Higher Network Activity Induced by Tactile Compared to Electrical Stimulation of Leech Mechanoreceptors

The tiny ensemble of neurons in the leech ganglion can discriminate the locations of touch stimuli on the skin as precisely as a human fingertip. The leech uses this ability to locally bend the body-wall away from the stimulus. It is assumed that a three-layered feedforward network of pressure mechanoreceptors, interneurons, and motor neurons controls this behavior. Most previous studies identified and characterized the local bend network based on electrical stimulation of a single pressure mechanoreceptor, which was sufficient to trigger the local bend response. Recent studies showed, however, that up to six mechanoreceptors of three types innervating the stimulated patch of skin carry information about both touch intensity and location simultaneously. Therefore, we hypothesized that interneurons involved in the local bend network might require the temporally concerted inputs from the population of mechanoreceptors representing tactile stimuli, to decode the tactile information and to provide appropriate synaptic inputs to the motor neurons. We examined the influence of current injection into a single mechanoreceptor on activity of postsynaptic interneurons in the network and compared it to responses of interneurons to skin stimulation with different pressure intensities. We used voltage-sensitive dye imaging to monitor the graded membrane potential changes of all visible cells on the ventral side of the ganglion. Our results showed that stimulation of a single mechanoreceptor activates several local bend interneurons, consistent with previous intracellular studies. Tactile skin stimulation, however, evoked a more pronounced, longer-lasting, stimulus intensity-dependent network dynamics involving more interneurons. We concluded that the underlying local bend network enables a non-linear processing of tactile information provided by population of mechanoreceptors. This task requires a more complex network structure than previously assumed, probably containing polysynaptic interneuron connections and feedback loops. This small, experimentally well-accessible neuronal system highlights the general importance of selecting adequate sensory stimulation to investigate the network dynamics in the context of natural behavior

Dampening Spontaneous Activity Improves the Light Sensitivity and Spatial Acuity of Optogenetic Retinal Prosthetic Responses

Retinitis pigmentosa is a progressive retinal dystrophy that causes irreversible visual impairment and blindness. Retinal prostheses currently represent the only clinically available vision-restoring treatment, but the quality of vision returned remains poor. Recently, it has been suggested that the pathological spontaneous hyperactivity present in dystrophic retinas may contribute to the poor quality of vision returned by retinal prosthetics by reducing the signal-to-noise ratio of prosthetic responses. Here, we investigated to what extent blocking this hyperactivity can improve optogenetic retinal prosthetic responses. We recorded activity from channelrhodopsin-expressing retinal ganglion cells in retinal wholemounts in a mouse model of retinitis pigmentosa. Sophisticated stimuli, inspired by those used in clinical visual assessment, were used to assess light sensitivity, contrast sensitivity and spatial acuity of optogenetic responses; in all cases these were improved after blocking spontaneous hyperactivity using meclofenamic acid, a gap junction blocker. Our results suggest that this approach significantly improves the quality of vision returned by retinal prosthetics, paving the way to novel clinical applications. Moreover, the improvements in sensitivity achieved by blocking spontaneous hyperactivity may extend the dynamic range of optogenetic retinal prostheses, allowing them to be used at lower light intensities such as those encountered in everyday life

Styrene-divinylbenzene copolymers. II. The conservation of porosity in styrene-divinylbenzene copolymer matrices and derived ion-exchange resins

The collapse of pores in styrene-divinylbenzene copolymers and corresponding ion-exchange resins was studied during the removal of solvating liquids. The process can be followed in a most simple way by measuring the volume of the bead-shaped copolymers upon drying. Other parameters observed during drying were the apparent density and incidently the internal surface. The collapse of pores is considered to be a result of cohesional forces when solvated polymer chains are approaching each other by loss of solvent. The effect will thus be more pronounced in gel-type networks than in porous ones. In porous networks, the effect will be stronger in smaller pores than in larger ones. It is shown that crosslinks, increasing the rigidity of the structures, will favor the conservation of porosity. In ion-exchange resins the pore stability is best when the material is in its lowest state of hydration. Generally, the collapse of pores is a reversible process. The collapsed material can in most cases be reswollen by the proper choice of solvent

