This proposal is for a long-term and flexible research program designed to obtain key insights into the biology of learning and memory. Although flexibility is inherent in its design, such that novel observations made over the course of the research can and will be pursued without delay, the program is grounded in three major lines of research: (1) the molecular, cellular, and systems neuroscience that underlie the process of active forgetting, (2) the logic by which the brain organizes different types of olfactory memories among its component neurons, and (3) the identification and characterization of protein-coding and microRNA genes that function to suppress the process of memory formation. The active forgetting component stems from the recent identification of a signaling system that removes previously formed memories and is modulated by internal states of arousal and sleep, and by external sensory stimulation. This represents an unstudied area in the neuroscience of memory formation and offers tremendous opportunities for discovery in the molecular biology and systems neuroscience of the process. The second component is founded on innovative discoveries that allow the visualization of cellular memory traces ? changes in the response properties of neurons due to learning ? that offer a window into the logic behind how memories are organized in the brain. This component contrasts, as one example, how the brain organizes olfactory memories learned in association with a rewarding cue and those learned in association with an aversive cue, and delves into the underlying mechanisms. The third component derives from recent genetic screens that have provided a plethora of new genes, both protein- coding and microRNA-coding, which enhance memory when suppressed, thus representing new memory suppressor genes. The proposed behavioral, functional cellular imaging, and molecular genetic experiments will dissect the roles for these genes in different temporal forms of memory: short-, intermediate-, and long- term memory; as well as different operational phases of memory formation: acquisition, memory stability, or forgetting. The results will offer an unprecedented view of the constraints the brain uses to limit memory formation. There is a rich medical importance to this research given the well-documented problems of cognition associated with numerous neurological and psychiatric disorders.

Public Health Relevance

The majority of human neurological and psychiatric disorders involve impairment in learning and memory. This research program delves into the process of memory formation, with a focus on the brain mechanisms that mediate forgetting, how the brain organizes memories, and the roles for genes that suppress memory formation. The knowledge obtained from these studies will provide new information that may lead to diagnostics or therapies for brain disorders.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Unknown (R35)
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Special Emphasis Panel (ZNS1)
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Babcock, Debra J
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Scripps Florida
United States
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Crittenden, Jill R; Skoulakis, Efthimios M C; Goldstein, Elliott S et al. (2018) Drosophila mef2 is essential for normal mushroom body and wing development. Biol Open 7:
Muntean, Brian S; Zucca, Stefano; MacMullen, Courtney M et al. (2018) Interrogating the Spatiotemporal Landscape of Neuromodulatory GPCR Signaling by Real-Time Imaging of cAMP in Intact Neurons and Circuits. Cell Rep 24:1081-1084
Yu, Dinghui; Tan, Ying; Chakraborty, Molee et al. (2018) Elongator complex is required for long-term olfactory memory formation in Drosophila. Learn Mem 25:183-196
Berry, Jacob A; Phan, Anna; Davis, Ronald L (2018) Dopamine Neurons Mediate Learning and Forgetting through Bidirectional Modulation of a Memory Trace. Cell Rep 25:651-662.e5
Busto, Germain U; Guven-Ozkan, Tugba; Davis, Ronald L (2017) MicroRNA function in Drosophila memory formation. Curr Opin Neurobiol 43:15-24
Himmelreich, Sophie; Masuho, Ikuo; Berry, Jacob A et al. (2017) Dopamine Receptor DAMB Signals via Gq to Mediate Forgetting in Drosophila. Cell Rep 21:2074-2081
Cervantes-Sandoval, Isaac; Phan, Anna; Chakraborty, Molee et al. (2017) Reciprocal synapses between mushroom body and dopamine neurons form a positive feedback loop required for learning. Elife 6:
Davis, Ronald L; Zhong, Yi (2017) The Biology of Forgetting-A Perspective. Neuron 95:490-503