Polina Anikeeva - US grants

1253890
Anikeeva

Intellectual Merit

This CAREER proposal aims to bridge the gap between advanced optoelectronic
materials design and invasive and outdated devices used to treat neurological
disorders. By developing flexible, biocompatible polymer-based optoelectronic scaffolds
(OPTELS) a strategy for incorporating individual optically sensitive neurons into neural
recording and stimulation devices will be created. These trapped neurons will be
investigated as relays of optical stimulation or inhibition to intact neural networks, which
will potentially enable future clinical applications of optogenetics, a powerful optical
neural stimulation tool, without genetic modification of the patient. Specifically the
project will be focused on the following objectives: (1) Developing fiber-inspired
fabrication methods for hollow-core polymer-based OPTELS and employing them to
isolate key materials parameters (surface geometry, charge, flexibility) contributing to
survival and growth of electronically active neurons; (2) Using OPTELS to investigate
and control neuronal growth with the goal of axonal guidance along the OPTELS core.
The proposed study will explore chemical, optoelectronic and mechanical stimuli and
employ OPTELS ability to record and stimulate neural activity to determine factors
contributing to axonal growth; (3) Employing neurons trapped in OPTELS cores as relay
devices of optical neural interrogation. Genetic modification will be applied to the
neurons trapped within the OPTELS cores to enable expression of light-sensitive ion
channels - opsins. The controlled formation of synapses between these relay neurons
and the outside networks will be applied to the investigation of optogenetic interrogation
of the network without directly genetically modifying it.

Broader Impact

The proposed project will explore materials interfaces between optoelectronic devices
and neural tissues providing a pathway towards intimate physiological neuroprosthetic
devices for treatment of debilitating neurological conditions such as Parkinson's disease
or spinal cord injury. The educational and outreach components of the project are
designed to enhance materials engineering and optoelectronics education at MIT and at
inner city community colleges through classroom training and hands-on laboratory
internships. Specifically the outreach program aims to increase awareness about the
impact of engineering in medicine among community college students and teachers
through the seminar series "Medical Electronics and Optics: Life-saving Engineering",
and 10-week research and education summer internships in the PIs laboratory. In
addition new lecture material and device-design based assignments will be developed
for the core undergraduate course on optical and electronic materials and a graduate
photonics course will be adapted to senior undergraduates with the goal of advancing
optoelectronics knowledge among the students. The educational materials will be made
available to worldwide community of learners through an open MIT web-based
resource.

? DESCRIPTION (provided by applicant): The development of the high-resolution cell-specific map of the neural activity associated with a particular behavior presents one of the major challenges in modern neuroscience. This dynamic electrophysiological mapping is particularly difficult in behaviors with a strong temporal variability, such as learning or memory. It is furthr aggravated by the limited long-term stability of the existing high-density electrophysiological platforms and the inability to uniquely identify cell types during recording. This project strivesto develop novel multi-functional fiber-inspired neural probes (FINPs) for long- term simultaneous neural recording and optogenetic and pharmacological cell-type identification. Specifically, we will combine soft polymer-based materials with a fiber-inspired fabrication process to create a platform that seamlessly integrates hundreds of micrometer-size electrodes, waveguides and drug delivery channels, while minimizing the potential tissue response to chronic implantation. We will characterize our structures with respect to their tissue compatibility and long-term functionality in chronic experiments in collaboration with Dr. William Shain in Seattle Children's Research Institute (SCRI), who will share his knowledge of histological methods and image analysis. Furthermore, the utility of the proposed FINPs will be evaluated in a basic neuroscience study relevant to learning. FINPs will be used to measure the changes in activity (mPFC) neurons that project to the basolateral amygdala (BLA) as a previously learned fear response is extinguished. The combined behavioral and electrophysiological experiments will be performed in close collaboration with Dr. Alla Karpova at the Janelia Farm Research Campus (JFRC), who will contribute her expertise in mPFC physiology and cell identification techniques.

Abstract This project seeks to develop a wireless, minimally invasive bi-directional deep brain stimulation technology based on remote heating of magnetic nanoparticles. Reliably modulating the activity of specific neuronal populations is essential to establishing causal links between neural firing patterns and observed behaviors. Electrical stimulation, as well as its recent non-invasive alternatives, ultrasound and electromagnetic induction, do not discriminate between cell types and have limited spatial resolution. Genetic approaches such as DREADDs and optogenetics enable neural excitation and inhibition with exquisite precision in specific cell populations. However, they require long-term indwelling hardware (limiting clinical translation) or lack temporal resolution. In this project, we propose to evaluate a nanoparticle-based technology that can access the deep brain regions, excite and inhibit neurons, and be fully wireless after initial injection. The Anikeeva (MIT) and Pralle (SUNY Buffalo) groups have recently shown that heat dissipation by magnetic nanoparticles (MNPs) in alternating magnetic fields (AMFs) can trigger heat-sensitive capsaicin receptor TRPV1 and heat-sensitive chloride channel anoctamine 1 (ANO1), respectively. These, in turn, can depolarize or silence neurons, and we have preliminary evidence for effects both in vitro and in vivo. Finally, the Anikeeva group has made advances in nanomaterials chemistry that enables multiplexing: independent heating of multiple MNP types (implying control of multiple neighboring neural populations) using AMF with distinct amplitudes and frequencies. Our objective is to combine these technologies into a magnetothermal toolbox and demonstrate its ability to shape animal behavior, by manipulating a well-characterized midbrain reward circuit. We will refine the ANO1 inhibitory technology and demonstrate control of place aversion in mice (Aim 1), then merge this technology with TRPV1-facilitated excitation in context of magnetic multiplexing to show bi-directional control of place aversion/preference (Aim 2). From this proof of concept, Aim 3 seeks to demonstrate that the toolkit can also control a more complex behavior (gambling/ probabilistic reward learning) in a larger species (rat). We will carry out this project through a tightly integrated combination of expertise in nanoscale engineering (Anikeeva, Pralle), targeted neural modulation (Anikeeva, Pralle), behavior manipulation through midbrain modulation (Widge) and clinical psychiatric deep brain stimulation (Widge).

