In situ assembly of an injectable cardiac stimulator.

Without intervention, cardiac arrhythmias pose a risk of fatality. However, timely intervention can be challenging in environments where transporting a large, heavy defibrillator is impractical, or emergency surgery to implant cardiac stimulation devices is not feasible. Here, we introduce an injectable cardiac stimulator, a syringe loaded with a nanoparticle solution comprising a conductive polymer and a monomer that, upon injection, forms a conductive structure around the heart for cardiac stimulation. Following treatment, the electrode is cleared from the body, eliminating the need for surgical extraction. The mixture adheres to the beating heart in vivo without disrupting its normal rhythm. The electrofunctionalized injectable cardiac stimulator demonstrates a tissue-compatible Young's modulus of 21 kPa and a high conductivity of 55 S/cm. The injected electrode facilitates electrocardiogram measurements, regulates heartbeat in vivo, and rectifies arrhythmia. Conductive functionality is maintained for five consecutive days, and no toxicity is observed at the organism, organ, or cellular levels.

In situ assembly of bioresorbable organic bioelectronics in the brain.

Bioelectronics can potentially complement classical therapies in nonchronic treatments, such as immunotherapy and cancer. In addition to functionality, minimally invasive implantation methods and bioresorbable materials are central to nonchronic treatments. The latter avoids the need for surgical removal after disease relief. Self-organizing substrate-free organic electrodes meet these criteria and integrate seamlessly into dynamic biological systems in ways difficult for classical rigid solid-state electronics. Here we place bioresorbable electrodes with a brain-matched shear modulus-made from water-dispersed nanoparticles in the brain-in the targeted area using a capillary thinner than a human hair. Thereafter, we show that an optional auxiliary module grows dendrites from the installed conductive structure to seamlessly embed neurons and modify the electrode's volume properties. We demonstrate that these soft electrodes set off a controlled cellular response in the brain when relaying external stimuli and that the biocompatible materials show no tissue damage after bioresorption. These findings encourage further investigation of temporary organic bioelectronics for nonchronic treatments assembled in vivo.

Alpha-synuclein cell-to-cell transfer and seeding in grafted dopaminergic neurons in vivo.

Several people with Parkinson's disease have been treated with intrastriatal grafts of fetal dopaminergic neurons. Following autopsy, 10-22 years after surgery, some of the grafted neurons contained Lewy bodies similar to those observed in the host brain. Numerous studies have attempted to explain these findings in cell and animal models. In cell culture, α-synuclein has been found to transfer from one cell to another, via mechanisms that include exosomal transport and endocytosis, and in certain cases seed aggregation in the recipient cell. In animal models, transfer of α-synuclein from host brain cells to grafted neurons has been shown, but the reported frequency of the event has been relatively low and little is known about the underlying mechanisms as well as the fate of the transferred α-synuclein. We now demonstrate frequent transfer of α-synuclein from a rat brain engineered to overexpress human α-synuclein to grafted dopaminergic neurons. Further, we show that this model can be used to explore mechanisms underlying cell-to-cell transfer of α-synuclein. Thus, we present evidence both for the involvement of endocytosis in α-synuclein uptake in vivo, and for seeding of aggregation of endogenous α-synuclein in the recipient neuron by the transferred α-synuclein. Finally, we show that, at least in a subset of the studied cells, the transmitted α-synuclein is sensitive to proteinase K. Our new model system could be used to test compounds that inhibit cell-to-cell transfer of α-synuclein and therefore might retard progression of Parkinson neuropathology.

Prominent system of RFamide immunoreactive neurons in the rhopalia of box jellyfish (Cnidaria: Cubozoa).

The four visual sensory structures of a cubomedusa, the rhopalia, display a surprisingly elaborate organization by containing two lens eyes and four bilaterally paired pigment cup eyes. Peptides containing the peptide sequence Arg-Phe-NH2 (RFamide) occur in close association with visual structures of cnidarians, including the rhopalia and rhopalial stalk of cubomedusae, suggesting that RFamide functions as a neuronal marker for certain parts of the visual system of medusae. Using immunofluorescence we give a detailed description of the organization of the RFamide-immunoreactive (ir) nervous system in the rhopalia and rhopalial stalk of the cubomedusae Tripedalia cystophora and Carybdea marsupialis. The bilaterally symmetric RFamide-ir nervous system contains four cell groups and three morphologically different cell types. Neurites spread throughout the rhopalia and occur in close vicinity of the pigment cup eyes and the lower lens eye. Two commissures connect the two sides of the system and neurites of one rhopalial cell group extend into the rhopalial stalk. The RFamide-ir nervous system in the rhopalia of cubomedusae is more widespread and comprises more cells than earlier discerned. We suggest that the system might not only integrate visual input but also signals from other senses. One of the RFamide-ir cell groups is favorably situated to represent pacemaker neurons that set the swimming rhythm of the medusa.

