Although in the last ten years there have been significant inroads into the molecular, cellular and systemsmechanisms that mediate the early stages of contextual fear conditioning, a model of emotional memory,later stages of this process remain poorly understood. Recently our laboratory reported genetic, imagingand reversible lesion evidence that supports the idea that long-term memory for contextual conditioningdepends on cortical regions, such as the anterior cingulate. Now, we propose to use a combination ofgenetics, transgenics, electrophysiology and 2-photon in vivo imaging to unravel the molecular and cellularmechanisms of cortical plasticity that underlie remote emotional memory.
The specific aims of Project 1 are:1- To identify genes specifically required for remote memory for contextual conditioning. In our ReverseForward Genetic (RFG) pilot screen, out of 55 transgenics and KOs selected with a random numbergenerator from the Jackson Laboratory collection, we found that 2 affect specifically 7-day memory (remote)for contextual conditioning, without disrupting 1-day memory (recent), general activity levels or shockreactivity. We now propose to extend this screen and test contextual fear conditioning in another 350transgenic and KO mutants. These mutants will then be screened for somatosensory (Project 2) and visual(Project 3) plasticity deficits, as a preamble for mechanistic studies (see below) to unravel the molecular andphysiological mechanisms underlying the later stages of cortical and behavioral plasticity.2- To derive region and temporally specific mutations for genes that affect long-term memory for contextualconditioning. We propose to use the loxP/Cre recombinase system to control the cell types, brain regionsand temporal expression of the mutations isolated in aim 1. The resulting mice will be tested for memorydeficits and will also be studied in Projects 2 and 3.3- To uncover cortical molecular mechanisms underlying the turnover and stability of spines in the anteriorcingulate. Plasticity, including behavioral plasticity (i.e. remote memory), is thought to involve changes inneuronal structure required for consolidation and stability of stored information. We propose to use 2-photonscanning confocal in vivo imaging to examine whether mutations that affect remote memory also affectturnover and stability of spines in cortical regions required for remote memory (i.e. anterior cingulate) intrained and untrained (contextual conditioning) mutants and controls. These studies will parallel relatedimaging studies carried out in Projects 2 and 3.All together, the studies described here and related studies in Projects 2 and 3 will unravel fundamentalmolecular, cellular and structural mechanisms of how the neocortex encodes and stores information. Thesefindings will have a key impact on how we study and treat disorders associated with emotional memory.
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