano-molar affinity for TSPO, which was better than that of DPA-714. Particularly, 11a exhibited a subnano-molar TSPO binding affinity with suitable lipophilicity for in vivo brain studies. After radiolabeling with fluorine-18, [18F]11a was used for a dynamic positron emission tomography (PET) study in a rat LPS-induced neuroinflammation model; the inflammatory lesion was clearly visualized with a superior target-to-background ratio compared to [18F]DPA-714. An immunohistochemical examination of the dissected brains confirmed that the uptake location of [18F]11a in the PET study was consistent with a positively activated microglia region. This study proved that [18F]11a could be employed as a potential PET tracer for detecting neuroinflammation and could give possibility for diagnosis of other diseases, such as cancers related with TSPO expression.