Acute and Chronic Neural Stimulation via Mechano-Sensitive Ion Channels

Abstract

Neural stimulation techniques for eliciting calcium influx can elucidate the physiological roles of specific neural populations. To overcome some of the limitations of existing techniques such as poor specificity and noxious effects of heat, I developed a technology for non-invasive control of neural activities using magnetic forces and magnetic nanoparticles (MNPs) which offer deep tissue penetration and controllable dosage. Extensive investigations with different neurotoxins and experimental conditions support that the mechanism of magnetic stimulation that involves membrane-bound MNPs transducing magnetic forces into mechanical stretching of the cell membrane to enhance the opening probability of mechano-sensitive N-type calcium ion channels to induce calcium influx.Making use of the ability of neural networks to actively regulate their ratio of excitatory to inhibitory ion channel/receptor, I also performed chronic magnetic stimulation on fragile X iii syndrome (FXS) model neural networks. We found that chronic magnetic stimulation reduced the density of N-type calcium ion channels whose expression is increased in FXS. This technique demonstrates the potential of using bio-magnetic/mechanical forces to modulate expressions of mechano-sensitive ion channels where they are over-expressed in diseases such as abnormal nociception.Nonetheless, there are still a few areas where the technique can be improved. Firstly, it is the use of MNPs with more uniform properties to have greater control on magnetic stimulations.Secondly, the technique needs to be useful for in vivo studies. Therefore, I started researching on magnetotactic bacteria (MTB) which produce biological MNPs with superior properties such as uniform sizes and highly homogenous magnetic properties with the goal of harvesting MNPs from them.MTB, however, grow extremely slowly and the number of MNPs produced/bacterium is low. One way to overcome this problem is to evolve MTB over-producers of MNPs but this strategy is constrained by the absence of a selection platform that is quantitative and offer high throughput. To overcome this problem, I combined random chemical mutagenesis and selection using a magnetic ratcheting platform to generate and isolate MTB over-producers that produce twice as many MNPs/bacterium after 5 rounds of mutation/selection. I next designed a magnetic microfluidic device and demonstrate as a proof of concept, that it can be coupled to a bioreactor for high throughput microfluidic selection of MTB over-producers.iv

Magnetic nanoparticles in nanomedicine: a review of recent advances

“…The element that contains an odd number of protons and/or neutrons in its nucleus, such as 1 H, 2 H, 13 C, 14 N, 15 N, 17 O, 23 Na, 31 P, etc, exhibits intrinsic magnetic moment (namely, spin), which is the primary origin of the magnetic resonance signal. Single proton hydrogen 1 H is one particularly favorable element for nuclear magnetic resonance (NMR) and MRI applications due to its high intrinsic sensitivity and high abundance in water and lipid molecules.…”

“…Their unique characteristics such as high surface to volume ratio and size-dependent magnetic properties are drastically different from those of their bulk materials. MNPs have been receiving tremendous attention in multiple areas such as data storage, spintronics, catalyst, neural stimulation, and gyroscopic sensors, etc [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]. In this review, the physical properties of MNPs such as saturation magnetization and magnetic anisotropy are given in section 2.1.…”

Non-Heating Alternating Magnetic Field Nanomechanical Stimulation of Biomolecule Structures via Magnetic Nanoparticles as the Basis for Future Low-Toxic Biomedical Applications

“…For example, MNPs activated by ~50 Hz AMF were employed to stimulate ionic channels and stem cell differentiation. This is of great interest in terms of the non-invasive treatment of various neurodegenerative diseases [ 132 , 133 , 134 , 135 ].…”

Nano and Microtechnologies for the Study of Magnetotactic Bacteria

“…[25] Next, by exploiting the balance between frictional drag in fluids and magnetic field gradient in a microchannel, a mixed population of live, wild-type Magnetospirillum magneticum (AMB-1) was separated from mutants producing about 2.2× more magnetosomes with efficacy similar to theoretical estimates. [26] The same platform was also adapted to isolate wild-type Magnetospirillum gryphiswaldense (MSR-1) from its ΔmamAB mutant counterparts, which do not produce magnetosomes, with sensitivity up to 80% and isolation purity up to 95% as confirmed with a gold standard, fluorescent-activated cell sorter (FACS) technique (Figure 2a). [25] The magnetic microfluidic platform also offers 25-fold higher throughput than the one fabricated by Myklatun et al (25000 cells min −1 vs 1000 cells min −1 ).…”

“…This problem was recently overcome by inhibiting rapid flagellar movement with transient cold, alkaline treatments which preserved cell viability . Next, by exploiting the balance between frictional drag in fluids and magnetic field gradient in a microchannel, a mixed population of live, wild‐type Magnetospirillum magneticum (AMB‐1) was separated from mutants producing about 2.2× more magnetosomes with efficacy similar to theoretical estimates . The same platform was also adapted to isolate wild‐type Magnetospirillum gryphiswaldense (MSR‐1) from its Δ mamAB mutant counterparts, which do not produce magnetosomes, with sensitivity up to 80% and isolation purity up to 95% as confirmed with a gold standard, fluorescent‐activated cell sorter (FACS) technique ( Figure a) .…”