Encoding of Tactile Stimuli by Mechanoreceptors and Interneurons of the Medicinal Leech

For many animals processing of tactile information is a crucial task in behavioral contexts like exploration, foraging, and stimulus avoidance. The leech, having infrequent access to food, developed an energy efficient reaction to tactile stimuli, avoiding unnecessary muscle movements: The local bend behavior moves only a small part of the body wall away from an object touching the skin, while the rest of the animal remains stationary. Amazingly, the precision of this localized behavioral response is similar to the spatial discrimination threshold of the human fingertip, although the leech skin is innervated by an order of magnitude fewer mechanoreceptors and each midbody ganglion contains only 400 individually identified neurons in total. Prior studies suggested that this behavior is controlled by a three-layered feed-forward network, consisting of four mechanoreceptors (P cells), approximately 20 interneurons and 10 individually characterized motor neurons, all of which encode tactile stimulus location by overlapping, symmetrical tuning curves. Additionally, encoding of mechanical force was attributed to three types of mechanoreceptors reacting to distinct intensity ranges: T cells for touch, P cells for pressure, and N cells for strong, noxious skin stimulation. In this study, we provide evidences that tactile stimulus encoding in the leech is more complex than previously thought. Combined electrophysiological, anatomical, and voltage sensitive dye approaches indicate that P and T cells both play a major role in tactile information processing resulting in local bending. Our results indicate that tactile encoding neither relies on distinct force intensity ranges of different cell types, nor location encoding is restricted to spike count tuning. Instead, we propose that P and T cells form a mixed type population, which simultaneously employs temporal response features and spike counts for multiplexed encoding of touch location and force intensity. This hypothesis is supported by our finding that previously identified local bend interneurons receive input from both P and T cells. Some of these interneurons seem to integrate mechanoreceptor inputs, while others appear to use temporal response cues, presumably acting as coincidence detectors. Further voltage sensitive dye studies can test these hypotheses how a tiny nervous system performs highly precise stimulus processing

Human iPSC differentiation to retinal organoids in response to IGF1 and BMP4 activation is line- and method-dependent

Induced pluripotent stem cell (iPSC)‐derived retinal organoids provide a platform to study human retinogenesis, disease modeling, and compound screening. Although retinal organoids may represent tissue structures with greater physiological relevance to the in vivo human retina, their generation is not without limitations. Various protocols have been developed to enable development of organoids with all major retinal cell types; however, variability across iPSC lines is often reported. Modulating signaling pathways important for eye formation, such as those involving bone morphogenetic protein 4 (BMP4) and insulin‐like growth factor 1 (IGF1), is a common approach used for the generation of retinal tissue in vitro. We used three human iPSC lines to generate retinal organoids by activating either BMP4 or IGF1 signaling and assessed differentiation efficiency by monitoring morphological changes, gene and protein expression, and function. Our results showed that the ability of iPSC to give rise to retinal organoids in response to IGF1 and BMP4 activation was line‐ and method‐dependent. This demonstrates that careful consideration is needed when choosing a differentiation approach, which would also depend on overall project aims

Late Miocene Mediterranean desiccation: topography and significance of the 'Salinity Crisis' erosion surface on-land in southeast Spain: Comment

One of the most striking aspects of the Mediterranean "Messinian Salinity Crisis" as observed in landbased sections, is the basin-wide synchronicity in facies change (Krijgsman et al., 1999a). The Messinian succession of the Caltanisetta Basin on Sicily serves as the classical standard for these facies changes, which can also be recognised elsewhere in the Mediterranean, i.e. on Cyprus, Crete, northern Italy and southern Spain. It starts with an alternation of open marine marls and sapropels, passes via diatomites into evaporitic limestones, gypsum and halite of the "Lower Evaporites" (of marine origin) and, following an erosional unconformity, ends with the "Upper Evaporites" and associated fresh to brackish water deposits of the Lago Mare that are essentially of non-marine origin and contain a caspi-brackish ostracode fauna. The erosional unconformity between the "Lower and Upper Evaporites" is assumed to reflect the phase of most extreme sea level drawdown in the Mediterranean that caused significant erosion and localised channel entrenchment on the continental shelves and slopes

