Remotely Controlled Proton Generation for Neuromodulation.

Understanding and modulating proton-mediated biochemical processes in living organisms have been impeded by the lack of tools to control local pH. Here, we design nanotransducers capable of converting noninvasive alternating magnetic fields (AMFs) into protons in physiological environments by combining magnetic nanoparticles (MNPs) with polymeric scaffolds. When exposed to AMFs, the heat dissipated by MNPs triggered a hydrolytic degradation of surrounding polyanhydride or polyester, releasing protons into the extracellular space. pH changes induced by these nanotransducers can be tuned by changing the polymer chemistry or AMF stimulation parameters. Remote magnetic control of local protons was shown to trigger acid-sensing ion channels and to evoke intracellular calcium influx in neurons. By offering a wireless modulation of local pH, our approach can accelerate the mechanistic investigation of the role of protons in biochemical signaling in the nervous system.

Influence of Magnetic Fields on Electrochemical Reactions of Redox Cofactor Solutions.

Redox cofactors mediate many enzymatic processes and are increasingly employed in biomedical and energy applications. Exploring the influence of external magnetic fields on redox cofactor chemistry can enhance our understanding of magnetic-field-sensitive biological processes and allow the application of magnetic fields to modulate redox reactions involving cofactors. Through a combination of experiments and modeling, we investigate the influence of magnetic fields on electrochemical reactions in redox cofactor solutions. By employing flavin mononucleotide (FMN) cofactor as a model system, we characterize magnetically induced changes in Faradaic currents. We find that radical pair intermediates have negligible influence on current increases in FMN solution upon application of a magnetic field. The dominant mechanism underlying the observed current increases is the magneto-hydrodynamic effect. We extend our analyses to other diffusion-limited electrochemical reactions of redox cofactor solutions and arrive at similar conclusions, highlighting the opportunity to use this framework in redox cofactor chemistry.

Magnetoelectric Nanodiscs Enable Wireless Transgene-Free Neuromodulation.

Deep-brain stimulation (DBS) with implanted electrodes revolutionized treatment of movement disorders and empowered neuroscience studies. Identifying less invasive alternatives to DBS may further extend its clinical and research applications. Nanomaterial-mediated transduction of magnetic fields into electric potentials offers an alternative to invasive DBS. Here, we synthesize magnetoelectric nanodiscs (MENDs) with a core-double shell Fe3O4-CoFe2O4-BaTiO3 architecture with efficient magnetoelectric coupling. We find robust responses to magnetic field stimulation in neurons decorated with MENDs at a density of 1 µg/mm2 despite individual-particle potentials below the neuronal excitation threshold. We propose a model for repetitive subthreshold depolarization, which combined with cable theory, corroborates our findings in vitro and informs magnetoelectric stimulation in vivo. MENDs injected into the ventral tegmental area of genetically intact mice at concentrations of 1 mg/mL enable remote control of reward behavior, setting the stage for mechanistic optimization of magnetoelectric neuromodulation and inspiring its future applications in fundamental and translational neuroscience.

Magnetically Actuated Fiber-Based Soft Robots.

Broad adoption of magnetic soft robotics is hampered by the sophisticated field paradigms for their manipulation and the complexities in controlling multiple devices. Furthermore, high-throughput fabrication of such devices across spatial scales remains challenging. Here, advances in fiber-based actuators and magnetic elastomer composites are leveraged to create 3D magnetic soft robots controlled by unidirectional fields. Thermally drawn elastomeric fibers are instrumented with a magnetic composite synthesized to withstand strains exceeding 600%. A combination of strain and magnetization engineering in these fibers enables programming of 3D robots capable of crawling or walking in magnetic fields orthogonal to the plane of motion. Magnetic robots act as cargo carriers, and multiple robots can be controlled simultaneously and in opposing directions using a single stationary electromagnet. The scalable approach to fabrication and control of magnetic soft robots invites their future applications in constrained environments where complex fields cannot be readily deployed.

Modulating cell signalling in vivo with magnetic nanotransducers.

Weak magnetic fields offer nearly lossless transmission of signals within biological tissue. Magnetic nanomaterials are capable of transducing magnetic fields into a range of biologically relevant signals in vitro and in vivo. These nanotransducers have recently enabled magnetic control of cellular processes, from neuronal firing and gene expression to programmed apoptosis. Effective implementation of magnetically controlled cellular signalling relies on careful tailoring of magnetic nanotransducers and magnetic fields to the responses of the intended molecular targets. This primer discusses the versatility of magnetic modulation modalities and offers practical guidelines for selection of appropriate materials and field parameters, with a particular focus on applications in neuroscience. With recent developments in magnetic instrumentation and nanoparticle chemistries, including those that are commercially available, magnetic approaches promise to empower research aimed at connecting molecular and cellular signalling to physiology and behaviour in untethered moving subjects.

Probing Neuro-Endocrine Interactions Through Remote Magnetothermal Adrenal Stimulation.

Exposure to stressful or traumatic stimuli may alter hypothalamic-pituitary-adrenal (HPA) axis and sympathoadrenal-medullary (SAM) reactivity. This altered reactivity may be a component or cause of mental illnesses. Dissecting these mechanisms requires tools to reliably probe HPA and SAM function, particularly the adrenal component, with temporal precision. We previously demonstrated magnetic nanoparticle (MNP) technology to remotely trigger adrenal hormone release by activating thermally sensitive ion channels. Here, we applied adrenal magnetothermal stimulation to probe stress-induced HPA axis and SAM changes. MNP and control nanoparticles were injected into the adrenal glands of outbred rats subjected to a tone-shock conditioning/extinction/recall paradigm. We measured MNP-triggered adrenal release before and after conditioning through physiologic (heart rate) and serum (epinephrine, corticosterone) markers. Aversive conditioning altered adrenal function, reducing corticosterone and blunting heart rate increases post-conditioning. MNP-based organ stimulation provides a novel approach to probing the function of SAM, HPA, and other neuro-endocrine axes and could help elucidate changes across stress and disease models.

