Impairments in memory function can range from the moderately inconvenient benign forgetfulness with normal aging to the devastating losses associated with Alzheimer's disease. In addition, alterations in the mechanisms that underlie normal memory are thought to underlie psychiatric disorders such as depression and post-traumatic stress disorder and may contribute to relapse in addiction. This grant uses animal models to identify the cellular and molecular mechanisms of memory formation. We use a genetic technique that allows us to introduce genes into specific parts of the brain and to turn them on or off at different times either during learning or during memory retrieval. For example, in one study we looked at a mouse model of a human genetic disorder (Rubenstein Taybi Syndrome) associated with both developmental abnormalities and severe cognitive impairment. One question that we addressed was whether the cognitive defects found in adults were due a defect in brain development or due to abnormal gene function in the adult brain. By inducing the genetic lesion only in the adult we could show that it produced learning and memory defects acutely and that these defects could be reversed by turning off the defective gene. We also showed that the behavioral defects could be reversed in this mouse model with a drug that targeted the biochemical defect. We apply this approach to a number of different cellular signaling pathways in neurons that are thought to underlie memory. We also use a genetic approach to analyze the anatomical structure of memory. Using this approach we hope to identify the individual neurons that contribute specific memories. We use this to address questions such as: "Are the neurons activated during learning reactivated during recall?" and "Does the pattern of neuronal activation change as memories consolidate over time?" By studying the specific cellular circuits that underlie memory we hope to more readily identify the underlying cellular and molecular mechanisms.

Public Health Relevance

This grant examines the mechanisms of learning and memory, from how brain cells are activated with learning to what genes and molecules in the cells are important for the formation of memories. We do these studies in mice because they are surprisingly similar to humans both genetically and in terms of brain structure. Memory is a basic element of brain function that is altered in many disease states from the degenerative diseases of aging like Alzheimer's to psychiatric disorders such as schizophrenia and post-traumatic stress disorder. One of the genes we work on is the mouse analogue of a gene that produces a form of mental retardation in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH057368-14
Application #
8208054
Study Section
Neurobiology of Learning and Memory Study Section (LAM)
Program Officer
Asanuma, Chiiko
Project Start
1997-07-01
Project End
2012-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
14
Fiscal Year
2012
Total Cost
$379,900
Indirect Cost
$179,425
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Cai, Denise J; Aharoni, Daniel; Shuman, Tristan et al. (2016) A shared neural ensemble links distinct contextual memories encoded close in time. Nature 534:115-8
Sanders, Jeff; Mayford, Mark (2016) Chronic fluoxetine dissociates contextual from auditory fear memory. Neurosci Lett 632:152-6
Drane, Laurel; Ainsley, Joshua A; Mayford, Mark R et al. (2014) A transgenic mouse line for collecting ribosome-bound mRNA using the tetracycline transactivator system. Front Mol Neurosci 7:82
Mayford, Mark (2014) The search for a hippocampal engram. Philos Trans R Soc Lond B Biol Sci 369:20130161
Cowansage, Kiriana K; Shuman, Tristan; Dillingham, Blythe C et al. (2014) Direct reactivation of a coherent neocortical memory of context. Neuron 84:432-41
Sanders, Jeff; Mayford, Mark; Jeste, Dilip (2013) Empathic fear responses in mice are triggered by recognition of a shared experience. PLoS One 8:e74609
Garner, Aleena R; Rowland, David C; Hwang, Sang Youl et al. (2012) Generation of a synthetic memory trace. Science 335:1513-6
Sanders, Jeff; Cowansage, Kiriana; Baumgartel, Karsten et al. (2012) Elimination of dendritic spines with long-term memory is specific to active circuits. J Neurosci 32:12570-8
Bibb, James A; Mayford, Mark R; Tsien, Joe Z et al. (2010) Cognition enhancement strategies. J Neurosci 30:14987-92
Matsuo, Naoki; Reijmers, Leon; Mayford, Mark (2008) Spine-type-specific recruitment of newly synthesized AMPA receptors with learning. Science 319:1104-7

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