Neural ensemble interactions underlying memory consolidation

Episodic memory formation and spatial navigation are core functions of the hippocampus. Embedded in a path integration based navigational system, the hippocampus generates orthogonal codes for different environments. To separate events within the same spatial map, the magnitude of individual place cell firing is modulated by external sensory information. The rate differences are also expressed to separate different running directions within an environment. Previous work suggested that the maps can be perturbed by external cues, but that the rate perturbations are not associatively stored. The present result shows that the rate code is reinstated offline and thus likely associatively stored, which fits well with the theory that describes the hippocampus as generating an index code for episodic memories to assist in retrieval of distributed information stored in the cortex. Lastly, this thesis addresses the methodological challenges of current electrophysiological techniques in detecting excitatory local connectivity on the example of the prefrontal cortex.AI-HS scholarship to CDS and Polaris Award to BL

Prognosefaktoren beim nichtkleinzelligen Bronchialkarzinom - Inzidenz von p53, bcl-2, HER-2, HSP27, HSP60 und HSP70 in nichtkleinzelligen Bronchialkarzinomen des Stadiums IIIA

Das Bronchialkarzinom stellt weltweit 25% aller durch Tumoren bedingten Todesfälle dar. Die Prognose von Patienten mit einem NSCLC Stadium IIIA konnte durch den Einsatz multimodaler Therapien in den letzten 5 Jahren deutlich verbessert werden. Dennoch beträgt die 5-Jahresüberlebenszeit dieser Patienten nur 25%. Um eine weitere Verbesserung der Prognose zu erreichen, erscheint die Erstellung individueller Therapiekonzepte notwendig. Aus diesem Grunde ist es unabdingbar, das biologische Verhalten von Primärtumoren intensiver zu berücksichtigen, um für den Einzelnen durch Erstellung eines Risikoprofils eine adaptierte Therapie zu ermöglichen. Bisher ist jedoch nicht eindeutig geklärt, welche Faktoren bei der Vielzahl an Veränderungen eine wichtige Rolle spielen. Ziel der vorliegenden Arbeit war es, geeignete Marker bei 34 Patienten mit einem nichtkleinzelligem Bronchialkarzinom des Stadiums IIIA zu finden, die eine Aussage über das maligne Potential sowie das Ansprechen auf Strahlen- und oder Chemotherapie eines Tumors zulassen, um so eine individuell angepaßte Therapie und Prognose in Zukunft zu ermöglichen. Wir haben uns dabei auf Faktoren (p53, bcl-2, HER-2, HSP70, HSP60 und HSP27) konzentriert, die nach den vorliegenden Daten als zentrale Regulatoren im Zellzyklus agieren oder von Bedeutung für die Immunantwort auf maligne Zellen sind. Für den immunhistochemischen Nachweis dieser Faktoren wurde die Biotin-Streptavidin-Methode eingesetzt. Einzig der Nachweis von p53 erfolgte durch die Avidin-Biotin-Komplex-Methode aufgrund des eingesetzten Antikörpers. Von den in Formalin fixierten und in Paraffin eingelegten Tumor- und Lymphknotenproben wurden dazu 4 mm dicke Schnittpräparate angefertigt. Diese wurden entparaffiniert und rehydriert und dann nach den methodenspezifischen Färbeprotokollen weiterbearbeitet. Im Rahmen der vorliegenden Arbeit konnte p53 in 16 von 34 (47,05 %), HER-2 in 3 von 30 (10 %), HSP27 in 29 von 34 (85,29 %), HSP60 in 21 von 34 (61,76 %) und HSP70 in 8 von 34 Fällen (23,52 %) als eindeutig positiv ermittelt werden. Von dem ebenfalls untersuchten bcl-2 Genprodukt konnte in keinem der untersuchten Primärtumoren eine verwertbare, als eindeutig positiv (>10% der Tumorzellen) zu beurteilende Überexpression festgestellt werden. Es konnten für die einzelnen Faktoren keine signifikanten Korrelationen mit den vorliegenden histopathologischen Daten der Patienten ermittelt werden. In 27 Fällen lagen auch Lymphknotenproben vor. Beim Vergleich der Färbungen der Primärtumoren mit denen der dazugehörigen Lymphknoten konnten keine signifikanten Unterschiede festgestellt werden, obwohl es in einzelnen Fällen zu Veränderungen im nachgewiesenen Proteinmuster gekommen war. Auch intratumorale Veränderungen des Proteinmusters konnten anhand von unterschiedlichen Proben eines Primärtumors festgestellt werden. Inwieweit der immunhistochemische Nachweis der genannten Parameter eine prognostische Relevanz besitzt, wird in einer zweiten Untersuchung geprüft werden

