Learning-induced trophic activity is thought to be critical for maintaining health of the aging brain. We report here that learning, acting through an unexpected pathway, activates synaptic receptors for one of the brain's primary trophic factors. Unsupervised learning, but not exploratory activity alone, robustly increased the number of postsynaptic densities associated with activated (phosphorylated) forms of BDNF's TrkB receptor in adult rat hippocampus; these increases were blocked by an NMDA receptor antagonist. Similarly, stimulation of hippocampal slices at the learning-related theta frequency increased synaptic TrkB phosphorylation in an NMDA receptor-dependent fashion. Theta burst stimulation, which was more effective in this regard than other stimulation patterns, preferentially engaged NMDA receptors that, in turn, activated Src kinases. Blocking the latter, or scavenging extracellular TrkB ligands, prevented theta-induced TrkB phosphorylation. Thus, synaptic TrkB activation was dependent upon both ligand presentation and postsynaptic signaling cascades. These results show that afferent activity patterns and cellular events involved in memory encoding initiate BDNF signaling through synaptic TrkB, thereby ensuring that learning will trigger neurotrophic support.BDNF | NMDA receptor | Src kinase | theta burst stimulation | TrkB E nvironmental enrichment and learning modify brain anatomy (1) and chemistry (2, 3) in older animals and slow cognitive decline and the onset of dementia in aged humans (4). Although multiple factors likely contribute to these effects, it is generally agreed that trophic factors play a central role. These releasable peptides stimulate growth and help maintain neuronal viability (5, 6) and are logical candidates for the agency whereby experience slows age-related deterioration of brain networks (7). However, there is little evidence that learning or learning-related patterns of electrical activity actually stimulate neurotrophic signaling at brain synapses. The absence of tests of the learning/ trophic signaling hypothesis is likely due to difficulties in sampling the activation state of proteins in the very small percentage of synapses affected by physiologically relevant patterns of activity or by learning itself (8, 9). Recent advances in restorative deconvolution microscopy have partly obviated these problems (8, 10). We used these techniques in the present studies to test the hypothesis that learning and learning-related brain rhythms cause the rapid activation of BDNF's TrkB receptor within synapses of the adult hippocampus.BDNF is of particular interest with regard to experience and aging because its expression by cortical neurons is both regulated by activity (11) and related to age-associated changes in brain anatomy and functioning (12). Accordingly, we focused on BDNF and asked if a 30 min period of a ubiquitous form of mammalian learning (i.e., unsupervised learning of a novel environment) increases the number of synapses containing the activated form of TrkB (13). W...
To date, no consensus exists regarding indication, technique, or efficacy of distal perfusion cannulae (DPC) in preventing limb ischemia among patients receiving venoarterial extracorporeal membrane oxygenation (VA-ECMO). We aim to examine the available literature and report association between DPC and risk of limb ischemia. PubMed/Medline, Scopus, Cochrane Central Register of Controlled Trials, Google Scholar, and bibliographies of included studies were searched from database inception until August 2016. Original studies describing the DPC placement technique and incidence of limb ischemia following DPC placement among VA-ECMO patients were included for systematic review. Studies with a comparison group of patients without DPC were included for meta-analysis. Two authors independently screened title/abstracts, reviewed full texts, and extracted data from the eligible studies. Meta-analysis was performed using the Mantel-Haenszel method under a random-effects model. Statistical heterogeneity was examined with the I2 statistic (RevMan Version 5.3). Of 542 title/abstracts screened, 62 full text articles were selected for review, yielding 22 retrospective observational studies, for a total of 779 patients with 132 limb ischemia events. There was significant variation in DPC indication, cannula type, and placement technique among the studies. Compared to no DPC, the presence of a DPC was associated with at least a 15.7% absolute reduction in the incidence of limb ischemia (9.74 vs. 25.42%; risk ratio 0.41; 95% confidence interval 0.26-0.65, P < 0.01; heterogeneity statistic I2 = 28%). There was no statistically significant difference in mortality in the pooled dataset comparing DPC versus no DPC. In adults treated with VA-ECMO, DPC placement was associated with a lower incidence of limb ischemia. Currently no consensus guidelines exist regarding indication for DPC placement. Given the association described in this analysis, future prospective trials are warranted to establish a causal relationship and optimal technique for the use of DPC in patients treated with VA-ECMO.
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