A role for fast rhythmic bursting neurons in cortical gamma oscillations in vitro

Basic cellular and network mechanisms underlying gamma frequency oscillations (30–80 Hz) have been well characterized in the hippocampus and associated structures. In these regions, gamma rhythms are seen as an emergent property of networks of principal cells and fast-spiking interneurons. In contrast, in the neocortex a number of elegant studies have shown that specific types of principal neuron exist that are capable of generating powerful gamma frequency outputs on the basis of their intrinsic conductances alone. These fast rhythmic bursting (FRB) neurons (sometimes referred to as "chattering" cells) are activated by sensory stimuli and generate multiple action potentials per gamma period. Here, we demonstrate that FRB neurons may function by providing a large-scale input to an axon plexus consisting of gap-junctionally connected axons from both FRB neurons and their anatomically similar counterparts regular spiking neurons. The resulting network gamma oscillation shares all of the properties of gamma oscillations generated in the hippocampus but with the additional critical dependence on multiple spiking in FRB cells

GABA-enhanced collective behavior in neuronal axons underlies persistent gamma-frequency oscillations

Gamma (30–80 Hz) oscillations occur in mammalian electroencephalogram in a manner that indicates cognitive relevance. In vitro models of gamma oscillations demonstrate two forms of oscillation: one occurring transiently and driven by discrete afferent input and the second occurring persistently in response to activation of excitatory metabotropic receptors. The mechanism underlying persistent gamma oscillations has been suggested to involve gap-junctional communication between axons of principal neurons, but the precise relationship between this neuronal activity and the gamma oscillation has remained elusive. Here we demonstrate that gamma oscillations coexist with high-frequency oscillations (>90 Hz). High-frequency oscillations can be generated in the axonal plexus even when it is physically isolated from pyramidal cell bodies. They were enhanced in networks by nonsomatic -aminobutyric acid type A (GABAA) receptor activation, were modulated by perisomatic GABAA receptor-mediated synaptic input to principal cells, and provided the phasic input to interneurons required to generate persistent gamma-frequency oscillations. The data suggest that high-frequency oscillations occurred as a consequence of random activity within the axonal plexus. Interneurons provide a mechanism by which this random activity is both amplified and organized into a coherent network rhythm

Selective inhibition of extra-synaptic α5-GABA_A receptors by S44819, a new therapeutic agent

In the mammalian central nervous system (CNS) GABAA receptors (GABAARs) mediate neuronal inhibition and are important therapeutic targets. GABAARs are composed of 5 subunits, drawn from 19 proteins, underpinning expression of 20-30 GABAAR subtypes. In the CNS these isoforms are heterogeneously expressed and exhibit distinct physiological and pharmacological properties. We report the discovery of S44819, a novel tricyclic oxazolo-2,3-benzodiazepine-derivative, that selectively inhibits α5-subunit-containing GABAARs (α5-GABAARs). Current α5-GABAAR inhibitors bind to the “benzodiazepine site”. However, in HEK293 cells expressing recombinant α5-GABAARs, S44819 had no effect on 3H-flumazenil binding, but displaced the GABAAR agonist 3H-muscimol and competitively inhibited the GABA-induced responses. Importantly, we reveal that the α5-subunit selectivity is uniquely governed by amino acid residues within the α-subunit F-loop, a region associated with GABA binding. In mouse hippocampal CA1 neurons, S44819 enhanced long-term potentiation (LTP), blocked a tonic current mediated by extrasynaptic α5-GABAARs, but had no effect on synaptic GABAARs. In mouse thalamic neurons, S44819 had no effect on the tonic current mediated by δ-GABAARs, or on synaptic (α1β2γ2) GABAARs. In rats, S44819 enhanced object recognition memory and reversed scopolamine-induced impairment of working memory in the eight-arm radial maze. In conclusion, S44819 is a first in class compound that uniquely acts as a potent, competitive, selective antagonist of recombinant and native α5-GABAARs. Consequently, S44819 enhances hippocampal synaptic plasticity and exhibits pro-cognitive efficacy. Given this profile, S44819 may improve cognitive function in neurodegenerative disorders and facilitate post-stroke recovery

