Magnetothermal Neuromodulation

Abstract

To understand the phenotypical and aberrant aspects of brain functions, circuital elements within the brain need to be perturbed and the effects correlated. However, the fast dynamics and the complex heterogeneity of neural systems make this challenging. In the past ten years, significant progress has been made in developing genetic tools to target neuron types, for stimulation and observation. Stimulating distinct cell types in the brain, by genetically expressing microbial opsins with guided patterned light has enabled gain and loss of function analyses of neuronal networks. Similarly, genetically expressing designer drug receptor in the cells, have yielded a remote, albeit a much slower methodology for neuronal manipulation. Magnetothermal neuromodulation technique takes inspiration from the need for a remote stimulation technique that can approach the time scales of optical stimulation, without the need for any physical tethers or implants. We used alternating magnetic fields as the signal, as it is minimally attenuated by the tissues. The signal is then transduced by superparamagnetic nanoparticles that undergo magnetic relaxation and lose internal energy as heat. These nanoparticles are delivered to the cell membrane, where they are targeted to the surface proteins. The cells are genetically made thermosensitive by overexpressing membrane ion channels, like TRPV1, Anoctamin1, and TREK1. Under alternating magnetic fields, the plasma membrane of the nanoparticle decorated cells heated, opening the ion channels and activating the cells. Core-shell nanoparticles with two inorganic constituents were used. We developed a model based optimization technique, to tune the composition ratio in nanoparticles, and maximize the heat generation. We characterized the heat transfer from nanoparticles to their microenvironment, and showed the effect of geometry of nanoparticle arrangement. We also characterized hyperthermic properties of biosynthesized nanoparticles. To demonstrate remote Magnetothermal activation in behaving mice, we activated TRPV1 overexpressing neurons to initiate involuntary running, rotation around the body axis and freezing of gait in mice. We then magnetothermally suppressed neuronal activities by overexpressing Potassium efflux channel, TREK-1 or Chloride influx channel TMEM16A. This technique was used to silence dopaminergic neurons of the ventral tegmental area and alter mice’s innate preference for dark over brightly lit spaces. The thesis lays the groundwork for magnetothermal neuromodulation and paves way for combining the same with other stimulation and feedback modalities, to create a unique feedback controlled, chronic, implant free neurostimulation toolkit, for and neuroscience discoveries with the potential for therapeutic use.