Optimizing a Rodent Model of Parkinson's Disease for Exploring the Effects and Mechanisms of Deep Brain Stimulation

Deep brain stimulation (DBS) has become a treatment for a growing number of neurological and psychiatric disorders, especially for therapy-refractory Parkinson's disease (PD). However, not all of the symptoms of PD are sufficiently improved in all patients, and side effects may occur. Further progress depends on a deeper insight into the mechanisms of action of DBS in the context of disturbed brain circuits. For this, optimized animal models have to be developed. We review not only charge transfer mechanisms at the electrode/tissue interface and strategies to increase the stimulation's energy-efficiency but also the electrochemical, electrophysiological, biochemical and functional effects of DBS. We introduce a hemi-Parkinsonian rat model for long-term experiments with chronically instrumented rats carrying a backpack stimulator and implanted platinum/iridium electrodes. This model is suitable for (1) elucidating the electrochemical processes at the electrode/tissue interface, (2) analyzing the molecular, cellular and behavioral stimulation effects, (3) testing new target regions for DBS, (4) screening for potential neuroprotective DBS effects, and (5) improving the efficacy and safety of the method. An outlook is given on further developments of experimental DBS, including the use of transgenic animals and the testing of closed-loop systems for the direct on-demand application of electric stimulation

A comparative analysis of detachment forces and energies in initial and mature cell-material interaction

Single cell force spectroscopy (SCFS) enables data on interaction forces to be acquired during the very early adhesion phase. However, SCFS detachment forces and energies have not been compared so far with the forces and energies after maturation of the cell-material contact on a single cell level and with comparable time resolution. We used FluidFM (R) to physically attach single cells to the cantilever by aspiration through a microfluidic channel, in order to achieve the higher forces required for detaching maturely adhering cells. Combining these two approaches allowed us to compare cell adhesion in the initial and maturation phases of adhesion for two exemplary cell-substrate combinations - L929 fibroblasts on fibronectin and MC3T3 osteoblasts on collagen type I. Uncoated glass substrates were used as a reference. For both cell lines, SCFS measurements after contact times of 5, 15 and 30 s revealed significantly higher maximum detachment forces (MDFs) and energies on glass compared to the protein-coated surfaces in the 0.5-4 nN (1-40 fJ) range. FluidFM (R) measurements after 1, 2 and 3 days of culture revealed a significant absolute increase in the MDFs and detachment energies for both cell lines on protein-coated substrates to values of about 600 nN and 10 pJ. On glass, the MDFs were similar for MC3T3 cells, while they were significantly lower for L929 cells. For both cell types, the differences in detachment energy were significant. These differences underline the importance of investigating early and mature adhesion states to obtain a holistic assessment of the cell-material interactions.The authors are grateful to the DFG (German Research Council) graduate school GRK1505/2 "Welisa" and grant number BA 2479/2-1 for funding the position of P. Wysotzki, as well as the consumables for the experiments. We also acknowledge the ERC (European Research Council), Grant Number 617989 for the financial support given. We are grateful to Dr. W. Baumann (Department of Biophysics, Univ. of Rostock) for helpful discussions

The influence of topographic microstructures on the initial adhesion of L929 fibroblasts studied by single-cell force spectroscopy

Single-cell force spectroscopy was used to investigate the initial adhesion of L929 fibroblasts onto periodically grooved titanium microstructures (height ~6 μm, groove width 20 μm). The position-dependent local adhesion strength of the cells was correlated with their rheological behavior. Spherical cells exhibited a significantly lower Young’s modulus (<1 kPa) than that reported for spread cells, and their elastic properties can roughly be explained by the Hertz model for an elastic sphere. While in contact with the planar regions of the substrate, the cells started to adapt their shape through slight ventral flattening. The process was found to be independent of the applied contact force for values between 100 and 1,000 pN. The degree of flattening correlated with the adhesion strength during the first 60 s. Adhesion strength can be described by fast exponential kinetics as \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$C_{1} \left[ {1 - \exp \left( { - C_{2} \cdot t} \right)} \right]$$\end{document} with C1 = 2.34 ± 0.19 nN and C2 = 0.09 ± 0.02 s−1. A significant drop in the adhesion strength of up to 50% was found near the groove edges. The effect can be interpreted by the geometric decrease of the contact area, which indicates the inability of the fibroblasts to adapt to the shape of the substrate. Our results explain the role of the substrate’s topography in contact guidance and suggest that rheological cell properties must be considered in cell adhesion modeling

