Impact of mechanical microenvironment on neural connectivity
Abstract
In many disease systems, notably cancer and wound-healing, researchers and pharmaceutical companies have observed that the propertie,s of the physical microenvironment around the diseased tissue plays a key role in effectively delivering treatment. Moreover, in som,e cases, treatments are targeted at this surrounding tissue instead of the primary injury. For example, the application of electric,shocks post-orthopedic surgery has been shown to accelerate healing, and changes in the mechanical environment of the pancreas can i,ncrease chemotherapeutic delivery. In contrast, the primary physical change that neuroscientists have focused on is electrical stimu,lation. As a result, the effect of mechanical gradients or of changes in pressure on neural activity has been under-investigated. On,e challenge is related to the limited methods for applying mechanical forces and simultaneously measuring physiological responses.Ne,ural microtissues or minibrains replicate the essential characteristics of the in vivo brain that are required to study the complex,states of injury and disease. Of particular importance are the inclusion of the heterogeneous cell populations of the brain, and the, essential neural electrical functional activity and connectivity. In past work, the Co-PIs team have reported that 3D self-assembl,ed neural microtissues composed of primary postnatal rat cortical cells have a brain-like tissue stiffness, mature neuronal electrop,hysiology, and contain multiple neural cell types. Additionally, by perfusing therapeutics or other chemicals (oxygen, glucose) thro,ugh the microtissue, the co-PIs team was able to modify the neural network connectivity. Notably, all of the software and analytica,l tools required to quantitate connectivity from confocal imaging data has been established. This combination of prior work and prel,iminary data sets the stage for the present effort modulating not only the chemical but also the mechanical microenvironment around,the microtissue.To quantitatively modify the mechanical environment while simultaneously monitoring for change in electrical activit,y requires the development of a new instrument that does not interfere with imaging or the microtissue physiology. Over the past yea,r, the PIs team has developed a technique for dynamically tuning the mechanical stiffness around an organoid. The system combines a, magnetically-actuatable hydrogel (magnetogel) with an electromagnet sample holder. Although it is currently optimized for use with,cancer spheroids, one of the goals of the present effort is to modify and validate the system for use with neural microtissues. To f,urther push the capabilities of the system, they have developed a new imaging agent that localizes in the cell membrane. This two-ph,oton imaging probe is able to both modulate and report the electrical activity of the neuron. In preliminary measurements using neur,al microtissues as a collaborative effort, the imaging molecule has shown promising results.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 13, 2022
- Source ID
- N000142212466
Entities
People
- Andrea Armani
Organizations
- Office of Naval Research
- United States Navy
- University of Southern California