Minimal Size of Cell Assemblies Coordinated by Gamma Oscillations

In networks of excitatory and inhibitory neurons with mutual synaptic coupling, specific drive to sub-ensembles of cells often leads to gamma-frequency (25–100 Hz) oscillations. When the number of driven cells is too small, however, the synaptic interactions may not be strong or homogeneous enough to support the mechanism underlying the rhythm. Using a combination of computational simulation and mathematical analysis, we study the breakdown of gamma rhythms as the driven ensembles become too small, or the synaptic interactions become too weak and heterogeneous. Heterogeneities in drives or synaptic strengths play an important role in the breakdown of the rhythms; nonetheless, we find that the analysis of homogeneous networks yields insight into the breakdown of rhythms in heterogeneous networks. In particular, if parameter values are such that in a homogeneous network, it takes several gamma cycles to converge to synchrony, then in a similar, but realistically heterogeneous network, synchrony breaks down altogether. This leads to the surprising conclusion that in a network with realistic heterogeneity, gamma rhythms based on the interaction of excitatory and inhibitory cell populations must arise either rapidly, or not at all. For given synaptic strengths and heterogeneities, there is a (soft) lower bound on the possible number of cells in an ensemble oscillating at gamma frequency, based simply on the requirement that synaptic interactions between the two cell populations be strong enough. This observation suggests explanations for recent experimental results concerning the modulation of gamma oscillations in macaque primary visual cortex by varying spatial stimulus size or attention level, and for our own experimental results, reported here, concerning the optogenetic modulation of gamma oscillations in kainate-activated hippocampal slices. We make specific predictions about the behavior of pyramidal cells and fast-spiking interneurons in these experiments.Collaborative Research in Computational NeuroscienceNational Institutes of Health (U.S.) (grant 1R01 NS067199)National Institutes of Health (U.S.) (grant DMS 0717670)National Institutes of Health (U.S.) (grant 1R01 DA029639)National Institutes of Health (U.S.) (grant 1RC1 MH088182)National Institutes of Health (U.S.) (grant DP2OD002002)Paul G. Allen Family FoundationnGoogle (Firm

Trends in Spinal Surgery for Pott\u27s Disease (2000-2016): An Overview and Bibliometric Study.

Study Design: Systematic review. Objectives: (1) What are the surgical indications? Have they changed over time since the year 2000? (2) What is the current surgical approaches of choice? Have they changed over time since the year 2000? Do they vary by geographical region? (3) What are the most common outcome measures following surgery? Methods: Electronic databases and reference lists of key articles were searched from database inception from January 1, 2000 to December 31, 2016 to identify studies specifically evaluating surgical indications, current surgical approaches, and outcome measures for spinal tuberculosis. Results: Six randomized controlled trials were identified from our search (1 excluded: no surgical arm identified after review) Neurological deficit, instability and deformity were common indications identified. Surgical approach included predominantly anterior for cervical spine and posterior for thoracic and lumbar spine. Combined approach was preferred in pediatric cases. Degree of deformity correction, neurological outcomes, and fusion formed the main bases of assessing surgical outcomes. Conclusions: Majority of the current literature is from South Asia. The presence of neurological compromise, deformity, and instability were the primary criteria for surgical intervention. The preferred approach varied with the anatomical region of the spine in adults. Outcome measures predominantly involved deformity correction, neurological deficit, and fusion

Organic pollutants in sea-surface microlayer and aerosol in thecoastal environment of Leghorn—(Tyrrhenian Sea)

The levels of dissolved and particle-associated n-alkanes, alkylbenzenes, phthalates, PAHs, anionic surfactants and surfactant fluorescent organic matter ŽSFOM. were measured in sea-surface microlayer ŽSML. and sub-surface water ŽSSL. samples collected in the Leghorn marine environment in September and October 1999. Nine stations, located in the Leghorn harbour and at increasing distances from the Port, were sampled three times on the same day. At all the stations, SML concentrations of the selected organic compounds were significantly higher than SSL values and the enrichment factors ŽEFsSML concentrationrSSL concentration. were greater in the particulate phase than in the dissolved phase. SML concentrations varied greatly among the sampling sites, the highest levels Žn-alkanes 3674 mgrl, phthalates 177 mgrl, total PAHs 226 mgrl. being found in the particulate phase in the Leghorn harbour. To improve the knowledge on pollutant exchanges between sea-surface waters and atmosphere, the validity of spray drop adsorption model ŽSDAM. was verified for SFOM, surface-active agents, such as phthalates, and compounds which can interact with SFOM, such as n-alkanes and PAHs. q2001 Elsevier Science B.V. All rights reserved