Mission. This multidisciplinary symposium intends to bring together experts from academia and medical devices industry working on electronic, chemical, biological and mechanical aspects of the interaction between the synthetic devices and neural tissues. Invited talks showcasing applications of specific materials properties to neuronal monitoring and ?functional devices. As materials design for neural interfaces manipulation will promote the discussion between the members of the community inspiring the future development of multi-- is closely coupled to areas of bioengineering as well as developing treatments for neurological disorders, we believe that this symposium addresses the scientific mission of both the NIBIB and NINDS. Synopsis. Mammalian nervous system contains billions neurons and glia connected into intricate networks through a variety of chemical, electrical, and mechanical signals. Disruptions to inter-cellular and inter-regional communication within the nervous system often lead to debilitating neurological and psychiatric conditions such as Parkinson's disease or major depression. To understand the complexity of neural signaling and develop therapeutic approaches to the diseases of the nervous system, neural interface devices have been under investigation for the past 30 years. Neural tissues, however, possess low elastic moduli that are in stark contrast with traditional wafer-built electronics. This mismatch often leads to foreign body response following implantation. It has been recently recognized that the design of an interface between the brain and a synthetic sensor is a materials science problem. The Symposium BM8: Materials Design for Neural Interfaces will discuss the recent progress in development of flexible and organic electronics, and bio- and nanomaterials aimed at creating multifunctional and minimally invasive probes. The symposium will also highlight the advances in materials chemistry that have enabled novel imaging approaches such as tissue clearing techniques and synthetic activity indicators allowing not only to probe the dynamics but understand the structure of neural pathways. The result of our symposium will be a roadmap of future materials-driven neural interface research.

Abstract Scalable approaches to modulate neural activity during complex behaviors are essential to basic study of normal and aberrant brain function. Here we aim to develop a wireless magnetomechanical neuromodulation technique suitable for remote excitation of genetically identifiable neuronal populations. This approach will rely on the ability of anisotropic synthetic magnetic nanodiscs to transduce torques to cell membranes in weak slow-varying magnetic fields. Our preliminary findings indicate that weak magnetomechanical torques robustly induce activity in sensory mechanoreceptive neurons. These observations will be extended first to magnetomechanical neuromodulation of genetically specified brain neurons targeted with nanodiscs via SNAP-tag or nanobody- based strategies. Our approach will further be refined by sensitizing specific neurons to mechanical stimuli via expression of a mechanosensitive cation channel TRPV4 (transient receptor potential vanilloid family member 4). Unlike magnetothermal techniques that rely on heat dissipated by isotropic magnetic nanoparticles in high- frequency alternating magnetic fields, magnetomechanical approach can be implemented with off-the-shelf low- power electronics and is readily scalable to volumes necessary to conduct behavioral assays in rodents and neuromodulation experiments in larger models including future studies in humans. We will evaluate our proposed targeted magnetomechanical neuromodulation approach by investigating its ability to shape dopamine- dependent behaviors in a mouse model of reward and motivation processing.

Abstract The information flow between the peripheral organs and the brain is increasingly recognized as bidirectional, with activity in peripheral circuits influencing high-level behaviors including mood, motivation, and stress. To establish mechanistic links between activity of peripheral neurons and brain circuits, we will develop a species- agnostic framework for targeting and remote modulation of specific cells within the peripheral organs and the brain during behavior. Our framework will combine the homing, modulation, and contrast properties of synthetic magnetic nanomaterials with the targeting specificity of viral vectors. Magnetic nanomaterials have recently emerged as versatile transducers of remotely applied weak magnetic fields into thermal, chemical, or mechanical stimuli perceived by ion channels. We will dramatically expand the palette of magnetic nanotransducers to enable receptor-specific remote magnetic modulation of neurons (or other electrogenic cells) anywhere in the body during free behavior. Moreover, we will leverage recent advances in adeno-associated viral vectors for targeting specific cells and tissues by creating an array of fusions of nanotransducers and viral capsids. This will allow for magnetic guidance and localization of the hybrid magnetic- viral fusions to the locations of interest following systemic delivery regardless of the model organism. We will apply our framework to elucidate circuits connecting the enteric (gut) nervous system to the midbrain structures. Recent work has drawn links between gastrointestinal dysfunction and social and mood disorders as well as demonstrated vagal transmission of the enteric signals to the brain. By applying receptor-specific modulation to the enteric neurons we intend to test the hypothesis that their activity influences midbrain pathways governing reward and motivation, and possibly motor behaviors. In addition to empowering studies of gut-brain circuits, our species-agnostic framework can be extended to investigate connections between any peripheral organ and the brain thus opening opportunities to develop peripheral organ interventions for neurological and mental conditions.