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A crucial aspect of neural engineering is the ability to manipulate proteins that are substantially involved in axonal outgrowth and maintenance. Previous work in this field has shown that applying low-magnitude (piconewton) forces to early stage neurons can result in altered distributions of critical structural proteins, such as the microtubule-associated protein Tau. Uncovering the mechanisms of Tau redistribution could provide a tool for manipulating dysregulated forms of the protein. This study examined how the transport of Tau responded to intra-axonal nanomagnetic forces (NMFs) in primary cortical and hippocampal neurons. High magnification, live cell fluorescent imaging was employed to visualize the transport of both full-length human Tau (hTau40) and amine-terminated, starch-coated fluorescent magnetic nanoparticles (afMNPs) to observe how these cell-internal forces could impact the transport of hTau40 within the axon. Here, we found that afMNPs acted by pulling on hTau40 puncta under NMF application, especially within cortical cells, where afMNPs were more likely to be found within the axon. Forces greater than 1 pN enabled differentiated transport speeds and displacement of hTau40 based on relative force direction. This data indicates that NMF can be utilized to engineer hTau40 transport, even in cells at later stages of maturation. 

Neurons differentiate mechanical stimuli force and rate to elicit unique functional responses, driving the need for further tools to generate various mechanical stimuli. Here, cell-internal nanomagnetic forces (iNMF) are introduced by manipulating internalized magnetic nanoparticles with an external magnetic field across cortical neuron networks in vitro. Under iNMF, cortical neurons exhibit calcium (Ca2+) influx, leading to modulation of activity observed through Ca2+ event rates. Inhibiting particle uptake or altering nanoparticle exposure time reduced the neuronal response to nanomagnetic forces, exposing the requirement of nanoparticle uptake to induce the Ca2+ response. In highly active cortical networks, iNMF robustly modulates synchronous network activity, which is lasting and repeatable. Using pharmacological blockers, it is shown that iNMF activates mechanosensitive ion channels to induce the Ca2+ influx. Then, in contrast to transient mechanically evoked neuronal activity, iNMF activates Ca2+-activated potassium (KCa) channels to stabilize the neuronal membrane potential and induce network activity shifts. The findings reveal the potential of magnetic nanoparticle-mediated mechanical stimulation to modulate neuronal circuit dynamics, providing insights into the biophysics of neuronal computation. 

Archetypal analysis (AA) is a versatile data analysis method to cluster distinct features within a data set. Here, we demonstrate a framework showing the power of AA to spatio-temporally resolve events in calcium imaging, an imaging modality commonly used in neurobiology and neuroscience to capture neuronal communication patterns. After validation of our AA-based approach on synthetic data sets, we were able to characterize neuronal communication patterns in recorded calcium waves. Clinical relevance– Transient calcium events play an essential role in brain cell communication, growth, and network formation, as well as in neurodegeneration. To reliably interpret calcium events from personalized medicine data, where patterns may differ from patient to patient, appropriate image processing and signal analysis methods need to be developed for optimal network characterization.