Vulnerability of Smart Grid-enabled Protection Relays to IEMI

The electricity sector has been undergoing transformations towards the smart grid concept, which aims to improve the robustness, efficiency, and flexibility of the power system. This transition has been achieved by the introduction of smart electronic devices (SEDs) and advanced automatic control and communication systems. Despite the benefits of such modernization, safety issues have emerged with significant concern by experts and entities worldwide. One of these issues is known as Intentional Electromagnetic Interference (IEMI), where offenders employ high-power electromagnetic sources to maliciously disrupt or damage electronic devices. One of the possible gateways for IEMI attacks targeting the smart grids is the microprocessor-based protection relays. On the one hand, the malfunctioning of these devices can lead to equipment damage, including high-voltage equipment (e.g., power transformers), which represent one of the most high-cost items of energy infrastructure. On the other hand, a possible misleading triggering of these devices could cause cascading effects along the various nodes of the power system, resulting in widespread blackouts. Thus, this study presents the possible recurring effects of IEMI exposure of a typical protection relay used in smart grid substations as part of the SCADA (Supervisory Control and Data Acquisition) system. For this purpose, a test setup containing a smart grid protective unit, a monitoring box, and the device's wiring harness is exposed to radiated IEMI threats with high-power narrowband signals using a TEM waveguide and horn antennas. The effects during the test campaigns are observed by means of an IEMI-hardened camera system and a software developed to real-time monitor the device's fibre optic communication link, which is established according to the IEC 60870-5-105 protocol. The results revealed failures ranging from display deviation to various types of protection relay shutdown. Moreover, the consequences of the identified failures in a power substation are discussed to feed into a risk analysis regarding the threat of IEMI to power infrastructures.</p

Iatrogenic Bowel Injury Following Minimally Invasive Lateral Approach to the Lumbar Spine: A Retrospective Analysis of 3 Cases.

Study Design: Retrospective cohort study. Objective: Anterior approaches are often used during lumbar interbody fusion procedures. Visceral injuries (bowel injuries) are rare but represent a primary risk during anterior approaches to the lumbar spine. Left untreated, these injuries can result in significant complications. The aim of this study was to investigate the presentation and management of bowel injury cases following anterior approaches to the lumbar spine to raise the surgeon\u27s awareness of this rare complication. Methods: All direct anterior, oblique anterior, and transpsoas lumbar interbody fusion surgeries performed at our institution between 2012 and 2016 were analyzed retrospectively. Charts were screened for cases requiring return to the operating room owing to a suspected bowel injury and details of the case were extracted for illustrative purposes. Results: A total of 775 anterior lumbar surgeries were conducted at a single tertiary care institution between July 2012 and June 2017. A total of 590 transpsoas lumbar interbody fusion (TPIF) surgeries were performed. Four patients, each having undergone TPIF, were suspected of bowel injury and underwent an exploratory laparotomy. At surgery, 3 patients were confirmed to have a bowel injury, giving a procedure-specific incidence of 0.51% and overall incidence of 0.39%. Among the 3 confirmed bowel injury cases, average delay between surgery and visceral injury diagnosis was 4.7 days (range 3-7 days). Conclusions: We noted abdominal pain, distention, and fever as the most common findings in the setting of a visceral injury. A high index of suspicion and computed tomography imaging remain critical for identifying postoperative bowel injuries

Neuregulin and dopamine modulation of hippocampal gamma oscillations is dependent on dopamine D4 receptors

The neuregulin/ErbB signaling network is genetically associated with schizophrenia and modulates hippocampal γ oscillations—a type of neuronal network activity important for higher brain processes and altered in psychiatric disorders. Because neuregulin-1 (NRG-1) dramatically increases extracellular dopamine levels in the hippocampus, we investigated the relationship between NRG/ErbB and dopamine signaling in hippocampal γ oscillations. Using agonists for different D1- and D2-type dopamine receptors, we found that the D4 receptor (D4R) agonist PD168077, but not D1/D5 and D2/D3 agonists, increases γ oscillation power, and its effect is blocked by the highly specific D4R antagonist L-745,870. Using double in situ hybridization and immunofluorescence histochemistry, we show that hippocampal D4R mRNA and protein are more highly expressed in GAD67-positive GABAergic interneurons, many of which express the NRG-1 receptor ErbB4. Importantly, D4 and ErbB4 receptors are coexpressed in parvalbumin-positive basket cells that are critical for γ oscillations. Last, we report that D4R activation is essential for the effects of NRG-1 on network activity because L-745,870 and the atypical antipsychotic clozapine dramatically reduce the NRG-1–induced increase in γ oscillation power. This unique link between D4R and ErbB4 signaling on γ oscillation power, and their coexpression in parvalbumin-expressing interneurons, suggests a cellular mechanism that may be compromised in different psychiatric disorders affecting cognitive control. These findings are important given the association of a DRD4 polymorphism with alterations in attention, working memory, and γ oscillations, and suggest potential benefits of D4R modulators for targeting cognitive deficits