Information encoding in the brain is thought to be reflected in the pattern of activation of excitatory neurons in response to a given stimulus. This suggests that, in essence, a neural cell type is defined by the various stimuli and conditions that recruit its electrical activity. Alterations in activity in specific brain regions are associated wth a variety of neurological and psychiatric diseases and the pharmacological interventions to treat these diseases alter activity in specific circuits. The cellular and molecular changes that underli complex cognitive functions such as learning and memory are likely to occur at critical specific points in the circuits activated by the relevant stimuli. A great deal of effort in neuroscience is focused on defining these activated circuits however, currently available techniques are limited to discrete brain areas, lack cellular specificity, or provide a record of activity at only a singl time point preventing the identification of consistent patterns of network activation from noise or the identification of network changes over time in response to intervention. The approach that we will develop in this grant uses a single florescent marker to identify neural activity patterns t two independent time points. This provides a number of advantages over existing technology including, the ability to analyze the brain using high throughput automated imaging techniques, to identify specific cell populations in brain slices based on their activation patterns in the whoe animal for electrophysiological, morphological, or molecular studies, and the ability to apply FACS sorting techniques to the isolation of individual nuclei for epigenetic studies. The two time points at which activity is reported can be separated by at least one week allowing the analysis of circuit changes and target cell populations that are responsive to prolonged behavioral or pharmacological intervention. This should be useful in identifying the critical changes in the brain in response to these therapies.

Public Health Relevance

The pattern of nerve cells activation in response to a given stimulus is a critical component of information processing in the brain. We have developed a technique that allows the molecular tagging of neurons based on their electrical activity at 2 independent time points. This approach can be applied to the understanding of normal brain function and dysfunction in disease models and in the characterization of therapeutic agents that treat neurological and psychiatric disease.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Special Emphasis Panel (ZRG1-CB-D (50))
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Wu, Da-Yu
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Scripps Research Institute
La Jolla
United States
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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
Mayford, Mark; Reijmers, Leon (2015) Exploring Memory Representations with Activity-Based Genetics. Cold Spring Harb Perspect Biol 8:a021832
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; 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