Immunohistochemical evidence for multiple photosystems in box jellyfish.

Cubomedusae (box jellyfish) possess a remarkable visual system with 24 eyes distributed in four sensory structures termed rhopalia. Each rhopalium is equipped with six eyes: two pairs of pigment cup eyes and two unpaired lens eyes. Each eye type probably captures specific features of the visual environment. To investigate whether multiple types of photoreceptor cells are present in the rhopalium, and whether the different eye types possess different types of photoreceptors, we have used immunohistochemistry with a range of vertebrate opsin antibodies to label the photoreceptors, and electroretinograms (ERG) to determine their spectral sensitivity. All photoreceptor cells of the two lens eyes of the box jellyfish Tripedalia cystophora and Carybdea marsupialis displayed immunoreactivity for an antibody directed against the zebrafish ultraviolet (UV) opsin, but not against any of eight other rhodopsin or cone opsin antibodies tested. In neither of the two species were the pigment cup eyes immunoreactive for any of the opsin antibodies. ERG analysis of the Carybdea lower lens eyes demonstrated a single spectral sensitivity maximum at 485 nm suggesting the presence of a single opsin type. Our data demonstrate that the lens eyes of box jellyfish utilize a single opsin and are thus color-blind, and that there is probably a different photopigment in the pigment cup eyes. The results support our hypothesis that the lens eyes and the pigment cup eyes of box jellyfish are involved in different and specific visual tasks.

Bilateral symmetric organization of neural elements in the visual system of a coelenterate, Tripedalia cystophora (Cubozoa).

Cubozoans differ from other cnidarians by their body architecture and nervous system structure. In the medusa stage they possess the most advanced visual system within the phylum, located in sophisticated sensory structures, rhopalia. The rhopalium is a club-shaped structure with paired pit-shaped pigment cup eyes, paired slit-shaped pigment cup eyes, and two complex camera-type eyes: one small upper lens eye and one large lower lens eye. The medusa carries four rhopalia and visual processing and locomotor rhythm generation takes place in the rhopalia. We show here a bilaterally symmetric organization of neurons, with commissures connecting the two sides, in the rhopalium of the cubozoan Tripedalia cystophora. The fortuitous observation that a subset of neurons is strongly immunoreactive for a PCNA (proliferating cell nuclear antigen)-like epitope allowed us to analyze the organization of these neurons in detail. Distinct PCNA-immunoreactive (PCNA-ir) nuclei form six bilateral pairs that are associated with the slit eyes, pit eyes, upper lens eye, and the posterior wall of the rhopalium. Three commissures connect the clusters of the two sides and all clusters in the rhopalium have connections to the area around the base of the stalk. This neuronal system provides an anatomical substrate for integration of visual signals from the different eyes.

Differentiation of ganglion cells and amacrine cells in the rat retina: correlation with expression of HuC/D and GAP-43 proteins.

In order to understand the development of retinal cells, we have studied the temporal expression of HuC/D protein in embryonic, postnatal and adult rat retina. During development and in the adult retina, practically all cell somata in the ganglion cell layer and the vast majority of conventional amacrine cells in the inner nuclear layer displayed HuC/D immunoreactivity. Most but not all ganglion cells expressed HuC/D at embryonic day 15, suggesting a delay between final mitosis and the initiation of HuC/D expression. Immunoreactivity for HuC/D was also evident in developing but not mature horizontal cells. Combined immunohistochemical visualization of HuC/D protein and the growth-associated protein (GAP-43) showed a distinct localization of GAP-43 in a specific compartment close to the somato-dendritic region of developing HuC/D-positive cell somata. The localization of GAP-43 immunoreactivity to a specific soma compartment became less evident during maturation. Immunoreactivity for HuC/D and GAP-43 was also discernible in horizontal cells at postnatal day 14. In the adult retina, most GAP-43 immunoreactivity was seen in the inner plexiform layer. Detailed analysis showed that HuC/D and GAP-43 expression is restricted to subsets of retinal neurons during development and in the mature retina. Thus, GAP-43 appears to be correlated with initial steps of differentiation and outgrowth of dendritic processes in HuC/D-positive ganglion and amacrine cells.