The Amyloid Precursor Protein Modulates the Position and Length of the Axon Initial Segment.

The amyloid precursor protein (APP) is linked to the genetics and pathogenesis of Alzheimer's disease (AD). It is the parent protein of the ß-amyloid (Aß) peptide, the main constituent of the amyloid plaques found in an AD brain. The pathways from APP to Aß are intensively studied, yet the normal functions of APP itself have generated less interest. We report here that glutamate stimulation of neuronal activity leads to a rapid increase in App gene expression. In mouse and human neurons, elevated APP protein changes the structure of the axon initial segment (AIS) where action potentials are initiated. The AIS is shortened in length and shifts away from the cell body. The GCaMP8f Ca2+ reporter confirms the predicted decrease in neuronal activity. NMDA antagonists or knockdown of App block the glutamate effects. The actions of APP on the AIS are cell-autonomous; exogenous Aß, either fibrillar or oligomeric, has no effect. In culture, APPSwe (a familial AD mutation) induces larger AIS changes than wild type APP. Ankyrin G and ßIV-spectrin, scaffolding proteins of the AIS, both physically associate with APP, more so in AD brains. Finally, in humans with sporadic AD or in the R1.40 AD mouse model, both females and males, neurons have elevated levels of APP protein that invade the AIS. In vivo as in vitro, this increased APP is associated with a significant shortening of the AIS. The findings outline a new role for the APP and encourage a reconsideration of its relationship to AD.SIGNIFICANCE STATEMENT While the amyloid precursor protein (APP) has long been associated with Alzheimer's disease (AD), the normal functions of the full-length Type I membrane protein have been largely unexplored. We report here that the levels of APP protein increase with neuronal activity. In vivo and in vitro, modest amounts of excess APP alter the properties of the axon initial segment. The ß-amyloid peptide derived from APP is without effect. Consistent with the observed changes in the axon initial segment which would be expected to decrease action potential firing, we show that APP expression depresses neuronal activity. In mouse AD models and human sporadic AD, APP physically associates with the scaffolding proteins of the axon initial segment, suggesting a relationship with AD dementia.

What can neuromorphic event-driven precise timing add to spike-based pattern recognition?

This letter introduces a study to precisely measure what an increase in spike timing precision can add to spike-driven pattern recognition algorithms. The concept of generating spikes from images by converting gray levels into spike timings is currently at the basis of almost every spike-based modeling of biological visual systems. The use of images naturally leads to generating incorrect artificial and redundant spike timings and, more important, also contradicts biological findings indicating that visual processing is massively parallel, asynchronous with high temporal resolution. A new concept for acquiring visual information through pixel-individual asynchronous level-crossing sampling has been proposed in a recent generation of asynchronous neuromorphic visual sensors. Unlike conventional cameras, these sensors acquire data not at fixed points in time for the entire array but at fixed amplitude changes of their input, resulting optimally sparse in space and time-pixel individually and precisely timed only if new, (previously unknown) information is available (event based). This letter uses the high temporal resolution spiking output of neuromorphic event-based visual sensors to show that lowering time precision degrades performance on several recognition tasks specifically when reaching the conventional range of machine vision acquisition frequencies (30-60 Hz). The use of information theory to characterize separability between classes for each temporal resolution shows that high temporal acquisition provides up to 70% more information that conventional spikes generated from frame-based acquisition as used in standard artificial vision, thus drastically increasing the separability between classes of objects. Experiments on real data show that the amount of information loss is correlated with temporal precision. Our information-theoretic study highlights the potentials of neuromorphic asynchronous visual sensors for both practical applications and theoretical investigations. Moreover, it suggests that representing visual information as a precise sequence of spike times as reported in the retina offers considerable advantages for neuro-inspired visual computations.

Real-Time High Speed Motion Prediction Using Fast Aperture-Robust Event-Driven Visual Flow.

Optical flow is a crucial component of the feature space for early visual processing of dynamic scenes especially in new applications such as self-driving vehicles, drones and autonomous robots. The dynamic vision sensors are well suited for such applications because of their asynchronous, sparse and temporally precise representation of the visual dynamics. Many algorithms proposed for computing visual flow for these sensors suffer from the aperture problem as the direction of the estimated flow is governed by the curvature of the object rather than the true motion direction. Some methods that do overcome this problem by temporal windowing under-utilize the true precise temporal nature of the dynamic sensors. In this paper, we propose a novel multi-scale plane fitting based visual flow algorithm that is robust to the aperture problem and also computationally fast and efficient. Our algorithm performs well in many scenarios ranging from fixed camera recording simple geometric shapes to real world scenarios such as camera mounted on a moving car and can successfully perform event-by-event motion estimation of objects in the scene to allow for predictions of upto 500 ms i.e., equivalent to 10 to 25 frames with traditional cameras.

A new experimental approach and signal processing scheme for the detection and quantitation of ³¹P brain neurochemicals from in vivo MRS studies using dual tuned (¹H/³¹P) head coil.