Astrochronology for the Messinian Sorbas basin (SE Spain) and orbital (precessional) forcing for evaporite cyclicity

The Sorbas basin of SE Spain contains one of the most complete sedimentary successions of the Mediterranean reflecting the increasing salinity during the Messinian salinity crisis. A detailed cyclostratigraphic study of these successions allows a correlation of the sedimentary cycle patterns to astronomical target curves. Here, we present an astrochronological framework for the Messinian of the central part of the Sorbas basin. This framework will form a solid basis for high-resolution correlations to the marginal carbonate facies and to the Central Mediterranean area. The early Messinian Abad Member contains 55 precession induced sedimentary cycles marked by homogeneous marl-opalrich bed alternations in the `Lower Abad' and by homogeneous marl-sapropel alternations in the `Upper Abad'. Astronomical tuning results in an age of 5.96 Ma for the transition to the Yesares evaporites and thus for the onset of the `Messinian salinity crisis'. The marl±sapropel cycles of the `Upper Abad' are replaced by gypsum±sapropel cycles (14) in the Yesares Member, indicating that the evaporite cyclicity is related to precession controlled oscillations in (circum) Mediterranean climate as well. As a consequence, gypsum beds correspond to precession maxima (insolation minima) and relatively dry climate, sapropelitic marls to precession minima (insolation maxima) and relatively wet climate. An alternative (glacio-eustatic) obliquity control for evaporite cyclicity can be excluded because the number of sedimentary cycles with a reversed polarity is too high. Sedimentation during the Abad, Yesares, and the overlying coastal sequences of the Sorbas Member, took place in a continuously marine environment, indicating that marine conditions in the Sorbas basin prevailed at least until 5.60-5.54 Ma. According to our scenario, deposition of the Yesares and Sorbas Member took place synchronously with deposition of the `Lower Evaporites' in the Central Mediterranean. Finally, the continental Zorreras Member consists of 8 sedimentary cycles of alternating reddish silts (dry climate) and yellowish sands (wet climate) which correlates very well with the `Upper Evaporites' and Lago Mare facies of the Mediterranean

Probing retinal function with a multi-layered simulator

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The Abad composite (SE Spain): a Messinian reference section for the Mediterranean and the APTS

A high-resolution integrated stratigraphy is presented for the Abad marls of the Sorbas and Nijar basins in SE Spain (preevaporitic Messinian of the Western Mediterranean). Detailed cyclostratigraphic and biostratigraphic analyses of partially overlapping subsections were needed to overcome stratigraphic problems in particular encountered at the complex transition from the Lower to the Upper Abad. The resulting Abad composite section contains a continuous stratigraphic record from the Tortonian/Messinian boundary up to the transition to the Messinian evaporites of the Yesares Member. All together, 18 calcareous plankton events were recognized which were shown to be synchronous throughout the Mediterranean by means of detailed (bed-to-bed) cyclostratigraphic correlations. The magnetostratigraphy allowed the identification of the four magnetic reversals of chron C3An in the Upper Abad. Details in the sedimentary cycle patterns allowed the Abad composite to be astronomically calibrated. This calibration to the 658N summer insolation curve of solution La90(1,1) yielded astronomical ages for all sedimentary cycles, calcareous plankton bioevents, ash layers and paleomagnetic reversals. Up to now, the Abad composite is the only astronomically well-calibrated section that provided a reliable cyclostratigraphy, magnetostratigraphy and calcareous plankton biostratigraphy. As such it will serve as a reference section both for the pre-evaporite Messinian in the Mediterranean as well as for the Messinian interval in the Astronomical Polarity Time Scale