Search

Guided by gut sensory cues, humans and animals prefer nutritive sugars over non-caloric sweeteners, but how the gut steers such preferences remains unknown. In the intestine, neuropod cells synapse with vagal neurons to convey sugar stimuli to the brain within seconds. Here, we found that cholecystokinin (CCK)-labeled duodenal neuropod cells differentiate and transduce luminal stimuli from sweeteners and sugars to the vagus nerve using sweet taste receptors and sodium glucose transporters. The two stimulus types elicited distinct neural pathways: while sweetener stimulated purinergic neurotransmission, sugar stimulated glutamatergic neurotransmission. To probe the contribution of these cells to behavior, we developed optogenetics for the gut lumen by engineering a flexible fiberoptic. We showed that preference for sugar over sweetener in mice depends on neuropod cell glutamatergic signaling. By swiftly discerning the precise identity of nutrient stimuli, gut neuropod cells serve as the entry point to guide nutritive choices.

Recording and modulating neural activityin vivoenables investigations of neural circuits during behavior. However, there is a dearth of tools for simultaneous recording and localized receptor modulation in large animal models. We address this limitation by translating multifunctional fiber-based neurotechnology previously only available for rodent studies to enable cortical and subcortical neural modulation in macaques. We record single unit and local field potential activity before, during, and after intracranial GABA infusions in the premotor cortex and putamen. We apply state-space models to characterize changes in neural activity and investigate how neural activity evoked by a working memory task varies in the presence of local inhibition. The recordings provide detailed insight into the electrophysiological effect of neurotransmitter receptor modulation in both cortical and subcortical structures in an awake, behaving macaque. Our results demonstrate a first-time translation of multifunctional fibers for causal studies in behaving non-human primates.

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 on 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.

Interactions of charge carriers with lattice vibrations, or phonons, play a critical role in unconventional electronic transport of metals and semimetals. Recent observations of phonon-mediated collective electron flow in bulk semimetals, termed electron hydrodynamics, present new opportunities in the search for strong electron-electron interactions in high carrier density materials. Here we present the general transport signatures of such a second-order scattering mechanism, along with analytical limits at the Eliashberg level of theory. We study electronic transport, using $ab$ $initio$ calculations, in finite-size channels of semimetallic ZrSiS and TaAs$_2$ with and without topological band crossings, respectively. The order of magnitude separation between momentum-relaxing and momentum-conserving scattering length-scales across a wide temperature range make both of them promising candidates for further experimental observation of electron hydrodynamics. More generally, our calculations show that the hydrodynamic transport regime can be realized in a much broader class of anisotropic metals and does not, to first order, rely on the topological nature of the bands. Finally, we discuss general design principles guiding future search for hydrodynamic candidates, based on the analytical formulation and our $ab$ $initio$ predictions. We find that systems with strong electron-phonon interactions, reduced electronic phase space, and suppressed phonon-phonon scattering at temperatures of interest are likely to feature hydrodynamic electron transport. We predict that layered and/or anisotropic semimetals composed of half-filled $d$-shells and light group V/VI elements with lower crystal symmetry are ideal candidates to observe hydrodynamic phenomena in future., Comment: 10 pages, 5 figures

Although targeted actuation of neurons via magnetic fields may benefit neuroscience research and medicine, some approaches have sparked controversy.

Immune surveillance of the brain is regulated by resident non-neuronal cells and the blood-brain barrier.1 Dys-regulation of immunosurveillance is a hallmark feature of several diseases2–5 including brain tumors6 that interact with and rely heavily on immune cells,7 suggesting that disrupting the neuroimmunology of tumors could slow their progression. Yet few tools are available to control brain immunology in vivo with local precision, and fewer yet are used for therapeutic intervention. 2 Here, we propose engineered cytokines as a neuroimmune-modulation platform. We demonstrate that the residence time of cytokines in the brain can be tuned by binding them to the extracellular matrix or synthetic scaffolds. We then show that the aluminum hydroxide adjuvant (alum) is retained in the brain >2 weeks. Tethering of inflammatory cytokines such as interleukins (IL) 2 and 12 to alum yields extended neuroinflammation and brain immunosurveillance after intracranial administration, while avoiding systemic toxicity. In mouse models of both immunologically hot and cold brain tumors, the intracranial deposition of alum-tethered cytokines causes significant delay in tumor progression. RNA profiling reveals that engineered cytokines engage both innate and adaptive immunity in the brain. These findings suggest that engineered cytokines can reprogram brain immunosurveillance, informing the development of future therapies for neuroimmune diseases.

