Memory is a fundamental biological process involving orchestration of a myriad of molecular and cellular interactions, within and across different brain regions. Memory, however, is not a neutral event to the brain, each experience can potentially modify brain networks, which can then subsequently influence how new information is processed. How past memories influence the organization of new memories at the cellular level remains largely unexplored. This proposal seeks to determine how the nature of specific past experiences influences cellular processes of memory formation within the hippocampus, a brain region known to be important for memory. These studies integrate rat behavior with genetic approaches and cellular imaging methods to provide a comprehensive view of the molecular and cellular dynamics of memory. It is anticipated that these studies will show that previous experiences do indeed alter the cellular dynamics of new information processing, and that these experience-dependent alterations require expression of a gene, Arc, critical for neural plasticity. Completion of the proposed studies will help elucidate both cellular and molecular substrates of memory within the mammalian hippocampus. Moreover, this project will afford outstanding training for undergraduate and graduate students and integrate with the broad based goals of the Center for Neurobiology of Learning and Memory (CNLM), where the studies will be conducted. The CNLM is active in K-12 education with regular school tours and lectures on brain and memory for the general public.
From the time of birth until the time of death, each person’s brain captures a lifetime of experiences, stored as memories, thoughts, emotions, and habits. These experiences are captured by specialized cells of the brain (neurons) and require changes in the expression of specific molecules (genes and proteins) and in the connections between neurons (synapses). It is common observation that earlier life events shape how an individual perceives subsequent events and then reacts to those events. Said another way, it is known that life experience strongly influences how individuals perceive and respond to experiences in the future at a behavioral level. The funded project asked the question, "How does the brain store experiences at the cellular level and how are these cellular representations modified by current and previous experience?" We addressed this critically important and largely unanswered question of modern neuroscience using rats as experimental subjects. We needed to use an animal model because our analyses required being able to monitor patterns of gene expression in brain tissue from the subjects. The combination of customized behavioral tests and cellular imaging of brain tissue allowed us to assess the patterns of activity of neurons in the brain, and how past activity of neurons during influenced new learning or during memory retrieval. Our molecular imaging methods allow us to see which populations of neurons where active at different time points when animals were learning new experiences or remembering past experiences. Moreover, the specific genes that we imaged (called Arc and Homer 1a) have been previously shown to be critical to the formation of long-term memories by their ability to modify synapses of neurons. As such, our studies tell us not only which neurons are active at specific times, but also which ones are likely undergoing changes to help store memories for that experience. Research from this project has been published in top tier journals and presented at national and international neuroscience meetings. In brief, our experiments defined many of the parameters controlling expression of Arc and Homer 1a in different populations of neurons in a brain region called the hippocampus during learning and memory retrieval. We focused our efforts on the hippocampus because past research had shown it to be a critical processing center for the formation of contextual memory—memory for places, things, and events. We also found that learning could dramatically change which neurons are active when a rat retrieves information about two environments it experienced in the past. Lastly, we found that the time interval between exposure to two learning events could dramatically influence how those two experiences were laid down in the brain at the level of individual neurons. Beyond the direct implications of this work to providing a basic understanding of how past experience shapes our ability to form new memories, funding provided by this project has provided excellent training for several undergraduate and three graduate students in my lab. In addition, we have discussed our research with K-12 students during lab tours at the Center for the Neurobiology of Learning and Memory (CNLM), and during public lectures on the UCI campus. In closing, the supported studies provided novel insight into how the temporal pattern of behavioral history influences the storage of learned experiences at the neuronal level. These studies show that temporal patterns of training can facilitate more independent cellular representations of experience, which could produce more rapid learning or stable long-term memory by reducing interference. As such, this basic neuroscience research could be beneficial in enhancing teaching in the classroom setting for students of varying intellectual ability.