Nanomaterials for Neural Interfaces

This review focuses on the application of nanomaterials for neural interfacing. The junction between nanotechnology and neural tissues can be particularly worthy of scientific attention for several reasons: (i) Neural cells are electroactive, and the electronic properties of nanostructures can be tailored to match the charge transport requirements of electrical cellular interfacing. (ii) The unique mechanical and chemical properties of nanomaterials are critical for integration with neural tissue as long-term implants. (iii) Solutions to many critical problems in neural biology/medicine are limited by the availability of specialized materials. (iv) Neuronal stimulation is needed for a variety of common and severe health problems. This confluence of need, accumulated expertise, and potential impact on the well-being of people suggests the potential of nanomaterials to revolutionize the field of neural interfacing. In this review, we begin with foundational topics, such as the current status of neural electrode (NE) technology, the key challenges facing the practical utilization of NEs, and the potential advantages of nanostructures as components of chronic implants. After that the detailed account of toxicology and biocompatibility of nanomaterials in respect to neural tissues is given. Next, we cover a variety of specific applications of nanoengineered devices, including drug delivery, imaging, topographic patterning, electrode design, nanoscale transistors for high-resolution neural interfacing, and photoactivated interfaces. We also critically evaluate the specific properties of particular nanomaterials—including nanoparticles, nanowires, and carbon nanotubes—that can be taken advantage of in neuroprosthetic devices. The most promising future areas of research and practical device engineering are discussed as a conclusion to the review.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/64336/1/3970_ftp.pd

Contributions to a Discussion of Spinosaurus aegyptiacus as a Capable Swimmer and Deep-Water Predator

The new findings on Spinosaurus’ swim tail strongly suggest that Spinosaurus was a specialized deep-water predator. However, the tail must be seen in the context of the propelled body. The comparison of the flow characteristics of Spinosaurus with geometrically similar animals and their swimming abilities under water must take their Reynolds numbers into account and provide a common context for the properties of Spinosaurus’ tail and dorsal sail. Head shape adaptations such as the head crest reduced hydrodynamic disturbance and facilitated stealthy advance, especially when hunting without visual contact, when Spinosaurus could have used its rostral integumentary mechanoreceptors for prey detection. The muscular neck permitted ‘pivot’ feeding, where the prey’s escape abilities were overcome by rapid dorsoventral head movement, facilitated by crest-mediated lower friction

The riddle of Spinosaurus aegyptiacus’ dorsal sail

Spinosaurus aegyptiacus was probably the largest predatory dinosaur of the Cretaceous period. A new study shows that it was a semiaquatic hunter. The function of Spinosaurus’ huge dorsal ‘sail’ remains unsolved, however. Three hypotheses have been proposed: (1) thermoregulation; (2) humpback storage; or (3) display. According to our alternative hypothesis, the submerged sail would have improved manoeuvrability and provided the hydrodynamic fulcrum for powerful neck and tail movements such as those made by sailfish or thresher sharks when stunning or injuring prey. Finally, it could have been employed as a screen for encircling prey underwater

Dielectrophoresis from the System’s Point of View: A Tale of Inhomogeneous Object Polarization, Mirror Charges, High Repelling and Snap-to-Surface Forces and Complex Trajectories Featuring Bifurcation Points and Watersheds

Microscopic objects change the apparent permittivity and conductivity of aqueous systems and thus their overall polarizability. In inhomogeneous fields, dielectrophoresis (DEP) increases the overall polarizability of the system by moving more highly polarizable objects or media to locations with a higher field. The DEP force is usually calculated from the object’s point of view using the interaction of the object’s induced dipole or multipole moments with the inducing field. Recently, we were able to derive the DEP force from the work required to charge suspension volumes with a single object moving in an inhomogeneous field. The capacitance of the volumes was described using Maxwell–Wagner’s mixing equation. Here, we generalize this system’s-point-of-view approach describing the overall polarizability of the whole DEP system as a function of the position of the object with a numerical “conductance field”. As an example, we consider high- and low conductive 200 µm 2D spheres in a square 1 × 1 mm chamber with plain-versus-pointed electrode configuration. For given starting points, the trajectories of the sphere and the corresponding DEP forces were calculated from the conductance gradients. The model describes watersheds; saddle points; attractive and repulsive forces in front of the pointed electrode, increased by factors &gt;600 compared to forces in the chamber volume where the classical dipole approach remains applicable; and DEP motions with and against the field gradient under “positive DEP” conditions. We believe that our approach can explain experimental findings such as the accumulation of viruses and proteins, where the dipole approach cannot account for sufficiently high holding forces to defeat Brownian motion

Resting microglial cells exhibit tubular membrane protrusions

Nano- and microtubular structures have recently become a subject of increasing interest due to their importance in biology and medicine as well as their technological potential. Such structures have been observed in anorganic (Iijima, 1991) as well as in organic (Schnur 1993; Oda et al. 1991) systems. Micro- and nanotubular protrusions of bilayer membranes have been found in cells (Kralj-Iglic et al. 1998; Kralj-Iglic et al. 2001a) and phospholipid vesicles (Kralj-Iglic et al. 2002; Kralj-Iglic et al. 2001b). In this work we describe membrane protrusions in microglial cells