Magnetic nanoparticles have garnered sustained research interest for their promise in biomedical applications including diagnostic imaging, triggered drug release, cancer hyperthermia, and neural stimulation. Many of these applications make use of heat dissipation by ferrite nanoparticles under alternating magnetic fields, with these fields acting as an externally administered stimulus that is either present or absent, toggling heat dissipation on and off. Here, we motivate and demonstrate an extension of this concept, magnetothermal multiplexing, in which exposure to alternating magnetic fields of differing amplitude and frequency can result in selective and independent heating of magnetic nanoparticle ensembles. The differing magnetic coercivity of these particles, empirically characterized by a custom high amplitude alternating current magnetometer, informs the systematic selection of a multiplexed material system. This work culminates in a demonstration of magnetothermal multiplexing for selective remote control of cellular signaling in vitro.

Multimaterial fibers engineered to integrate glasses, metals, semiconductors, and composites found applications in ubiquitous sensing, biomedicine, and robotics. The longitudinal symmetry typical of fibers, however, limits the density of functional interfaces with fiber-based devices. Here, thermal drawing and photolithography are combined to produce a scalable method for deterministically breaking axial symmetry within multimaterial fibers. Our approach harnesses a two-step polymerization in thiol–epoxy and thiol–ene photopolymer networks to create a photoresist compatible with high-throughput thermal drawing in atmospheric conditions. This, in turn, delivers meters of fiber that can be patterned along the length increasing the density of functional points. This approach may advance applications of fiber-based devices in distributed sensors, large area optoelectronic devices, and smart textiles., Thermally drawable photoresist based on thiol−epoxy/thiol−ene network enables high-throughput fabrication of hundreds of meters of longitudinally patternable multimaterial fibers.

Rotational invariance strongly constrains the viscosity tensor of classical fluids. When this symmetry is broken in anisotropic materials a wide array of novel phenomena become possible. We explore electron fluid behaviors arising from the most general viscosity tensors in two and three dimensions, constrained only thermodynamics and crystal symmetries. We find nontrivial behaviors in both two- and three-dimensional materials, including imprints of the crystal symmetry on the large-scale flow pattern. Breaking time-reversal symmetry introduces a non-dissipative Hall component to the viscosity tensor, and while this vanishes for 3D isotropic systems we show it need not for anisotropic materials. Further, for such systems we find that the electronic fluid stress can couple to the vorticity without breaking time-reversal symmetry. Our work demonstrates the anomalous landscape for electron hydrodynamics in systems beyond graphene, and presents experimental geometries to quantify the effects of electronic viscosity., In some materials electrons can behave hydrodynamically, exhibiting phenomena associated with classical viscous fluids. In this theory work, the authors show that the symmetries of the crystal lattices in which the electrons reside can lead to additional unique hydrodynamic effects.

Electronic fabrics necessitate both electrical conductivity and, like any textile, elastic recovery. Achieving both requirements on the scale of a single fiber remains an unmet need. Here, two approaches for achieving conductive fibers (10

A wide range of unconventional transport phenomena has recently been observed in single-crystal delafossite metals. Here, we present a theoretical framework to elucidate electron transport using a combination of first-principles calculations and numerical modeling of the anisotropic Boltzmann transport equation. Using PdCoO2 as a model system, we study different microscopic electron and phonon scattering mechanisms and establish the mean free path hierarchy of quasiparticles at different temperatures. We treat the anisotropic Fermi surface explicitly to numerically obtain experimentally-accessible transport observables, which bridge between the “diffusive,” “ballistic,” and “hydrodynamic” transport regime limits. We illustrate that the distinction between the “quasiballistic” and “quasihydrodynamic” regimes is challenging and often needs to be quantitative in nature. From first-principles calculations, we populate the resulting transport regime plots and demonstrate how the Fermi surface orientation adds complexity to the observed transport signatures in micrometer-scale devices. Our work provides key insights into microscopic interaction mechanisms on open hexagonal Fermi surfaces and establishes their connection to the macroscopic electron transport in finite-size channels.

