A key question in attempts to understand brain function is how does the electrical activity of neurons give rise to specific perceptions or memories? What is the neural representation of the external world or of past events? While there is a basic understanding of brain circuits at the macroscopic level between defined anatomical regions and to a lesser extent locally within brain regions, there are currently no techniques that allow the identification or manipulation of neuronal ensembles that represent a specific external stimulus or event. The primary goal of this proposal is to improve and extend upon a genetic approach that we have developed that uses the cfos promoter and the tetracycline system to allow the introduction of long lasting genetic tags into active neuronal ensembles (Reijmers et al. 2007;Matsuo et al. 2008). We will develop and validate transgenic mouse lines that allow the direct electrical and biochemical manipulation of environmentally activated neuronal ensembles. If successful, these mice will provide a tool that should be generally useful throughout a wide range of neuroscience disciplines.

Public Health Relevance

The human mind is made up of specific bits of knowledge and memories that are integrated within a relational network. Many neurological and neuropsychiatric disorders lead to a disruption of memories or of the cognitive framework in which these memories exists. In this proposal we develop mouse models that allow us to genetically alter, and thus manipulate electrically and molecularly, neurons that make up specific memories. These tools should be useful in dissecting the underlying circuit structure of specific memories, how they are accessed, and how they are disrupted in disease models.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-ETTN-G (52))
Program Officer
Satterlee, John S
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Scripps Research Institute
La Jolla
United States
Zip Code
Sanders, Jeff; Mayford, Mark (2016) Chronic fluoxetine dissociates contextual from auditory fear memory. Neurosci Lett 632:152-6
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