Thursday, April 3, 2025
4/3/2025
A serotonergic circuit controlling the circadian rhythm in Drosophila olfactory learning - The endogenous circadian clock modulates performance and cognitive function with rhythms in learning and memory evident across species. In our modern workforce individuals work at adverse circadian times resulting in impaired cognitive performance in these individuals, in addition to economic costs and public safety risks to society. Furthermore, circadian desynchronization, a rising public health problem, increases the risk of neurodegenerative diseases and cognitive impairments, which is projected to put a substantial economic burden on our healthcare system as the population ages. Defining the molecular mechanisms through which the circadian clock targets learning is crucial to identifying methods to not only prevent cognitive impairments but to optimize performance and health in modern society. The ability to enhance learning and memory at non- adaptive times of day would represent a significant advance in human health and performance. The long-term goal of this project is to define the neural circuits and molecular signaling pathways used by the central circadian oscillator to enforce a rhythm in olfactory learning in Drosophila melanogaster. Drosophila displays a robust circadian rhythm in short-term memory formation. The identity and function of both central clock neurons and olfactory learning circuits are well established in Drosophila, with many tools available to manipulate neuronal activity with great specificity, making Drosophila an ideal model for this study. The central hypothesis is that the endogenous circadian circuit modulates neurotransmission from the serotonergic DAL neurons to the Mushroom Bodies, activating 5-HT1A receptors in the Mushroom Bodies, resulting in circadian rhythms in learning. The rationale for the proposed research is that understanding an evolutionarily conserved mechanism for the circadian control of memory acquisition can be used to understand learning modulation better and to improve cognitive performance. This understanding will be developed with two specific aims: 1) Determine the role of the Dorsal Anterior Lateral Neurons in controlling the circadian rhythm in olfactory learning. 2) Determine if 5HT1A signaling in the α/β posterior neurons is required for the rhythm in olfactory learning. The proposed experiments will elucidate how and where the clock circuit alters the learning circuit. The approach is innovative because it focuses on improving cognitive performance by identifying mechanisms through which the circadian clock regulates learning to produce time-of-day dependent decrements in performance and cognitive function. The proposed research is significant because the neurocircuitry and molecular mechanism by which endogenous clocks directly regulate learning are poorly understood in any system. The impact of time-of-day on cognitive performance is widespread, and the consequences of out-of-phase performance can be devastating and costly. Ultimately, understanding the logic underlying circadian control of memory formation will permit further work to improve human health, alleviate some of the pressure on our healthcare system, and lower the economic burden from neurodegenerative diseases and cognitive impairment.
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