How does the brain encode experience so that future behaviors are changed? Altered neural function that long outlasts experience characterizes brain processes from learning to memory modification to resetting the circadian clock, which patterns behavioral changes over the day-night cycle. Underlying mechanisms are not understood. Consensus is emerging that stimulus-induced remodeling of the actin-based cellular architecture redistributes key informational proteins bound there. Which proteins mediate this change? The researcher will use the power of the mammalian circadian clock, where mechanisms, including plasticity, are evolutionarily ancient and conserved, and control of the rhythmic homeostatic patterning of daily behaviors is localized within one brain site, the suprachiasmatic nucleus (SCN). They will employ a cross-disciplinary approach, combining novel analytical chemistry that enables large-scale analysis and identification of actin-binding proteins in local brain regions with neurophysiology and behavior. The researcher will manipulate SCN actin state, comparing effects of natural neural signals on actin-associated proteins with reagents that directly activate or inhibit actin remodeling. This broad approach will permit discovery of protein complexity necessary for circadian neural and behavioral plasticity. Coupled proteomic and functional analyses will provide new insights on how sensory experience is integrated into a long-lasting response spanning molecular, cellular, brain and behavioral levels. Research on this evolutionarily ancient brain system will identify a set of core plasticity elements that may contribute critical emergent properties to all forms of brain plasticity. Thus, findings will impact understanding of fundamental principles of experience-induced brain adaptation. Beyond scientific inquiry, this study will provide training opportunities at the intersection of analytical chemistry and neuroscience for students in the laboratory, as well as outreach to undergraduates, especially minorities under-represented in science.
Neural plasticity, the functional adaptability of the nervous system, characterizes multiple brain processes, including learning and memory, homeostatic accommodations in sleep, and circadian clock progression and resetting. Our focus was on elucidating changes in the proteome that underlies the dynamic states of the near-24-hour (circadian) clock in the suprachiasmatic nucleus (SCN). This biological timing system orchestrates adaptive modulation of physiology, metabolism, and behavior of all mammals to key environmental variables, the daily and seasonal changes in light and darkness. Cellular changes that include protein expression and localization in neurons encode time-of-day and experience, modulating behavioral responses to an ever-changing world. Thus, our discovery of constellations of protein players is an important contribution to understanding this complex dynamic system. This multidisciplinary project bridged neurobiology, analytical chemistry, and bioinformatics to enable proteomic analysis of small samples of brain. In collaboration with analytical chemist Jonathan Sweedler, we to developed new analytical technologies, including methods for analyzing changes in proteins associated with the cytoskeleton, and made them available to the broad scientific community. Findings were presented at 15 scientific meetings. Products are 19 abstracts and 7 journal articles, including a ‘methods masterclass’ aimed at graduate students. BROADER IMPACTS: Intellectual Merit: The concept of circadian plasticity is emerging as a cellular process related to the neural plasticity that underlies learning and long-lasting changes in the brain. This study contributes to its development. A broader scientific contribution is a ‘state of the science’ paper on circadian plasticity, the cellular changes within the circadian system that encode experience. Experience-based remodeling of cellular substrates enables adaptive behavioral responses to dynamics in nature. This article focuses on cellular substrates of plasticity in the brain’s circadian clock within a set of complementary considerations of "Sleep and Circadian Rhythms in Plasticity and Memory". This volume will be published by Frontiers in Systems Neuroscience early in 2014. Frontiers, a Swiss open-access publisher, recently partnered with Nature Publishing Group to expand its researcher-driven Open Science platform. Frontiers articles are freely disseminated and widely read by broad scientific communities. Frontiers will compile an e-book, as soon as all contributing articles are published, that can be used in classes, and by funding agencies, journalists, and press agencies. Educational: In addition to scientific impacts, we accomplished several educational outcomes. A major goal of this project was to develop and implement an assessment of undergraduate biology majors to determine how experience in laboratory research might alter their views on the nature of science. We also developed new courses that bring cutting-edge research to undergraduates, contributed to cross-disciplinary education bridging biology/neuroscience with chemistry, material science, and engineering, and engaged under-served groups. This grant contributed to training 5 graduate students. 1. Views of the Nature of Science Course/Assessment Complementing our research goals is an educational goal to educate the next generation of scientists in neurobiology, especially the literature and techniques for probing neuromodulatory mechanisms in the brain’s circadian system. We developed a course, Discovery in Circadian Biology, that provides undergraduate students the opportunity to "learn by doing", acquiring neuroscience understanding and research skills by fostering interaction of students with primary research. Discovery in Circadian Biology enrolls undergraduates with the objective of introducing them as freshman/sophomores to bench research and primary literature. This multi-year course trained 38 students (17 women); 34 undertook post-graduate studies. We developed and implemented comprehensive assessment questionnaire and merit-tracking of skill and content goals. We developed and implemented an evaluation plan based on pre- and post-questionnaires that enable STEM-education researchers to determine the impact of the research experience and mentoring on the views of the nature of science on these University of Illinois students. 2. Cross-disciplinary Educational Interactions We actively engage with students across disciplines, including analytical chemistry and bioengineering. I participated in developing/delivering a discovery course designed to introduce first-semester biology and engineering freshmen to contemporary concepts in neuroscience and engineering, Interdisciplinary Research and Education in Biology, Engineering, and Health Science: Discovering Neuroscience Research: New Methods & Technologies for Understanding the Brain. I developed 2 capstone courses for seniors/grad students: Special Topics in Biological Rhythms in Health and Disease, and Special Topics in the Cytoskeleton. This course on the cytoskeleton, which was co-taught will actin biologist Bill Brieher, attracted students from the life sciences, neuroscience, biophysics, bioengineering, and mechanical engineering. We initiated a regular discussion group of chemistry, neuroscience, bioengineering, and cell biology graduate students working at the interface of these disciplines. 3. Interactions with Under-served Populations and Institutions I interact with minority-serving institutions, including City College of New York (CCNY), Morehouse College, and University of California at Merced. I traveled to UC-Merced to develop liaisons for enhancing educational and research activities, and interact with women and under-served minorities. These engagements offer opportunities to interface with highly promising under-served students, faculty, and institutions formally via lectures, and informally during poster presentations and research training.