Despite the critical role played by carbon monoxide (CO) in physiological and pathological signaling events, current approaches to deliver this messenger molecule are often accompanied by off-target effects and offer limited control over release kinetics. To address these challenges, we developed an electrochemical approach that affords on-demand release of CO through reduction of carbon dioxide (CO(2)) dissolved in the extracellular space. Electrocatalytic generation of CO by cobalt phthalocyanine molecular catalysts modulates signaling pathways mediated by a CO receptor, soluble guanylyl cyclase. Furthermore, by tuning the applied voltage during electrocatalysis, we explore the effect of the CO release kinetics on CO-dependent neuronal signaling. Finally, we integrate components of our electrochemical platform into microscale fibers to produce CO in a spatially-restricted manner and to activate signaling cascades in the targeted cells. By offering on-demand local synthesis of CO, our approach may facilitate the studies of physiological processes affected by this gaseous molecular messenger.

Connecting neural circuit output to behaviour can be facilitated by the precise chemical manipulation of specific cell populations1,2. Engineered receptors exclusively activated by designer small molecules enable manipulation of specific neural pathways3,4. However, their application to studies of behaviour has thus far been hampered by a trade-off between the low temporal resolution of systemic injection versus the invasiveness of implanted cannulae or infusion pumps2. Here, we developed a remotely controlled chemomagnetic modulation—a nanomaterials-based technique that permits the pharmacological interrogation of targeted neural populations in freely moving subjects. The heat dissipated by magnetic nanoparticles (MNPs) in the presence of alternating magnetic fields (AMFs) triggers small-molecule release from thermally sensitive lipid vesicles with a 20 s latency. Coupled with the chemogenetic activation of engineered receptors, this technique permits the control of specific neurons with temporal and spatial precision. The delivery of chemomagnetic particles to the ventral tegmental area (VTA) allows the remote modulation of motivated behaviour in mice. Furthermore, this chemomagnetic approach activates endogenous circuits by enabling the regulated release of receptor ligands. Applied to an endogenous dopamine receptor D1 (DRD1) agonist in the nucleus accumbens (NAc), a brain area involved in mediating social interactions, chemomagnetic modulation increases sociability in mice. By offering a temporally precise control of specified ligand–receptor interactions in neurons, this approach may facilitate molecular neuroscience studies in behaving organisms. Controlled delivery of neuromodulators in the brain might improve the understanding of the molecular basis of behaviour. In this letter, magnetic liposomes injected in deep brain regions release small molecules under remote magnetic stimulation, activating specific neuronal circuits in freely moving mice.

The field of neuromodulation is developing rapidly. Current techniques, however, are still limited as they i) either depend on permanent implants, ii) require invasive procedures, iii) are not cell-type specific, iv) involve slow pharmacokinetics or v) have a restricted penetration depth making it difficult to stimulate regions deep within the brain. Refinements into the different fields of neuromodulation are thus needed. In this review, we will provide background information on the different techniques of neuromodulation discussing their latest refinements and future potentials including the implementation of nanoparticles (NPs). In particular we will highlight the usage of magnetic nanoparticles (MNPs) as transducers in advanced neuromodulation. When exposed to an alternating magnetic field (AMF), certain MNPs can generate heat through hysteresis. This MNP heating has been promising in the field of cancer therapy and has recently been introduced as a method for remote and wireless neuromodulation. This indicates that MNPs may aid in the exploration of brain functions via neuromodulation and may eventually be applied for treatment of neuropsychiatric disorders. We will address the materials chemistry of MNPs, their biomedical applications, their delivery into the brain, their mechanisms of stimulation with emphasis on MNP heating and their remote control in living tissue. The final section compares and discusses the parameters used for MNP heating in brain cancer treatment and neuromodulation. Concluding, using MNPs for nanomaterial-mediated neuromodulation seem promising in a variety of techniques and could be applied for different neuropsychiatric disorders when more extensively investigated.