Brain (31)P-neurometabolites play an important role in energy and membrane metabolism. Unambiguous identification and quantification of these neurochemicals in different brain regions would be a great aid in advancing the understanding of metabolic processes in the nervous system. Phosphomonoester (PME), consisting of phosphoethanolamine (PE) and phosphocholine (PC), is the "building block" for membranes, while phosphodiesters (PDE), consisting of glycerophosphocholine (GPC) and glycerophosphoethanolamine (GPE) metabolites are involved in the membrane breakdown process. In the clinical setting, generating well-resolved spectra for PC, PE, GPC, and GPE could be crucial phospholipids in providing information regarding membrane metabolism. We present here a new experimental approach for generating well-resolved (31)P spectra for PC and PE as well as for GPC, GPE, and other (31)P metabolites. Our results (based on uni-dimensional (1D) and multi-voxel (31)P studies) indicate that an intermediate excitation pulse angle (35°) is best suited to obtain well-resolved PC/PE and GPC/GPE resonance peaks. Our novel signal processing scheme allows generating metabolite maps of different phospholipids include PC/PE and GPC/GPE using the 'time-domain-frequency-domain' method as referred to in the MATLAB programming language.

Optogenetic therapy: high spatiotemporal resolution and pattern discrimination compatible with vision restoration in non-human primates.

Vision restoration is an ideal medical application for optogenetics, because the eye provides direct optical access to the retina for stimulation. Optogenetic therapy could be used for diseases involving photoreceptor degeneration, such as retinitis pigmentosa or age-related macular degeneration. We describe here the selection, in non-human primates, of a specific optogenetic construct currently tested in a clinical trial. We used the microbial opsin ChrimsonR, and showed that the AAV2.7m8 vector had a higher transfection efficiency than AAV2 in retinal ganglion cells (RGCs) and that ChrimsonR fused to tdTomato (ChR-tdT) was expressed more efficiently than ChrimsonR. Light at 600 nm activated RGCs transfected with AAV2.7m8 ChR-tdT, from an irradiance of 1015 photons.cm-2.s-1. Vector doses of 5 × 1010 and 5 × 1011 vg/eye transfected up to 7000 RGCs/mm2 in the perifovea, with no significant immune reaction. We recorded RGC responses from a stimulus duration of 1 ms upwards. When using the recorded activity to decode stimulus information, we obtained an estimated visual acuity of 20/249, above the level of legal blindness (20/400). These results lay the groundwork for the ongoing clinical trial with the AAV2.7m8 - ChR-tdT vector for vision restoration in patients with retinitis pigmentosa.

Behavioural responses to a photovoltaic subretinal prosthesis implanted in non-human primates.

Retinal dystrophies and age-related macular degeneration related to photoreceptor degeneration can cause blindness. In blind patients, although the electrical activation of the residual retinal circuit can provide useful artificial visual perception, the resolutions of current retinal prostheses have been limited either by large electrodes or small numbers of pixels. Here we report the evaluation, in three awake non-human primates, of a previously reported near-infrared-light-sensitive photovoltaic subretinal prosthesis. We show that multipixel stimulation of the prosthesis within radiation safety limits enabled eye tracking in the animals, that they responded to stimulations directed at the implant with repeated saccades and that the implant-induced responses were present two years after device implantation. Our findings pave the way for the clinical evaluation of the prosthesis in patients affected by dry atrophic age-related macular degeneration.

Mapping of hippocampal pH and neurochemicals from in vivo multi-voxel 31P study in healthy normal young male/female, mild cognitive impairment, and Alzheimer's disease.

Magnetic resonance spectroscopy (MRS) plays an important role in the understanding of membrane and energy metabolism. The outcome of MRS experiments helps to derive important cellular conditions (e.g., intracellular pH, energy, membrane metabolism, etc.), which are directly related to neuronal health. We present a novel multi-voxel 31P MRS imaging experimental scheme along with an advanced 31P signal processing technique to determine the pH and neurochemicals from both hippocampal areas in shorter time (13.2 min) for subjects (e.g. healthy young male/female, mild cognitive impairment (MCI) and Alzheimer's disease (AD)). Significant (p = 0.005) decrease of phosphomonoester (PME) and increase of phosphodiester (PDE) (p < 0.001), γ-ATP (0.008), and PCr (p = 0.001) levels in the left hippocampus of AD patients (n = 6) compared to the control subjects (n = 12) were found based on post-hoc ANOVA. On the other hand, in the right hippocampus, decrease in PME (p = 0.008) and increase in PDE (p < 0.001) were significant between AD patients and controls. In case of AD subjects, pH in the left hippocampus is increased towards alkaline side compared to MCI but did not reach statistical significance level. The pH (left hippocampus) in AD is found to be negatively correlated (r = -0.829, p = 0.042) with PCr level (left hippocampus) in AD subjects. In the left hippocampus, the increase in pH to alkaline range (in normal aging, pH is decreased to acidic range) along with statistically significant increments of PCr, γ-ATP, and PDE as well as decrease of PME in AD subjects provide extremely crucial clinical information, which can be used as biomarker for AD and potentially aid in the diagnosis.