Sleep is critical for hippocampus-dependent memory consolidation. However, the underlying mechanisms of synaptic plasticity are poorly understood. The central controversy is on whether long-term potentiation (LTP) takes a role during sleep and which would be its specific effect on memory. To address this question, we used immunohistochemistry to measure phosphorylation of Ca2+/calmodulin-dependent protein kinase II (pCaMKIIα) in the rat hippocampus immediately after specific sleep-wake states were interrupted. Control animals not exposed to novel objects during waking (WK) showed stable pCaMKIIα levels across the sleep-wake cycle, but animals exposed to novel objects showed a decrease during subsequent slow-wave sleep (SWS) followed by a rebound during rapid-eye-movement sleep (REM). The levels of pCaMKIIα during REM were proportional to cortical spindles near SWS/REM transitions. Based on these results, we modeled sleep-dependent LTP on a network of fully connected excitatory neurons fed with spikes recorded from the rat hippocampus across WK, SWS and REM. Sleep without LTP orderly rescaled synaptic weights to a narrow range of intermediate values. In contrast, LTP triggered near the SWS/REM transition led to marked swaps in synaptic weight ranking. To better understand the interaction between rescaling and restructuring during sleep, we implemented synaptic homeostasis and embossing in a detailed hippocampal-cortical model with both excitatory and inhibitory neurons. Synaptic homeostasis was implemented by weakening potentiation and strengthening depression, while synaptic embossing was simulated by evoking LTP on selected synapses. We observed that synaptic homeostasis facilitates controlled synaptic restructuring. The results imply a mechanism for a cognitive synergy between SWS and REM, and suggest that LTP at the SWS/REM transition critically influences the effect of sleep: Its lack determines synaptic homeostasis, its presence causes synaptic restructuring.
RATIONALE: The Composite Asthma Severity Index (CASI) is a validated, multidimensional instrument for determining asthma severity using 5 domains: day symptoms and albuterol use, night symptoms and albuterol use, controller treatment, lung function, and exacerbations (Wildfire et al., JACI 2012). In this post hoc analysis from a randomized, controlled trial of omalizumab, CASI was examined as a tool for assessing impact of treatment intervention in children > _6 to <12 years with moderate-to-severe persistent allergic asthma. METHODS: Poisson regression analysis examined exacerbation rate reductions for omalizumab versus placebo at Week 24 stratified by median CASI score at baseline (< _7 (n5360) vs. >7 (n5216)). A higher CASI score indicates more severe asthma. Clinically significant exacerbations were defined as those requiring either systemic corticosteroid therapy or a doubling of baseline inhaled corticosteroid dose for > _3 days. RESULTS: Baseline age, sex, total IgE and eosinophil levels were similar between treatment groups and across CASI strata. The CASI>7 group had higher proportions of black children, males, lower mean percent predicted pre-bronchodilator FEV 1 , and greater maximum reversibility than the CASI< _7 group. Exacerbation rates were reduced by the following for omalizumab versus placebo: CASI< _7, 20% (-16%, 44%; p50.24); CASI>7, 45% (18%, 63%; p50.004). CONCLUSIONS: CASI is a useful clinical tool to identify children who are likely to achieve favorable response to omalizumab. In children with greater asthma severity, as measured by a higher CASI score, a significantly greater response to omalizumab was observed for exacerbation reduction versus placebo; children with lower CASI scores had nonsignificant differences in reductions in exacerbation rates.
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