Neurological and psychiatric conditions pose an increasing socioeconomic burden on our aging society. Our ability to understand and treat these conditions relies on the development of reliable tools to study the dynamics of the underlying neural circuits. Despite significant progress in approaches and devices to sense and modulate neural activity, further refinement is required on the spatiotemporal resolution, cell-type selectivity, and long-term stability of neural interfaces. Guided by the principles of neural transduction and by the materials properties of the neural tissue, recent advances in neural interrogation approaches rely on flexible and multifunctional devices. Among these approaches, multimaterial fibers have emerged as integrated tools for sensing and delivering of multiple signals to and from the neural tissue. Fiber-based neural probes are produced by thermal drawing process, which is the manufacturing approach used in optical fiber fabrication. This technology allows straightforward incorporation of multiple functional components into microstructured fibers at the level of their macroscale models, preforms, with a wide range of geometries. Here we will introduce the multimaterial fiber technology, its applications in engineering fields, and its adoption for the design of multifunctional and flexible neural interfaces. We will discuss examples of fiber-based neural probes tailored to the electrophysiological recording, optical neuromodulation, and delivery of drugs and genes into the rodent brain and spinal cord, as well as their emerging use for studies of nerve growth and repair.

Exposure to stress alters hypothalamic-pituitary-adrenal (HPA) axis reactivity; however, it is unclear exactly how or where within the HPA pathway these changes occur. Dissecting these mechanisms requires tools to reliably probe HPA 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 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 HPA and other neuro-endocrine axes and could help elucidate changes across stress and disease models.

To understand the underlying mechanisms of progressive neurophysiological phenomena, neural interfaces should interact bi-directionally with brain circuits over extended periods of time. However, such interfaces remain limited by the foreign body response that stems from the chemo-mechanical mismatch between the probes and the neural tissues. To address this challenge, we developed a multifunctional sensing and actuation platform consisting of multimaterial fibers intimately integrated within a soft hydrogel matrix mimicking the brain tissue. These hybrid devices possess adaptive bending stiffness determined by the hydration states of the hydrogel matrix. This enables their direct insertion into the deep brain regions, while minimizing tissue damage associated with the brain micromotion after implantation. The hydrogel hybrid devices permit electrophysiological, optogenetic, and behavioral studies of neural circuits with minimal foreign body responses and tracking of stable isolated single neuron potentials in freely moving mice over 6 months following implantation., Neural probes for experimental studies can cause tissue damage. Here the authors describe a probe incorporated with a hydrogel structure for adaptive bending stiffness to enable insertion to the rodent brain while minimising tissue damage.

Fiber drawing enables scalable fabrication of multifunctional flexible fibers that integrate electrical, optical and microfluidic modalities to record and modulate neural activity. Constraints on thermomechanical properties of materials, however, have prevented integrated drawing of metal electrodes with low-loss polymer waveguides for concurrent electrical recording and optical neuromodulation. Here we introduce two fabrication approaches: (1) an iterative thermal drawing with a soft, low melting temperature (Tm) metal indium, and (2) a metal convergence drawing with traditionally non-drawable high Tmmetal tungsten. Both approaches deliver multifunctional flexible neural interfaces with low-impedance metallic electrodes and low-loss waveguides, capable of recording optically-evoked and spontaneous neural activity in mice over several weeks. We couple these fibers with a light-weight mechanical microdrive (1g) that enables depth-specific interrogation of neural circuits in mice following chronic implantation. Finally, we demonstrate the compatibility of these fibers with magnetic resonance imaging (MRI) and apply them to visualize the delivery of chemical payloads through the integrated channels in real time. Together, these advances expand the domains of application of the fiber-based neural probes in neuroscience and neuroengineering.

Developing tools that are able to monitor transient neurochemical dynamics is important to decipher brain chemistry and function. Multifunctional polymer-based fibers have been recently applied to monitor and modulate neural activity. Here, we explore the potential of polymer fibers comprising six graphite-doped electrodes and two microfluidic channels within a flexible polycarbonate body as a platform for sensing pH and neurometabolic lactate. Electrodes were made into potentiometric sensors (responsive to pH) or amperometric sensors (lactate biosensors). The growth of an iridium oxide layer made the fiber electrodes responsive to pH in a physiologically relevant range. Lactate biosensors were fabricated via platinum black growth on the fiber electrode, followed by an enzyme layer, making them responsive to lactate concentration. Lactate fiber biosensors detected transient neurometabolic lactate changes in an in vivo mouse model. Lactate concentration changes were associated with spreading depolarizations, known to be detrimental to the injured brain. Induced waves were identified by a signature lactate concentration change profile and measured as having a speed of ∼2.7 mm/min (n = 4 waves). Our work highlights the potential applications of fiber-based biosensors for direct monitoring of brain metabolites in the context of injury.