Modular Integration of Hydrogel Neural Interfaces.

Thermal drawing has been recently leveraged to yield multifunctional, fiber-based neural probes at near kilometer length scales. Despite its promise, the widespread adoption of this approach has been impeded by (1) material compatibility requirements and (2) labor-intensive interfacing of functional features to external hardware. Furthermore, in multifunctional fibers, significant volume is occupied by passive polymer cladding that so far has only served structural or electrical insulation purposes. In this article, we report a rapid, robust, and modular approach to creating multifunctional fiber-based neural interfaces using a solvent evaporation or entrapment-driven (SEED) integration process. This process brings together electrical, optical, and microfluidic modalities all encased within a copolymer comprised of water-soluble poly(ethylene glycol) tethered to water-insoluble poly(urethane) (PU-PEG). We employ these devices for simultaneous optogenetics and electrophysiology and demonstrate that multifunctional neural probes can be used to deliver cellular cargo with high viability. Upon exposure to water, PU-PEG cladding spontaneously forms a hydrogel, which in addition to enabling integration of modalities, can harbor small molecules and nanomaterials that can be released into local tissue following implantation. We also synthesized a custom nanodroplet forming block polymer and demonstrated that embedding such materials within the hydrogel cladding of our probes enables delivery of hydrophobic small molecules in vitro and in vivo. Our approach widens the chemical toolbox and expands the capabilities of multifunctional neural interfaces.

TGFß promotes widespread enhancer chromatin opening and operates on genomic regulatory domains.

The Transforming Growth Factor-ß (TGFß) signaling pathway controls transcription by regulating enhancer activity. How TGFß-regulated enhancers are selected and what chromatin changes are associated with TGFß-dependent enhancers regulation are still unclear. Here we report that TGFß treatment triggers fast and widespread increase in chromatin accessibility in about 80% of the enhancers of normal mouse mammary epithelial-gland cells, irrespective of whether they are activated, repressed or not regulated by TGFß. This enhancer opening depends on both the canonical and non-canonical TGFß pathways. Most TGFß-regulated genes are located around enhancers regulated in the same way, often creating domains of several co-regulated genes that we term TGFß regulatory domains (TRD). CRISPR-mediated inactivation of enhancers within TRDs impairs TGFß-dependent regulation of all co-regulated genes, demonstrating that enhancer targeting is more promiscuous than previously anticipated. The area of TRD influence is restricted by topologically associating domains (TADs) borders, causing a bias towards co-regulation within TADs.

In Vivo Photopharmacology Enabled by Multifunctional Fibers.

Photoswitchable ligands can add an optical switch to a target receptor or signaling cascade and enable reversible control of neural circuits. The application of this approach, termed photopharmacology, to behavioral experiments has been impeded by a lack of integrated hardware capable of delivering both light and compounds to deep brain regions in moving subjects. Here, we devise a hybrid photochemical genetic approach to target neurons using a photoswitchable agonist of the capsaicin receptor TRPV1, red-AzCA-4. Using multifunctional fibers with optical and microfluidic capabilities, we delivered a transgene coding for TRPV1 into the ventral tegmental area (VTA). This sensitized excitatory VTA neurons to red-AzCA-4, allowing us to optically control conditioned place preference in mice, thus extending applications of photopharmacology to behavioral experiments. Applied to endogenous receptors, our approach may accelerate future studies of molecular mechanisms underlying animal behavior.

Transgene-free remote magnetothermal regulation of adrenal hormones.

The field of bioelectronic medicines seeks to modulate electrical signaling within peripheral organs, providing temporally precise control of physiological functions. This is usually accomplished with implantable devices, which are often unsuitable for interfacing with soft and highly vascularized organs. Here, we demonstrate an alternative strategy for modulating peripheral organ function, which relies on the endogenous expression of a heat-sensitive cation channel, transient receptor potential vanilloid family member 1 (TRPV1), and heat dissipation by magnetic nanoparticles (MNPs) in remotely applied alternating magnetic fields. We use this approach to wirelessly control adrenal hormone secretion in genetically intact rats. TRPV1-dependent calcium influx into the cells of adrenal cortex and medulla is sufficient to drive rapid release of corticosterone and (nor)epinephrine. As altered levels of these hormones have been correlated with mental conditions such as posttraumatic stress disorder and major depression, our approach may facilitate the investigation of physiological and psychological impacts of stress.

In situ electrochemical generation of nitric oxide for neuronal modulation.

Understanding the function of nitric oxide, a lipophilic messenger in physiological processes across nervous, cardiovascular and immune systems, is currently impeded by the dearth of tools to deliver this gaseous molecule in situ to specific cells. To address this need, we have developed iron sulfide nanoclusters that catalyse nitric oxide generation from benign sodium nitrite in the presence of modest electric fields. Locally generated nitric oxide activates the nitric oxide-sensitive cation channel, transient receptor potential vanilloid family member 1 (TRPV1), and the latency of TRPV1-mediated Ca2+ responses can be controlled by varying the applied voltage. Integrating these electrocatalytic nanoclusters with multimaterial fibres allows nitric oxide-mediated neuronal interrogation in vivo. The in situ generation of nitric oxide in the ventral tegmental area with the electrocatalytic fibres evoked neuronal excitation in the targeted brain region and its excitatory projections. This nitric oxide generation platform may advance mechanistic studies of the role of nitric oxide in the nervous system and other organs.