Kiri S. Urlsperger`ile, Nürnberg

http://tartu.ester.ee/record=b1901107~S1*es

Experience-dependent firing rate remapping generates directional selectivity in hippocampal place cells

When rodents engage in irregular foraging in an open-field environment, hippocampal principal cells exhibit place-specific firing that is statistically independent of the direction of traverse through the place field. When the path is restricted to a track, however, in-field rates differ substantially in opposite directions. Frequently, the representations of the track in the two directions are essentially orthogonal. We show that this directionally selective firing is not hard-wired, but develops through experience-dependent plasticity. During the rats' first pass in each direction, place fields were highly directionally symmetric, whereas over subsequent laps, the firing rates in the two directions gradually but substantially diverged. We conclude that, even on a restricted track, place cell firing is initially determined by allocentric position, and only later, the within-field firing rates change in response to differential sensory information or behavioral cues in the two directions. In agreement with previous data, place fields near local cues, such as textures on the track, developed less directionality than place fields on a uniform part of the track, possibly because the local cues reduced the net difference in sensory input at a given point. Directionality also developed in an open environment without physical restriction of the animal's path, when rats learned to run along a specified path. In this case, directionality developed later than on the running track, only after the rats began to run in a stereotyped manner. Although the average population firing rates exhibited little if any change over laps in either direction, the direction-specific firing rates in a given place field were up-or down-regulated with about equal probability and magnitude, which was independent in the two directions, suggesting some form of competitive mechanism (e.g., LTP/LTD) acting coherently on the set of synapses conveying external information to each cell

Prosthetic shoulder arthroplasty in patients 40 years or younger: outcomes stratified by diagnosis and surgery

Background The outcomes of patients 50–55 years old or younger undergoing prosthetic shoulder arthroplasty (PSA) may not generalize to younger patients. We report outcomes following PSA in a consecutive series of patients 40 years or younger. We hypothesize that total shoulder arthroplasty (TSA) provides better outcome and durability than resurfacing hemiarthroplasty (RHA). Methods Patients were stratified by diagnosis and surgical procedure performed, RHA or TSA. Active range of motion and self-assessed outcome were evaluated preoperatively and at final follow-up. Results Twenty-nine consecutive PSAs were identified in 26 patients, comprising 9 TSAs and 20 RHAs, with a minimum of 2-year follow-up. Twelve PSAs were performed for chondrolysis. Mean active forward elevation, abduction, external rotation, and internal rotation improved significantly (p<0.001 for all). Mean pain score improved from 6.3 to 2.1, Simple Shoulder Test from 4.0 to 9.0, and American Shoulder and Elbow Surgeons score from 38 to 75 (p<0.001 for all). Patients undergoing RHA and TSA had similar outcomes; but three RHAs required revision, two of these within 4 years of implantation. Four of five patients undergoing revision during the study period had an original diagnosis of chondrolysis. Conclusions PSA in young patients provides substantial improvement in active range of motion and patient reported outcomes irrespective of diagnosis and glenoid management. However, patients undergoing RHA, especially for chondrolysis, frequently require subsequent revision surgery, so that RHA should be considered with caution in young patients and only after shared decision-making and counsel on the risk of early revision to TSA

Long-term recordings improve the detection of weak excitatory-excitatory connections in rat prefrontal cortex

Sherpa Romeo yellow journal. Open access article. Creative Commons Attribution-Noncommercial-ShareAlike 3.0 Unported License (CC BY-NC-SA 3.0) applies.Characterization of synaptic connectivity is essential to understanding neural circuit dynamics. For extracellularly recorded spike trains, indirect evidence for connectivity can be inferred from short-latency peaks in the correlogram between two neurons. Despite their predominance in cortex, however, significant interactions between excitatory neurons (E) have been hard to detect because of their intrinsic weakness. By taking advantage of long duration recordings, up to 25 h, from rat prefrontal cortex, we found that 7.6% of the recorded pyramidal neurons are connected. This corresponds to 70% of the local E–E connection probability that has been reported by paired intracellular recordings(11.6%). This value is significantly higher than previous reports from extracellular recordings, but still a substantial underestimate. Our analysis showed that long recording times and strict significance thresholds are necessary to detect weak connections while avoiding false-positive results, but will likely still leave many excitatory connections undetected. In addition, we found that hyper-reciprocity of connections in prefrontal cortex that was shown previously by paired intracellular recordings was only present in short-distance, but not in long distance (300 micrometers or more) interactions. As hyper-reciprocity is restricted to local clusters, it might be a mini columnar effect. Given the current surge of interest in very high-density neural spike recording (e.g., NIH BRAIN Project) it is of paramount importance that we have statistically reliable methods for estimating connectivity from cross-correlation analysis available. We provide an important step in this direction.Ye

