Magnetic Modulation on Targeted Neural Circuits in Autism

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Project Summary and Abstract My overall career goal is to establish an independent research program focused on leveraging cutting-edge technologies of materials engineering, genetic manipulation and neurobehavioral science to study neural circuits underlying autism spectrum disorders (ASDs). I hypothesize that a remotely controlled magnetic neuromodulation tool will link precise circuit-level neural modulation to behavioral outcomes, and thus empower neural circuitry interrogation with systems neuroscience. To realize this goal, I have received training in extensive research fields including materials engineering, nanotechnology, cellular neurophysiology, and neuroscience. With this award, in my future career I will open up a new interdisciplinary research pathway of developing remotely controlled magnetic tools that enable pharmacological and gene-editing intervention on specific neural circuits along with the behavioral assessment on freely moving mice and awake, untethered non-human primates (NHPs). In the mentored phase, I will work under the supervision of Professor Polina Anikeeva - an expert in optoelectronic and magnetic neural interfaces, with the guidance of my advisory committee consisting of Professors Guoping Feng, Feng Zhang, Mriganka Sur, and Zhigang He. With their strong supports, I will receive additional training in gene editing, social behavioral test design and experimental experience with autism models of mice and marmosets, which will equip me with the knowledge and skills necessary to further the study of neural underpinnings of ASDs and launch my independent career. The work in mentored phase will be done at the Research Laboratory of Electronics and the McGovern Institute for Brain Research at MIT, which offer an active multidisciplinary research atmosphere, expansive infrastructural resources and a valuable intellectual community necessary for the implementation of the proposed project. During my Simons postdoctoral training at MIT, I established a chemomagnetic technique to pharmacologically modulate identifiable neural populations with behavioral assessment in freely moving mice. Hence, my immediate goal is to advance this technique into a multiplexed toolkit that enables multiple-site bidirectional control of circuit-level neural modulation. In Aim 1, I will improve the chemical synthesis of magnetic nanoparticles (MNPs) and liposomal nanocarriers to enable multiplexing control with paired ligand-receptors under disparate magnetic field conditions and implement the multiple-site neural modulation of brain structures that coordinate social behaviors. Next (Aim 2), I will advance this magnetic technique with gene editing approaches to enable non-viral gene delivery to cell-type specific neural circuits relevant to social processing. In the independent phase (Aim 3), I will validate the magnetic modulation on the targeted neural circuits to ameliorate social behavior deficits in transgenic mice, e.g. Shank3- /-. With the advanced magnetic electronics apparatuses, I will further adapt this technique to social interaction assessment in marmosets and introduce a potential magnetic field-assisted theranostic platform for ASDs.