Phosphatidylinositol 3-kinase (PI3K) and its downstream targets, including Akt (also known as protein kinase B, PKB), mammalian target of rapamycin (mTOR), the 70-kDa ribosomal S6 kinase (p70S6k), and the eukaryotic initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1), may play important roles in long-term synaptic plasticity and memory in many brain regions, such as the hippocampus and the amygdala. The present study investigated the role of the PI3K/Akt-mTOR signaling pathway in the medial prefrontal cortex (mPFC), also a crucial neural locus for the control of cognition and emotion. Western blot analysis of mPFC tissues showed an activation of phosphorylation of Akt at the Ser473 residues, mTOR, p70S6k, and 4E-BP1 in response to long-term potentiation (LTP)-inducing high-frequency stimulation (HFS). Infusion of PI3K inhibitors (wortmannin and LY294002) and an mTOR inhibitor (rapamycin) into the mPFC in vivo suppressed HFS-induced LTP as well as the phosphorylation of PI3K/Akt-mTOR signaling pathway. In parallel, these inhibitors interfered with the long-term retention of trace fear memory examined 3 d and 6 d after the trace fear conditioning training, whereas short-term trace fear memory and object recognition memory were kept intact. These results provide evidence of involvement of activation of the PI3K/Akt-mTOR signaling pathway in the mPFC for LTP and long-term retention of trace fear memory. 相似文献
Traditional mediation analysis assumes that a study population is homogeneous and the mediation effect is constant over time, which may not hold in some applications. Motivated by smoking cessation data, we propose a latent class dynamic mediation model that explicitly accounts for the fact that the study population may consist of different subgroups and the mediation effect may vary over time. We use a proportional odds model to accommodate the subject heterogeneities and identify latent subgroups. Conditional on the subgroups, we employ a Bayesian hierarchical nonparametric time-varying coefficient model to capture the time-varying mediation process, while allowing each subgroup to have its individual dynamic mediation process. A simulation study shows that the proposed method has good performance in estimating the mediation effect. We illustrate the proposed methodology by applying it to analyze smoking cessation data.
I shall show that the main argument forms of Wittgenstein's Tractatus and Kant's Critique of Pure Reason are Modus Tollens. I shall then argue that the main arguments of both books beg the question by addressing only one sub‐argument in each, although it is still in controversy whether begging the question is a genuine fallacy. 相似文献