Reactivation of rate remapping in CA3

Sherpa Romeo yellow journal. Open access article. Creative Commons Attribution 4.0 International License (CC BY 4.0) appliesThe hippocampus is thought to contribute to episodic memory by creating, storing, and reactivating patterns that are unique to each experience, including different experiences that happen at the same location. Hippocampus can combine spatial and contextual/episodic information using a dual coding scheme known as “global” and “rate” remapping. Global remapping selects which set of neurons can activate at a given location. Rate remapping readjusts the firing rates of this set depending on current experience, thus expressing experience-unique patterns at each location. But can the experience-unique component be retrieved spontaneously? Whereas reactivation of recent, spatially selective patterns in hippocampus is well established, it is never perfect, raising the issue of whether the experiential component might be absent. This question is key to the hypothesis that hippocampus can assist memory consolidation by reactivating and broadcasting experience-specific “index codes” to neocortex. In CA3, global remapping exhibits attractor-like dynamics, whereas rate remapping apparently does not, leading to the hypothesis that only the former can be retrieved associatively and casting doubt on the general consolidation hypothesis. Therefore, we studied whether the rate component is reactivated spontaneously during sleep. We conducted neural ensemble recordings from CA3 while rats ran on a circular track in different directions (in different sessions) and while they slept. It was shown previously that the two directions of running result in strong rate remapping. During sleep, the most recent rate distribution was reactivated preferentially. Therefore, CA3 can retrieve patterns spontaneously that are unique to both the location and the content of recent experience.Ye

Network-selectivity and stimulus-discrimination in the primary visual cortex : cell-assembly dynamics

Abstract : Visual neurons coordinate their responses in relation to the stimulus; however, the complex interplay between a stimulus and the functional dynamics of an assembly still eludes neuroscientists. To this aim, we recorded cell assemblies from multi-electrodes in the primary visual cortex of anaesthetized cats in response to randomly presented sine-wave drifting gratings whose orientation tilted in 22.5° steps. Cross-correlograms divulged the functional connections at all the tested orientations. We show that a cell-assembly discriminates between orientations by recruiting a ‘salient’ functional network at every presented orientation, wherein, the connections and their strengths (peak-probabilities in the cross-correlogram) change from one orientation to another. Within these assemblies, closely tuned neurons exhibited increased connectivity and connection-strengths than differently tuned neurons. Minimal connectivity between untuned neurons suggests the significance of neuronal selectivity in assemblies. This study reflects upon the dynamics of functional connectivity, and brings to the fore the importance of a ‘signature’ functional network in an assembly that is strictly related to a specific stimulus. Apparently, it points to the fact that an assembly is the major ‘functional unit’ of information processing in cortical circuits, rather than the individual neurons

An international study to standardize the detection and quantitation of BCR-ABL transcripts from stabilized peripheral blood preparations by quantitative RT-PCR

Due to the lack of comparability of BCR-ABL mRNA quantification results generated by various methodologies in different laboratories, an international multicenter trial was started with the participation of six laboratories (platforms: LightCycler™, LC, n=3; TaqMan™, TM, n=3). One hundred and eighty-six PB samples derived from healthy donors were spiked with serial dilutions (1:20 to 1:2×106) of b2a2, b3a2 or e1a2 BCR-ABL positive white blood cells (WBC) from leukemic patients. After PAXgene™ stabilization, blinding, freezing and distribution, standardized RNA extraction, cDNA synthesis, PCR protocols and data evaluation were carried out. There was no significant difference in the results achieved using LC and TM technologies, but a considerable overall variation (CV=0.74 for ratios BCR-ABL/ABL). Up to a dilution of 1:1,000, 27/30 of the 2.5 mL samples tested positive. For higher dilutions, a PB volume of 5 or 10 ml was required to improve sensitivity. The study showed the feasibility of RQ-PCR standardization independent of the PCR machine used