Guided by gut sensory cues, humans and animals prefer nutritive sugars over non-caloric sweeteners, but how the gut steers such preferences remains unknown. In the intestine, neuropod cells synapse with vagal neurons to convey sugar stimuli to the brain within seconds. Here, we found that cholecystokinin (CCK)-labeled duodenal neuropod cells differentiate and transduce luminal stimuli from sweeteners and sugars to the vagus nerve using sweet taste receptors and sodium glucose transporters. The two stimulus types elicited distinct neural pathways: while sweetener stimulated purinergic neurotransmission, sugar stimulated glutamatergic neurotransmission. To probe the contribution of these cells to behavior, we developed optogenetics for the gut lumen by engineering a flexible fiberoptic. We showed that preference for sugar over sweetener in mice depends on neuropod cell glutamatergic signaling. By swiftly discerning the precise identity of nutrient stimuli, gut neuropod cells serve as the entry point to guide nutritive choices.

The 3D local atomic structures and crystal defects at the interfaces of heterostructures control their electronic, magnetic, optical, catalytic and topological quantum properties, but have thus far eluded any direct experimental determination. Here we determine the 3D local atomic positions at the interface of a MoS2-WSe2 heterojunction with picometer precision and correlate 3D atomic defects with localized vibrational properties at the epitaxial interface. We observe point defects, bond distortion, atomic-scale ripples and measure the full 3D strain tensor at the heterointerface. By using the experimental 3D atomic coordinates as direct input to first principles calculations, we reveal new phonon modes localized at the interface, which are corroborated by spatially resolved electron energy-loss spectroscopy. We expect that this work will open the door to correlate structure-property relationships of a wide range of heterostructure interfaces at the single-atom level.

Deep brain stimulation (DBS) has long been used to alleviate symptoms in patients suffering from psychiatric and neurological disorders through stereotactically implanted electrodes that deliver current to subcortical structures via wired pacemakers. The application of DBS to modulate neural circuits is, however, hampered by its mechanical invasiveness and the use of chronically implanted leads, which poses a risk for hardware failure, hemorrhage, and infection. Here, we demonstrate that a wireless magnetothermal approach to DBS (mDBS) can provide similar therapeutic benefits in two mouse models of Parkinson’s disease, the bilateral 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and in the unilateral 6-hydroxydopamine (6-OHDA) model. We show magnetothermal neuromodulation in untethered moving mice through the activation of the heat-sensitive capsaicin receptor (transient receptor potential cation channel subfamily V member 1, TRPV1) by synthetic magnetic nanoparticles. When exposed to an alternating magnetic field, the nanoparticles dissipate heat, which triggers reversible firing of TRPV1-expressing neurons. We found that mDBS in the subthalamic nucleus (STN) enables remote modulation of motor behavior in healthy mice. Moreover, mDBS of the STN reversed the motor deficits in a mild and severe parkinsonian model. Consequently, this approach is able to activate deep-brain circuits without the need for permanently implanted hardware and connectors., Nature Communications, 12 (1), ISSN:2041-1723

To reversibly manipulate neural circuits with increased spatial and temporal control, photoswitchable ligands can add an optical switch to a target receptor or signaling cascade. This approach, termed photopharmacology, has been enabling to molecular neuroscience, however, its application 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 capsaicin receptor (TRPV1), red-AzCA-4. Using the thermal drawing process we created multifunctional fibers that can deliver viruses, photoswitchable ligands, and light to deep brain regions in awake, freely moving mice. We implanted our fibers into the ventral tegmental area (VTA), a midbrain hub of the mesolimbic pathway, and used them to deliver a transgene coding for TRPV1. This sensitized excitatory VTA neurons to red-AzCA-4, and allowed us to optically control conditioned place preference using a mammalian ion-channel, thus extending applications of photopharmacology to behavioral experiments. Applied to endogenous receptors, our approach may accelerate studies of molecular mechanisms underlying animal behavior.

This paper discusses the development of Electronic, Optical, and Magnetic Properties of Materials as a MOOC offered on the edX platform. In particular, we discuss the decision to include comics and comic-based themes as a component of the homework assignments in the course. We present an A/B test conducted on the edX platform that compares the performance of students given the comic-based homework assignments with students given traditional homework assignments. No difference in performance is observed between the two groups. We also present survey data that compares the reactions of MOOC learners and residential university students to the comic-based homework assignments. The university students reported a high degree of enjoyment of the comic-based homework, while the MOOC learners had a more mixed reaction.

