Activity-dependent plasticity of transmitter release from nerve terminals in rat fast and slow muscles

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Stability of Negative Image Equilibria in Spike-Timing Dependent Plasticity

We investigate the stability of negative image equilibria in mean synaptic weight dynamics governed by spike-timing dependent plasticity (STDP). The neural architecture of the model is based on the electrosensory lateral line lobe (ELL) of mormyrid electric fish, which forms a negative image of the reafferent signal from the fish's own electric discharge to optimize detection of external electric fields. We derive a necessary and sufficient condition for stability, for arbitrary postsynaptic potential functions and arbitrary learning rules. We then apply the general result to several examples of biological interest.Comment: 13 pages, revtex4; uses packages: graphicx, subfigure; 9 figures, 16 subfigure

Long-Term Potentiation: One Kind or Many?

Do neurobiologists aim to discover natural kinds? I address this question in this chapter via a critical analysis of classification practices operative across the 43-year history of research on long-term potentiation (LTP). I argue that this 43-year history supports the idea that the structure of scientific practice surrounding LTP research has remained an obstacle to the discovery of natural kinds

Novel Mouse Model Reveals Distinct Activity-Dependent and –Independent Contributions to Synapse Development

The balanced action of both pre- and postsynaptic organizers regulates the formation of neuromuscular junctions (NMJ). The precise mechanisms that control the regional specialization of acetylcholine receptor (AChR) aggregation, guide ingrowing axons and contribute to correct synaptic patterning are unknown. Synaptic activity is of central importance and to understand synaptogenesis, it is necessary to distinguish between activity-dependent and activity-independent processes. By engineering a mutated fetal AChR subunit, we used homologous recombination to develop a mouse line that expresses AChR with massively reduced open probability during embryonic development. Through histological and immunochemical methods as well as electrophysiological techniques, we observed that endplate anatomy and distribution are severely aberrant and innervation patterns are completely disrupted. Nonetheless, in the absence of activity AChRs form postsynaptic specializations attracting motor axons and permitting generation of multiple nerve/muscle contacts on individual fibers. This process is not restricted to a specialized central zone of the diaphragm and proceeds throughout embryonic development. Phenotypes can be attributed to separate activity-dependent and -independent pathways. The correct patterning of synaptic connections, prevention of multiple contacts and control of nerve growth require AChR-mediated activity. In contrast, myotube survival and acetylcholine-mediated dispersal of AChRs are maintained even in the absence of AChR-mediated activity. Because mouse models in which acetylcholine is entirely absent do not display similar effects, we conclude that acetylcholine binding to the AChR initiates activity-dependent and activity-independent pathways whereby the AChR modulates formation of the NMJ

A Novel Labeling Approach Identifies Three Stability Levels of Acetylcholine Receptors in the Mouse Neuromuscular Junction In Vivo

The turnover of acetylcholine receptors at the neuromuscular junction is regulated in an activity-dependent manner. Upon denervation and under various other pathological conditions, receptor half-life is decreased., in our setup the same animals are used throughout the whole measurement period, thereby permitting a dramatic reduction of animal numbers at increased data quality. We identified three stability levels of acetylcholine receptors depending on the presence or absence of innervation: one pool of receptors with a long half-life of ∼13 days, a second with an intermediate half-life of ∼8 days, and a third with a short half-life of ∼1 day. Data were highly reproducible from animal to animal and followed simple exponential terms. The principal outcomes of these measurements were reproduced by an optical pulse-labeling assay introduced recently.A novel assay to determine kinetics of acetylcholine receptor turnover with small animal numbers is presented. Our data show that nerve activity acts on muscle acetylcholine receptor stability by at least two different means, one shifting receptor lifetime from short to intermediate and another, which further increases receptor stability to a long lifetime. We hypothesize on possible molecular mechanisms

Growth regulation of simian and human AIDS-related non-Hodgkin's lymphoma cell lines by TGF-β1 and IL-6

BACKGROUND: AIDS-related non-Hodgkin's lymphoma (AIDS-NHL) is the second most frequent cancer associated with AIDS, and is a frequent cause of death in HIV-infected individuals. Experimental analysis of AIDS-NHL has been facilitated by the availability of an excellent animal model, i.e., simian Acquired Immunodeficiency Syndrome (SAIDS) in the rhesus macaque consequent to infection with simian immunodeficiency virus. A recent study of SAIDS-NHL demonstrated a lymphoma-derived cell line to be sensitive to the growth inhibitory effects of the ubiquitous cytokine, transforming growth factor-beta (TGF-beta). The authors concluded that TGF-beta acts as a negative growth regulator of the lymphoma-derived cell line and, potentially, as an inhibitory factor in the regulatory network of AIDS-related lymphomagenesis. The present study was conducted to assess whether other SAIDS-NHL and AIDS-NHL cell lines are similarly sensitive to the growth inhibitory effects of TGF-beta, and to test the hypothesis that interleukin-6 (IL-6) may represent a counteracting positive influence in their growth regulation. METHODS: Growth stimulation or inhibition in response to cytokine treatment was quantified using trypan blue exclusion or colorimetric MTT assay. Intracellular flow cytometry was used to analyze the activation of signaling pathways and to examine the expression of anti-apoptotic proteins and distinguishing hallmarks of AIDS-NHL subclass. Apoptosis was quantified by flow cytometric analysis of cell populations with sub-G1 DNA content and by measuring activated caspase-3. RESULTS: Results confirmed the sensitivity of LCL8664, an immunoblastic SAIDS-NHL cell line, to TGF-beta1-mediated growth inhibition, and further demonstrated the partial rescue by simultaneous treatment with IL-6. IL-6 was shown to activate STAT3, even in the presence of TGF-beta1, and thereby to activate proliferative and anti-apoptotic pathways. By comparison, human AIDS-NHL cell lines differed in their responsiveness to TGF-beta1 and IL-6. Analysis of a recently derived AIDS-NHL cell line, UMCL01-101, indicated that it represents immunoblastic AIDS-DLCBL. Like LCL-8664, UMCL01-101 was sensitive to TGF-beta1-mediated inhibition, rescued partially by IL-6, and demonstrated rapid STAT3 activation following IL-6 treatment even in the presence of TGF-beta1. CONCLUSION: These studies indicate that the sensitivity of immunoblastic AIDS- or SAIDS-DLBCL to TGF-beta1-mediated growth inhibition may be overcome through the stimulation of proliferative and anti-apoptotic signals by IL-6, particularly through the rapid activation of STAT3

Towards screening Barrett’s Oesophagus: current guidelines, imaging modalities and future developments

Barrett’s oesophagus is the only known precursor to oesophageal adenocarcinoma (OAC). Although guidelines on the screening and surveillance exist in Barrett’s oesophagus, the current strategies are inadequate. Oesophagogastroduodenoscopy (OGD) is the gold standard method in screening for Barrett’s oesophagus. This invasive method is expensive with associated risks negating its use as a current screening tool for Barrett’s oesophagus. This review explores current definitions, epidemiology, biomarkers, surveillance, and screening in Barrett’s oesophagus. Imaging modalities applicable to this condition are discussed, in addition to future developments. There is an urgent need for an alternative non-invasive method of screening and/or surveillance which could be highly beneficial towards reducing waiting times, alleviating patient fears and reducing future costs in current healthcare services. Vibrational spectroscopy has been shown to be promising in categorising Barrett’s oesophagus through to high-grade dysplasia (HGD) and OAC. These techniques need further validation through multicentre trials