The long-range goal is to understand how animals process and remember events in time and provide a neuroanatomically guided theoretical framework for understanding memory disorders. The objective of the present application is to validate an animal model of episodic memory in rats and identify the underlying neural substrates. The central hypothesis is that answering an unexpected question after incidental encoding requires episodic memory that is dependent upon the hippocampus. Preliminary studies, in which the CA3 region of the hippocampus was temporarily inactivated before memory storage, support this hypothesis. The PIs will test the central hypothesis by accomplishing three specific aims: (1) To test the hypothesis that answering an unexpected question requires episodic memory. The role of episodic memory, response, and spatial processes in answering unexpected questions will be assessed. Regions implicated in both episodic memory and spatial processing (CA3 region of the hippocampus) as well as response learning (dorsolateral striatum) will be inactivated to test the hypothesis that answering an unexpected question requires episodic memory. (2) To test the hypothesis that answering an unexpected question requires long-term memory. Episodic memory in humans is part of long-term memory. The working hypothesis is that the CA1 region of the hippocampus is implicated in long-term aspects of episodic memory whereas CA3 is required for episodic memory after both short and long delays. CA3 and CA1 will be inactivated under varying retention-interval challenges to map out the retention function for incidentally encoded episodes. The working hypothesis is that CA3 inactivation is expected to impair episodic memory under short- and long-interval delays, consistent with preliminary data, whereas CA1 is required to bridge long delays. (3) To test the hypothesis that CA3 subserves retrieval of episodic memories. In preliminary studies, inactivation of CA3 before memory storage impaired episodic memory. It is not known if CA3 subserves storage or retrieval of episodic memories. CA3 will be inactivated after storage but before retrieval to test the working hypothesis that CA3 subserves episodic memory retrieval. Health relatedness of the project: Identifying mechanisms that govern episodic memory may significantly benefit society by providing insights into deficits in memory associated with brain injuries, amnesia, Alzheimer's disease or other human memory pathologies. Identifying mechanisms that govern episodic memory may improve our understanding of the neural substrates subserving episodic memory and foster development of treatments for human memory disorders. Indeed, deficits in memory function are key features of many psychiatric disorders and improving memory ability is an important objective for therapies of psychiatric disorders and Alzheimer's disease. Ultimately, a better understanding of the functional neuroanatomy of episodic memory systems offer the potential to develop anatomically targeted pharmacological and molecular treatments for memory disorders.

Public Health Relevance

Deficits in episodic memory are implicated in disorders of memory, which impose a significant socioeconomic burden on society. Thus, the study of normal and impaired episodic memory is an urgent public health need. A better understanding of episodic memory impairments may ultimately (1) facilitate understanding the neurobiological bases of human memory disorders, (2) improve translational potential when testing new therapies with animals, and (3) reduce both escalating healthcare costs and unnecessary suffering in patients and their families.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Biobehavioral Regulation, Learning and Ethology Study Section (BRLE)
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Osborn, Bettina D
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Indiana University Bloomington
Schools of Arts and Sciences
United States
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Crystal, Jonathon D; Smith, Alexandra E (2014) Binding of episodic memories in the rat. Curr Biol 24:2957-61
Crystal, Jonathon D; Alford, Wesley T (2014) Validation of a rodent model of source memory. Biol Lett 10:20140064
Crystal, Jonathon D (2014) Where is the skepticism in animal metacognition? J Comp Psychol 128:152-4; discussion 160-2