Temporal Modulation of Spike-Timing-Dependent Plasticity

Spike-timing-dependent plasticity (STDP) has attracted considerable experimental and theoretical attention over the last decade. In the most basic formulation, STDP provides a fundamental unit – a spike pair – for quantifying the induction of long-term changes in synaptic strength. However, many factors, both pre- and postsynaptic, can affect synaptic transmission and integration, especially when multiple spikes are considered. Here we review the experimental evidence for multiple types of nonlinear temporal interactions in STDP, focusing on the contributions of individual spike pairs, overall spike rate, and precise spike timing for modification of cortical and hippocampal excitatory synapses. We discuss the underlying processes that determine the specific learning rules at different synapses, such as postsynaptic excitability and short-term depression. Finally, we describe the success of efforts toward building predictive, quantitative models of how complex and natural spike trains induce long-term synaptic modifications

Cryo-EM structures of herpes simplex virus type 1 portal vertex and packaged genome.

Herpesviruses are enveloped viruses that are prevalent in the human population and are responsible for diverse pathologies, including cold sores, birth defects and cancers. They are characterized by a highly pressurized pseudo-icosahedral capsid-with triangulation number (T) equal to 16-encapsidating a tightly packed double-stranded DNA (dsDNA) genome1-3. A key process in the herpesvirus life cycle involves the recruitment of an ATP-driven terminase to a unique portal vertex to recognize, package and cleave concatemeric dsDNA, ultimately giving rise to a pressurized, genome-containing virion4,5. Although this process has been studied in dsDNA phages6-9-with which herpesviruses bear some similarities-a lack of high-resolution in situ structures of genome-packaging machinery has prevented the elucidation of how these multi-step reactions, which require close coordination among multiple actors, occur in an integrated environment. To better define the structural basis of genome packaging and organization in herpes simplex virus type 1 (HSV-1), we developed sequential localized classification and symmetry relaxation methods to process cryo-electron microscopy (cryo-EM) images of HSV-1 virions, which enabled us to decouple and reconstruct hetero-symmetric and asymmetric elements within the pseudo-icosahedral capsid. Here we present in situ structures of the unique portal vertex, genomic termini and ordered dsDNA coils in the capsid spooled around a disordered dsDNA core. We identify tentacle-like helices and a globular complex capping the portal vertex that is not observed in phages, indicative of herpesvirus-specific adaptations in the DNA-packaging process. Finally, our atomic models of portal vertex elements reveal how the fivefold-related capsid accommodates symmetry mismatch imparted by the dodecameric portal-a longstanding mystery in icosahedral viruses-and inform possible DNA-sequence recognition and headful-sensing pathways involved in genome packaging. This work showcases how to resolve symmetry-mismatched elements in a large eukaryotic virus and provides insights into the mechanisms of herpesvirus genome packaging

Postsynaptic protein organization revealed by electron microscopy.

Neuronal synapses are key devices for transmitting and processing information in the nervous system. Synaptic plasticity, generally regarded as the cellular basis of learning and memory, involves changes of subcellular structures that take place at the nanoscale. High-resolution imaging methods, especially electron microscopy (EM), have allowed for quantitative analysis of such nanoscale structures in different types of synapses. In particular, the semi-ordered organization of neurotransmitter receptors and their interacting scaffolds in the postsynaptic density have been characterized for both excitatory and inhibitory synapses by studies using various EM techniques such as immuno-EM, electron tomography of high-pressure freezing and freeze-substituted samples, and cryo electron tomography. These techniques, in combination with new correlative approaches, will further facilitate our understanding of the molecular organization underlying diverse functions of neuronal synapses

Accumulation of Dense Core Vesicles in Hippocampal Synapses Following Chronic Inactivity.

The morphology and function of neuronal synapses are regulated by neural activity, as manifested in activity-dependent synapse maturation and various forms of synaptic plasticity. Here we employed cryo-electron tomography (cryo-ET) to visualize synaptic ultrastructure in cultured hippocampal neurons and investigated changes in subcellular features in response to chronic inactivity, a paradigm often used for the induction of homeostatic synaptic plasticity. We observed a more than 2-fold increase in the mean number of dense core vesicles (DCVs) in the presynaptic compartment of excitatory synapses and an almost 20-fold increase in the number of DCVs in the presynaptic compartment of inhibitory synapses after 2 days treatment with the voltage-gated sodium channel blocker tetrodotoxin (TTX). Short-term treatment with TTX and the N-methyl-D-aspartate receptor (NMDAR) antagonist amino-5-phosphonovaleric acid (AP5) caused a 3-fold increase in the number of DCVs within 100 nm of the active zone area in excitatory synapses but had no significant effects on the overall number of DCVs. In contrast, there were very few DCVs in the postsynaptic compartments of both synapse types under all conditions. These results are consistent with a role for presynaptic DCVs in activity-dependent synapse maturation. We speculate that these accumulated DCVs can be released upon reactivation and may contribute to homeostatic metaplasticity

DNA-Packing Portal and Capsid-Associated Tegument Complexes in the Tumor Herpesvirus KSHV.

Assembly of Kaposi's sarcoma-associated herpesvirus (KSHV) begins at a bacteriophage-like portal complex that nucleates formation of an icosahedral capsid with capsid-associated tegument complexes (CATCs) and facilitates translocation of an ∼150-kb dsDNA genome, followed by acquisition of a pleomorphic tegument and envelope. Because of deviation from icosahedral symmetry, KSHV portal and tegument structures have largely been obscured in previous studies. Using symmetry-relaxed cryo-EM, we determined the in situ structure of the KSHV portal and its interactions with surrounding capsid proteins, CATCs, and the terminal end of KSHV's dsDNA genome. Our atomic models of the portal and capsid/CATC, together with visualization of CATCs' variable occupancy and alternate orientation of CATC-interacting vertex triplexes, suggest a mechanism whereby the portal orchestrates procapsid formation and asymmetric long-range determination of CATC attachment during DNA packaging prior to pleomorphic tegumentation/envelopment. Structure-based mutageneses confirm that a triplex deep binding groove for CATCs is a hotspot that holds promise for antiviral development

Nearby SNR: a possible common origin to multi-messenger anomalies in spectra, ratios and anisotropy of cosmic rays

The multi-messenger anomalies, including spectral hardening or excess for nuclei, leptons, ratios of $\bar p/p$ and B/C, and anisotropic reversal, were observed in past years. AMS-02 experiment also revealed different spectral break for positron and electron at 284 GeV and beyond TeV respectively. It is natural to ask whether all those anomalies originate from one unified physical scenario. In this work, the spatially-dependent propagation (SDP) with a nearby SNR source is adopted to reproduce above mentioned anomalies. There possibly exists dense molecular cloud(DMC) around SNRs and the secondary particles can be produced by pp-collision or fragmentation between the accelerated primary cosmic rays and DMC. As a result, the spectral hardening for primary, secondary particles and ratios of $B/C$ and $\bar p/p$ can be well reproduced. Due to the energy loss at source age of 330 kyrs, the characteristic spectral break-off for primary electron is at about 1 TeV hinted from the measurements. The secondary positron and electron from charged pion take up $5\%$ energy from their mother particles, so the positron spectrum has a cut-off at $\sim$250 GeV. Therefore, the different spectral break for positron and electron together with other anomalies can be fulfilled in this unified physical scenario. More interesting is that we also obtain the featured structures as spectral break-off at 5 TV for secondary particles of Li, Be, B, which can be served to verify our model. We hope that those tagged structures can be observed by the new generation of space-borne experiment HERD in future.Comment: 16 pages, 12 figure