Modeling the Molecular Networks that Underlie the Formation and Consolidation of Memory

PROJECT SUMMARY/ABSTRACT
This proposal will test the hypothesis that learning and memory can be improved by using computationally
designed training protocols that optimize the interactions among kinase cascades and transcription factors
involved in the induction of long-term memory (LTM). Three model systems will be used: long-term sensitization,
fear conditioning and extinction, and inhibitory avoidance learning. This hypothesis is based on our previous
work demonstrating that computationally designed protocols maximizing the overlap of activities between protein
kinase A (PKA) and the mitogen-activated protein kinase (MAPK) isoform termed extracellular signal-regulated
kinase (ERK) enhance long-term synaptic facilitation (LTF) and LTM for sensitization, as well as the acquisition
and extinction of fear learning. This proposal has two key innovative aspects. First, we utilize a novel, multi-
disciplinary strategy to enhance learning and improve different types of memory retrieval. Pharmacological
interventions to improve learning and memory, and rescue memory deficits, have been ongoing for many
decades, but these approaches rely on trial-and-error and are highly nonspecific. In contrast, the strategy we
have developed, combining biologically realistic computational models with empirical approaches, enables us to
efficiently and systematically explore the molecular processes that underlie different types of long-term synaptic
plasticity, and predict individual training protocols to optimize learning and memory. Second, to our knowledge,
our groups are the first to develop a computational model describing the possible mechanism underlying infantile
learning and the apparent rapid forgetting associated with infantile amnesia. Our simulations suggest that altered
regulation of basal activities of kinases and transcription factors in infant animals contributes to fast forgetting of
infantile memory. Specific hypotheses to be tested by simulation and in vivo experiments include: Aim 1) LTF
and LTM for sensitization can be prolonged up to 7 days by novel computationally designed training protocols;
Aim 2) Computationally designed protocols based on the dynamics of amygdala kinases can enhance the
acquisition and extinction of conditioned fear memories; and Aim 3) The apparent rapid forgetting of infantile
memory observed in an inhibitory avoidance paradigm can be overcome by computationally designed protocols
based on the dynamics of hippocampal kinases. We believe that these predictions, combined with concurrent
empirical tests, will provide a proof of principle for an efficient strategy to enhance learning and improve memory
retrieval. Our study may have clinical relevance for interventions aiming at facilitating memory formation in a
series of psychiatric disorders associated with cognitive impairment in humans, as well as for improving
extinction-based therapies in patients suffering from anxiety-related disorders.

Grant Number: 5R01NS102490-09
NIH Institute/Center: NIH
Principal Investigator: John Byrne