Memory deficits affect a substantial portion of the population. Thus, a key goal of research on memory mechanisms is to develop strategies for improving long-term memory (LTM). Recently we developed a strategy for improving LTM, which relies on 'tuning' training protocols to match the dynamics of the underlying signaling pathways. Computational and empirical studies focused on the molecular pathways involved in long- term synaptic facilitation (LTF; a cellular correlate of LTM). A model of two signaling pathways that are critical for LTF (the cAMP/PKA and Raf/MEK/ERK pathways) was developed. Using simulations, a novel training protocol (the 'Enhanced' protocol) was tuned to match the dynamics of these two pathways and improve the simulated LTF. Empirical studies revealed that the Enhanced protocol indeed increased LTF in sensorimotor cultures, increased phosphorylation of CREB1 (a transcription factor that is critical for LTM formation), and improved LTM following behavioral training. The goals of the current proposal are to investigate the ways in which the Enhanced protocol affects downstream components of the molecular network underlying LTF and to apply this new strategy to restoring memory deficits (via novel training protocols and/or pharmacological interventions) that are induced by molecular lesions. The Specific Aims are: 1) Quantify activation of the cAMP/PKA and Raf/MEK/ERK pathways and the transcription factors CREB1, CREB2, and C/EBP in response to the Enhanced protocol. More detailed information about the dynamics of these pathways and their responses to training can further improve the predictive power of the computational model, and with an improved model, more complex features of LTM can be studied (see Aim 3). 2) Examine whether computationally designed pharmacological manipulations of the PKA and ERK pathways can increase LTF and long-term excitability (LTE, another cellular correlate of LTM). In principle, memory can be improved by administering drugs alone. However, drugs often have unacceptable side effects. Aim 2 will examine whether combinations of lower, less toxic doses of drugs can improve memory. 3) Determine whether computationally predicted training protocols and pharmacological regimens can restore impaired LTF and LTE. Memory impairment is often the result of mutations/deletions in genes controlling signaling pathways involved in LTM. Using RNAi technology, Aim 3 will examine whether memory impairment induced by molecular lesions can be overcome by computer-designed training protocols and/or pharmacological interventions. Although these studies will utilize a simple model system and the molecular defects will be acute rather than congenital, the results will provide important insights into the interactions among training protocols, pharmacological treatments and molecular defects. The success of these studies will help the development of a new paradigm for cognitive enhancement that can have broad generality, including improving human health.