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Optogenetics is a powerful technique that allows target-specific spatiotemporal manipulation of neuronal activity for dissection of neural circuits and therapeutic interventions. Recent advances in wireless optogenetics technologies have enabled investigation of brain circuits in more natural conditions by releasing animals from tethered optical fibers. However, current wireless implants, which are largely based on battery-powered or battery-free designs, still limit the full potential of in vivo optogenetics in freely moving animals by requiring intermittent battery replacement or a special, bulky wireless power transfer system for continuous device operation, respectively. To address these limitations, here we present a wirelessly rechargeable, fully implantable, soft optoelectronic system that can be remotely and selectively controlled using a smartphone. Combining advantageous features of both battery-powered and battery-free designs, this device system enables seamless full implantation into animals, reliable ubiquitous operation, and intervention-free wireless charging, all of which are desired for chronic in vivo optogenetics. Successful demonstration of the unique capabilities of this device in freely behaving rats forecasts its broad and practical utilities in various neuroscience research and clinical applications. Although wireless optogenetic technologies enable brain circuit investigation in freely moving animals, existing devices have limited their full potential, requiring special power setups. Here, the authors report fully implantable optogenetic systems that allow intervention-free wireless charging and controls for operation in any environment.

This Protocol Extension describes the low-cost production of rapidly customizable optical neural probes for in vivo optogenetics. We detail the use of a 3D printer to fabricate minimally invasive microscale inorganic light-emitting-diode-based neural probes that can control neural circuit activity in freely behaving animals, thus extending the scope of two previously published protocols describing the fabrication and implementation of optoelectronic devices for studying intact neural systems. The 3D-printing fabrication process does not require extensive training and eliminates the need for expensive materials, specialized cleanroom facilities and time-consuming microfabrication techniques typical of conventional manufacturing processes. As a result, the design of the probes can be quickly optimized, on the basis of experimental need, reducing the cost and turnaround for customization. For example, 3D-printed probes can be customized to target multiple brain regions or scaled up for use in large animal models. This protocol comprises three procedures: (1) probe fabrication, (2) wireless module preparation and (3) implantation for in vivo assays. For experienced researchers, neural probe and wireless module fabrication requires ~2 d, while implantation should take 30–60 min per animal. Time required for behavioral assays will vary depending on the experimental design and should include at least 5 d of animal handling before implantation of the probe, to familiarize each animal to their handler, thus reducing handling stress that may influence the result of the behavioral assays. The implementation of customized probes improves the flexibility in optogenetic experimental design and increases access to wireless probes for in vivo optogenetic research. This Protocol Extension describes the fabrication and implantation of 3D-printed neural probes for tethered or wireless optogenetics in freely moving rodents.

Billions of neurons in the brain coordinate together to control trillions of highly convoluted synaptic pathways for neural signal processing. Optogenetics is an emerging technique that can dissect such complex neural circuitry with high spatiotemporal precision using light. However, conventional approaches relying on rigid and tethered optical probes cause significant tissue damage as well as disturbance with natural behavior of animals, thus preventing chronic optogenetics. A microscale inorganic LED (μ-ILED) is an enabling optical component that can solve these problems by facilitating direct discrete spatial targeting of neural tissue, integration with soft, ultrathin probes as well as low power wireless operation. Here we review recent state-of-the art μ-ILED integrated soft wireless optogenetic tools suitable for use in freely moving animals and discuss opportunities for future developments.

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. Smartphone-controlled soft optofluidic probes with replaceable plug-like drug cartridges enable chronic in vivo pharmacology and optogenetics for the selective wireless manipulation of brain circuits in rodents.

Every region and people has peculiar economic characteristics and these features largely have roots in that region‟s social structure, social psychology and its dynamics. The capitalist economy of the United States has roots in individualismand Protestant Work Ethic, influenced both by Protestant religion and the social character of the Americans; the Client Economy of Saudi Arabia has deep linkages to its tribal social structure and the so-called Bazaar Economy of Afghanistan is profoundly embedded in the Pakhtun social structure of the country. The Pakhtuns of Pakistan have a peculiar social structure and social psychology thereof having profound and extensive influence on the region‟s economy particularly its largely underdevelopedcondition. The paper explores the characteristics of Pakhtun social structure and the interactive linkages between the social edifice and economic development or lack of it.

This protocol extension describes the fabrication of optofluidic neural probes and implantation for advanced in vivo pharmacology and optogenetics in freely moving rodents. This Protocol Extension describes the fabrication and technical procedures for implementing ultrathin, flexible optofluidic neural probe systems that provide targeted, wireless delivery of fluids and light into the brains of awake, freely behaving animals. As a Protocol Extension article, this article describes an adaptation of an existing Protocol that offers additional applications. This protocol serves as an extension of an existing Nature Protocol describing optoelectronic devices for studying intact neural systems. Here, we describe additional features of fabricating self-contained platforms that involve flexible microfluidic probes, pumping systems, microscale inorganic LEDs, wireless-control electronics, and power supplies. These small, flexible probes minimize tissue damage and inflammation, making long-term implantation possible. The capabilities include wireless pharmacological and optical intervention for dissecting neural circuitry during behavior. The fabrication can be completed in 1–2 weeks, and the devices can be used for 1–2 weeks of in vivo rodent experiments. To successfully carry out the protocol, researchers should have basic skill sets in photolithography and soft lithography, as well as experience with stereotaxic surgery and behavioral neuroscience practices. These fabrication processes and implementation protocols will increase access to wireless optofluidic neural probes for advanced in vivo pharmacology and optogenetics in freely moving rodents. This protocol is an extension to: Nat. Protoc.8, 2413–2428 (2013); doi:10.1038/nprot.2013.158; published online 07 November 2013