The atomic structure at the interface between two-dimensional (2D) and three-dimensional (3D) materials influences properties such as contact resistance, photo-response, and high-frequency electrical performance. Moir\'e engineering is yet to be utilized for tailoring this 2D/3D interface, despite its success in enabling correlated physics at 2D/2D interfaces. Using epitaxially aligned MoS2/Au{111} as a model system, we demonstrate the use of advanced scanning transmission electron microscopy (STEM) combined with a geometric convolution technique in imaging the crystallographic 32 A moir\'e pattern at the 2D/3D interface. This moir\'e period is often hidden in conventional electron microscopy, where the Au structure is seen in projection. We show, via ab initio electronic structure calculations, that charge density is modulated according to the moir\'e period, illustrating the potential for (opto-)electronic moir\'e engineering at the 2D/3D interface. Our work presents a general pathway to directly image periodic modulation at interfaces using this combination of emerging microscopy techniques., Comment: 14 pages and 5 figures

This work presents a modular, light-weight head-borne neuromodulation platform that achieves low-power wireless neuromodulation and allows real-time programmability of the stimulation parameters such as the frequency, duty cycle, and intensity. This platform is comprised of two parts: the main device and the optional intensity module. The main device is functional independently, however, the intensity control module can be introduced on demand. The stimulation is achieved through the use of energy-efficient μLEDs directly integrated in the custom-drawn fiber-based probes. Our platform can control up to 4 devices simultaneously and each device can control multiple LEDs in a given subject. Our hardware uses off-the-shelf components and has a plug and play structure, which allows for fast turn-over time and eliminates the need for complex surgeries. The rechargeable, battery-powered wireless platform uses Bluetooth Low Energy (BLE) and is capable of providing stable power and communication regardless of orientation. This presents a potential advantage over the battery-free, fully implantable systems that rely on wireless power transfer, which is typically direction-dependent, requires sophisticated implantation surgeries, and demands complex custom-built experimental apparatuses. Although the battery life is limited to several hours, this is sufficient to complete the majority of behavioral neuroscience experiments. Our platform consumes an average power of 0.5 mW, has a battery life of 12 hours., National Institute of Neurological Disorders and Stroke (Grant 5R01NS086804)

Machine learning is a valuable tool in the development of chemical technologies but its applications into supramolecular chemistry have been limited. Here, the utility of kernel-based support vector machine learning using density functional theory calculations as training data is evaluated when used to predict equilibrium binding coefficients of small molecules with cucurbit[7]uril (CB[7]). We find that utilising SVMs may confer some predictive ability. This algorithm was then used to predict the binding of drugs TAK-580 and selumetinib. The algorithm did predict strong binding for TAK-580 and poor binding for selumetinib, and these results were experimentally validated. It was discovered that the larger homologue cucurbit[8]uril (CB[8]) is partial to selumetinib, suggesting an opportunity for tunable release by introducing different concentrations of CB[7] or CB[8] into a hydrogel depot. We qualitatively demonstrated that these drugs may have utility in combination against gliomas. Finally, mass transfer simulations show CB[7] can independently tune the release of TAK-580 without affecting selumetinib. This work gives specific evidence that a machine learning approach to recognition of small molecules by macrocycles has merit and reinforces the view that machine learning may prove valuable in the development of drug delivery systems and supramolecular chemistry more broadly.

Magnetic nanomaterials in magnetic fields can serve as versatile transducers for remote interrogation of cell functions. In this study, we leveraged the transition from vortex to in-plane magnetization in iron oxide nanodiscs to modulate the activity of mechanosensory cells. When a vortex configuration of spins is present in magnetic nanomaterials, it enables rapid control over their magnetization direction and magnitude. The vortex configuration manifests in near zero net magnetic moment in the absence of a magnetic field, affording greater colloidal stability of magnetic nanomaterials in suspensions. Together, these properties invite the application of magnetic vortex particles as transducers of externally applied minimally invasive magnetic stimuli in biological systems. Using magnetic modeling and electron holography, we predict and experimentally demonstrate magnetic vortex states in an array of colloidally synthesized magnetite nanodiscs 98–226 nm in diameter. The magnetic nanodiscs applied as transducers of torque for remote control of mechanosensory neurons demonstrated the ability to trigger Ca(2+) influx in weak (≤28 mT), slowly varying (≤5 Hz) magnetic fields. The extent of cellular response was determined by the magnetic nanodisc volume and magnetic field conditions. Magnetomechanical activation of a mechanosensitive cation channel TRPV4 (transient receptor potential vanilloid family member 4) exogenously expressed in the non-mechanosensitive HEK293 cells corroborated that the stimulation is mediated by mechanosensitive ion channels. With their large magnetic torques and colloidal stability, magnetic vortex particles may facilitate basic studies of mechanoreception and its applications to control electroactive cells with remote magnetic stimuli.

