Jerry Yin, PhD - US grants

[unreadable] DESCRIPTION (provided by applicant): Since the dawn of language, one of the most intriguing questions has been the physical location of human memories in the brain. Neurologists have inferred anatomical function from studies of injury and disease to different areas of the brain. Experimental psychologists have used brain lesion as a tool to dissect function in experimental animals. We propose to use genetic tools to address this question in the common fruit fly, Drosophila melanogaster. This genetically tractable, genome-mined and experimentally pliable model organism exhibits complex neuronal functions such as learning and memory formation, circadian biology, sleep, and stereotyped behavioral responses to addictive drugs. Because of the rich history of genetics in this animal, the total access to the genome structure and information-coding capacity, and the variety of molecular tools that can be applied, it is likely that we will achieve a complete, multilevel understanding of complex neuronal function in this organism. There are two types of consolidated memory that exists for an olfactory-avoidance behavior in Drosophila, anesthesia-resistant memory (ARM) and long-term memory (LTM). We have disrupted and enhanced both of these processes through the reverse genetic manipulation of single genes. In parallel, we have developed new technology that allows both spatial (anatomical) and temporal control over the induction of transgenes. In this proposal, we will utilize this technology to conditionally express genes that inhibit each of these types of memory. Because we can control the brain regions where the disrupting genes are expressed, it will be possible to anatomically dissect these memories. This information will provide a first-glimpse of what a memory looks like in the three-dimensional space of the brain. In mammals, there are some very intriguing temporal properties of memory formation, suggesting that memory "consolidation" is not necessarily a process with a fixed starting and ending point in time. Since we can also control when the interfering genes are induced, we will analyze temporal questions about memory formation. These experiments should help us understand the complexity of memory formation and its relationship with on-going neuronal processes. Finally, we will test the feasibility of using the spatialtemporal system to ablate adult brain neurons, providing a totally complementary approach to many of the same issues. [unreadable] [unreadable]

PROJECT SUMMARY Sleep and memory formation are both complex neurobiological emergent processes of considerable interest. The relationship between them has been a contentious issue-is sleep really necessary for memory formation (the sleep/memory hypothesis)? In this proposal, we will try to answer in a definitive manner this age-old question. Both of these processes are also commonly disrupted in neurological, neurodegenerative, and psychiatric dysfunctions. Whether improving one or the other can have broad-spectrum benefits is not clear. It is also unknown if enhancing one process will improve the other. This proposal has three broad parts. In the first, we have identified a gene that is involved in regulating sleep. Mild overexpression of this gene alters sleep, and enhances memory formation. Disrupting the gene has extreme effects on sleep. The tests (increase gene, test sleep and memory; disrupt gene, test sleep and memory) will be repeated using a second inducible system to validate current data. We will also use the gene to try to overcome sleep deprivation's harmful effects on memory formation. In the second part, we test the importance of particular times of night in memory formation. Finally, we test the functional and molecular interaction between a newly identified gene that interacts with our sleep-regulating gene. Taken together, this data should provide strong support for the sleep/memory hypothesis. This work has immediate medical impact, since almost all patients diagnosed with neurodegenerative and psychiatric diseases have sleep and cognitive problems.