Customized Imaging System with Spatiotemporally Encoded Electric Field Modulation for Precise Manipulation of Neuronal Differentiation and Neuroplasticity

Project: Research project

Project Details

Description

Cells respond to simple stimuli with complex responses through the biochemical, electrical, and mechanical (BEM) signaling pathways. In our studies supported by the MURI project entitled Understanding and Controlling the Coupled Electrical, Chemical, & Mechanical Excitable Networks of Living Systems, we have investigated how these signaling pathways couple with each other and behave as excitable networks.

Recently we have pinpointed a new coupling mechanism that specific electric field (EF) can electrostatically influence protein interactions at the cell membrane to trigger downstream signaling pathways. This makes it possible to accurately manipulate (hack) specific cell signaling pathways by an external field that can be precisely delivered in time and space. For this DURIP proposal, we seek support for constructing a customized imaging system, to further investigate how this mechanism can be used to precisely modulate signaling pathways that are critical in cell development and differentiation, so that we can control the fate and behavior of cells and cell networks.

Specifically, here we will focus on the nervous system. Coordinated population activities in the brain is critical for information processing, which can be disrupted by injury or maldevelopment, leading to mental disorders. Conventional electric stimulation or pharmacological treatments cannot effectively induce long-term neuroplastic changes required for curing such disorders or for enhancing brain functions. An alternative approach is to enhance endogenous plasticity mechanisms and thus in effect allow the brain to rewire itself. This can be achieved by enhancing pathways that leads to synaptic plasticity, such as the extracellular-signal regulated kinase (ERK) signaling pathway. However, the conventional ways to intervene cell signaling pathways by injecting and washing away chemicals cannot provide fine control of the region, level and timing of ERK activities. Here based on our MURI project, we will explore a new way to modulate the activity of selected neurons populations and drive neuroplastic changes by tuning the ERK signaling pathway with spatiotemporally encoded non-Faradaic EF.

This DURIP seeks to purchase an inverted microscope with Perfect Focus system so that we can build on top of it a customized incubation and measurement system to deliver spatiotemporally encoded EF through integrated microelectrodes, and investigate long-term manipulation of neuron differentiation and neuroplasticity.

This DURIP will enable us: (1) At short time scales, to investigate direct evidence for AC EF modulation of ERK signaling pathways in cultured neuron cells. Specifically, we will track cell membrane deformation at nanometer scale precision in real time based on a new technique mechanically amplified detection of molecular interactions (MADMI). We will also investigate the optimal waveform, frequency, and timing of AC EF signals to effectively modulate the amplitude and frequency of ERK activities in cultured neurons, quantified by immunostaining and western blotting. (2) At long time scales, to investigate guided development of neuron networks and synaptic connections under different ERK modulations by AC EF. Specifically, we will explore how spatiotemporally encoded EF can be used to promote and guide interconnections between selected population of cultured primary neurons. In addition, PC12 cells will be used as another model system for investigating the effect of ERK modulation on cell proliferation and differentiation.

We believe that the techniques and knowledge obtained with the support of DURIP can lead to a new paradigm of controlling biophysical and biochemical processes in cells and find wide biomedical applications such as assisting wound healing, cancer therapy, and stem cell therapy.
StatusActive
Effective start/end date5/15/215/14/22

Funding

  • DOD-USAF-AFRL: Air Force Office of Scientific Research (AFOSR): $184,868.00

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