The development of new tools to interface with the nervous system, empowered by advances in electronics and materials science, has transformed neuroscience and is informing therapies for neurological and mental conditions. Although the vast majority of neural engineering research has focused on advancing tools to study the brain, understanding the peripheral nervous system and other organs can similarly benefit from these technologies. To realize this vision, the neural interface technologies need to address the biophysical, mechanical, and chemical challenges posed by the peripheral nerves and organs. In this Perspective, we discuss design considerations and recent technological advances to modulate electrical signaling outside the central nervous system. The innovations in bioelectronics borne out of interdisciplinary collaborations between biologists and physical scientists may not only advance fundamental study of peripheral (neuro)physiology but also empower clinical interventions for conditions including neurological, gastrointestinal, and immune dysfunction.

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 non-invasive 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 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 signalling in the nervous system.

Summary Paragraph/AbstractAnimals innately prefer caloric sugars over non-caloric sweeteners. Such preference depends on the sugar entering the intestine.1–4 Although the brain is aware of the stimulus within seconds,5–8 how the gut discerns the caloric sugar to guide choice is unknown. Recently, we discovered an intestinal transducer, known as the neuropod cell.9,10 This cell synapses with the vagus to inform the brain about glucose in the gut in milliseconds.10 Here, we demonstrate that neuropod cells distinguish a caloric sugar from a non-caloric sweetener using the electrogenic sodium glucose co-transporter 1 (SGLT1) or sweet taste receptors. Activation of neuropod cells by non-caloric sucralose leads to ATP release, whereas the entry of caloric sucrose via SGLT1 stimulates glutamate release. To interrogate the contribution of the neuropod cell to sugar preference, we developed a method to record animal preferences in real time while using optogenetics to silence or excite neuropod cells. We discovered that silencing these cells, or blocking their glutamatergic signaling, renders the animals unable to recognize the caloric sugar. And, exciting neuropod cells leads the animal to consume the non-caloric sweetener as if it were caloric. By transducing the precise identity of the stimuli entering the gut, neuropod cells guide an animal’s internal preference toward the caloric sugar.

In the presence of interactions, electrons in condensed-matter systems can behave hydrodynamically, exhibiting phenomena associated with classical fluids, such as vortices and Poiseuille flow. In most conductors, electron-electron interactions are minimized by screening effects, hindering the search for hydrodynamic materials; however, recently, a class of semimetals has been reported to exhibit prominent interactions. Here we study the current flow in the layered semimetal tungsten ditelluride by imaging the local magnetic field using a nitrogen-vacancy defect in a diamond. We image the spatial current profile within three-dimensional tungsten ditelluride and find that it exhibits non-uniform current density, indicating hydrodynamic flow. Our temperature-resolve current profile measurements reveal a non-monotonic temperature dependence, with the strongest hydrodynamic effects at approximately 20 K. We also report ab initio calculations showing that electron-electron interactions are not explained by the Coulomb interaction alone, but are predominantly mediated by phonons. This provides a promising avenue in the search for hydrodynamic flow and prominent electron interactions in high-carrier-density materials., Comment: 11 pages, 4 figures + supplementary material

Memories are believed to be encoded by sparse ensembles of neurons in the brain. However, it remains unclear whether there is functional heterogeneity within individual memory engrams, i.e., if separate neuronal subpopulations encode distinct aspects of the memory and drive memory expression differently. Here, we show that contextual fear memory engrams in the mouse dentate gyrus contain functionally distinct neuronal ensembles, genetically defined by the Fos- or Npas4-dependent transcriptional pathways. The Fos-dependent ensemble promotes memory generalization and receives enhanced excitatory synaptic inputs from the medial entorhinal cortex, which we find itself also mediates generalization. The Npas4-dependent ensemble promotes memory discrimination and receives enhanced inhibitory drive from local cholecystokinin-expressing interneurons, the activity of which is required for discrimination. Our study provides causal evidence for functional heterogeneity within the memory engram and reveals synaptic and circuit mechanisms used by each ensemble to regulate the memory discrimination-generalization balance.