Neurodegenerative disorders refer to a group of diseases commonly associated with abnormal protein accumulation and aggregation in the central nervous system. However, the exact role of protein aggregation in the pathophysiology of these disorders remains unclear. This gap in knowledge is due to the lack of experimental models that allow for the spatiotemporal control of protein aggregation, and the investigation of early dynamic events associated with inclusion formation. Here, we report on the development of a light-inducible protein aggregation (LIPA) system that enables spatiotemporal control of α-synuclein (α-syn) aggregation into insoluble deposits called Lewy bodies (LBs), the pathological hallmark of Parkinson disease (PD) and other proteinopathies. We demonstrate that LIPA-α-syn inclusions mimic key biochemical, biophysical, and ultrastructural features of authentic LBs observed in PD-diseased brains. In vivo, LIPA-α-syn aggregates compromise nigrostriatal transmission, induce neurodegeneration and PD-like motor impairments. Collectively, our findings provide a new tool for the generation, visualization, and dissection of the role of α-syn aggregation in PD.

Chronic in-vivo studies through multimodal modulation of neurons in the deep brain can render pivotal insights not only in identifying their roles for a specific activity, but also to decipher their contribution in various neurodegenerative diseases. To prevent askew effects, probes were implanted to directly reach the target sites and the spatiotemporal resolution was further improved by targeting key neural circuits using optogenetics and pharmacology. Multimodal optofluidic probes allow integrated access to the target region without the need for multiple surgeries thus reducing tissue damage as well as simplifying combinatorial stimulations. Conventional tools have relied on rigid metal cannulas and silica optical fibers, but they cause adverse tissue inflammation due to their large probe sizes, rigid materials and associated tethers which severely limit their chronic integration. However, minimally invasive, mechanically compliant and untethered probes are shown to significantly limit tissue scarring in freely moving animals as shown in recent advances in soft optofluidic probes controlled by wireless head mounts, however, they didn’t last long primarily due to exhaustion of the drugs and power. Moreover, they were limited to the brain due to their bulky head mounts with limited range, directionality, and selectivity. Here we introduce two wireless optofluidic (wOF) neural devices each solving unique challenges faced by previous state-of-the-art devices and commercial pumps. Firstly, is the Lego wOF device which enables: 1) uninterrupted drug supply using replaceable “Lego” drug cartridges and 2) an easy-to-use smartphone app that allows long wireless range (~100m), isotropic wireless access, no Line of Sight (LOS) handicap, Over The Air (OTA) updates, high target specificity and scalable closed loop systems within a large group as well as intuitive control through an easy to use app on any commercial handheld smartphone. Second is the fully implantable wOF device which enables: 1) both central and peripheral stimulation in any space critical location inside the body (92% smaller and 88% lighter than previous systems), and 2) battery-free operation using a soft, stretchable energy harvester that can conformally adhere to any curvilinear surface inside the body. Successful in-vivo studies in mice demonstrate their innate capability for programmable and chronic wireless pharmacology and optogenetics.

Neurodegenerative disorders refer to a group of diseases commonly associated with abnormal protein accumulation and aggregation in the central nervous system. However, the exact role of protein aggregation in the pathophysiology of these disorders remains unclear. This gap in knowledge is due to the lack of experimental models that allow for the spatiotemporal control of protein aggregation, and the investigation of early dynamic events associated with inclusion formation. Here, we report on the development of a light-inducible protein aggregation (LIPA) system that enables spatiotemporal control of [alpha]-synuclein ([alpha]-syn) aggregation into insoluble deposits called Lewy bodies (LBs), the pathological hallmark of Parkinson disease (PD) and other proteinopathies. We demonstrate that LIPA-[alpha]-syn inclusions mimic key biochemical, biophysical, and ultrastructural features of authentic LBs observed in PD-diseased brains. In vivo, LIPA-[alpha]-syn aggregates compromise nigrostriatal transmission, induce neurodegeneration and PD-like motor impairments. Collectively, our findings provide a new tool for the generation, visualization, and dissection of the role of [alpha]-syn aggregation in PD.

The use of rodents to acquire understanding of the function of neural circuits and of the physiological, genetic and developmental underpinnings of behaviour has been constrained by limitations in the scalability, automation and high-throughput operation of implanted wireless neural devices. Here we report scalable and modular hardware and software infrastructure for setting up and operating remotely programmable miniaturized wireless networks leveraging Bluetooth Low Energy for the study of the long-term behaviour of large groups of rodents. The integrated system allows for automated, scheduled and real-time experimentation via the simultaneous and independent use of multiple neural devices and equipment within and across laboratories. By measuring the locomotion, feeding, arousal and social behaviours of groups of mice or rats, we show that the system allows for bidirectional data transfer from readily available hardware, and that it can be used with programmable pharmacological or optogenetic stimulation. Scalable and modular wireless-network infrastructure should facilitate the remote operation of fully automated large-scale and long-term closed-loop experiments for the study of neural circuits and animal behaviour. The integration of scalable and modular hardware and software for the remote operation of programmable miniaturized wireless networks allows for the study of the behaviour of large groups of rodents.