Electrical intraspinal microstimulation (ISMS) at various sites along the cervical spinal cord permits forelimb muscle activation, elicits complex limb movements and may enhance functional recovery after spinal cord injury. Here, we explore optogenetic spinal stimulation (OSS) as a less invasive and cell type-specific alternative to ISMS. To map forelimb muscle activation by OSS in rats, adeno-associated viruses (AAV) carrying the blue-light sensitive ion channels channelrhodopsin-2 (ChR2) and Chronos were injected into the cervical spinal cord at different depths and volumes. Following an AAV incubation period of several weeks, OSS-induced forelimb muscle activation and movements were assessed at 16 sites along the dorsal surface of the cervical spinal cord. Three distinct movement types were observed. We find that AAV injection volume and depth can be titrated to achieve OSS-based activation of several movements. Optical stimulation of the spinal cord is thus a promising method for dissecting the function of spinal circuitry and targeting therapies following injury. NEW & NOTEWORTHY Optogenetics in the spinal cord can be used both for therapeutic treatments and to uncover basic mechanisms of spinal cord physiology. For the first time, we describe the methodology and outcomes of optogenetic surface stimulation of the rat spinal cord. Specifically, we describe the evoked responses of forelimbs and address the effects of different adeno-associated virus injection paradigms. Additionally, we are the first to report on the limitations of light penetration through the rat spinal cord.

Multifunctional devices for modulation and probing of neuronal activity during free behavior facilitate studies of functions and pathologies of the nervous system. Probes composed of stiff materials, such as metals and semiconductors, exhibit elastic and chemical mismatch with the neural tissue, which is hypothesized to contribute to sustained tissue damage and gliosis. Dense glial scars have been found to encapsulate implanted devices, corrode their surfaces, and often yield poor recording quality in long-term experiments. Motivated by the hypothesis that reducing the mechanical stiffness of implanted probes may improve their long-term reliability, a variety of probes based on soft materials have been developed. In addition to enabling electrical neural recording, these probes have been engineered to take advantage of genetic tools for optical neuromodulation. With the emergence of optogenetics, it became possible to optically excite or inhibit genetically identifiable cell types via expression of light-sensitive opsins. Optogenetics experiments often demand implantable multifunctional devices to optically stimulate, deliver viral vectors and drugs, and simultaneously record electrophysiological signals from the specified cells within the nervous system. Recent advances in microcontact printing and microfabrication techniques have equipped flexible probes with microscale light-emitting diodes (μLEDs), waveguides, and microfluidic channels. Complementary to these approaches, fiber drawing has emerged as a scalable route to integration of multiple functional features within miniature and flexible neural probes. The thermal drawing process relies on the fabrication of macroscale models containing the materials of interest, which are then drawn into microstructured fibers with predefined cross-sectional geometries. We have recently applied this approach to produce fibers integrating conductive electrodes for extracellular recording of single- and multineuron potentials, low-loss optical waveguides for optogenetic neuromodulation, and microfluidic channels for drug and viral vector delivery. These devices allowed dynamic investigation of the time course of opsin expression across multiple brain regions and enabled pairing of optical stimulation with local pharmacological intervention in behaving animals. Neural probes designed to interface with the spinal cord, a viscoelastic tissue undergoing repeated strain during normal movement, rely on the integration of soft and flexible materials to avoid injury and device failure. Employing soft substrates, such as parylene C and poly-(dimethylsiloxane), for electrode and μLED arrays permitted stimulation and recording of neural activity on the surface of the spinal cord. Similarly, thermally drawn flexible and stretchable optoelectronic fibers that resemble the fibrous structure of the spinal cord were implanted without any significant inflammatory reaction in the vicinity of the probes. These fibers enabled simultaneous recording and optogenetic stimulation of neural activity in the spinal cord. In this Account, we review the applications of multifunctional fibers and other integrated devices for optoelectronic probing of neural circuits and discuss engineering directions that may facilitate future studies of nerve repair and accelerate the development of bioelectronic medical devices.