Episodic memory plays a critical role in our daily lives, and disruption in episodic memory is associated with many common disease states including Alzheimer's disease and schizophrenia. Extensive research has shown that the hippocampal formation plays a critical role in memory processes. Neural signals such as theta (6-13 Hz) and gamma (30-140 Hz) oscillations recorded from electrodes implanted in the hippocampus are disrupted in these diseases and have been proposed to have a critical relationship to memory. A growing body of evidence suggests that the theta rhythm separates the hippocampus into distinct communication states, and that the frequency of gamma oscillations is reflective of this separation. In addition, modeling has shown that it is critical or memory systems to separate encoding/learning and retrieval/recollection activity, and that the theta separation may be reflective of a separation of these cognitive processes. Pharmacological studies have shown that cholinergic activity in the hippocampus is essential for encoding/learning behaviors;however, the mechanism of this action is not well understood. This study will experimentally link neural signals recorded from the hippocampus and distinct components of memory function. We will do this by taking advantage of the temporal and anatomical specificity of optogenetic manipulations. The specific optogenetic manipulations used in this study will allow us to silence rapidly either the cholinergic neurons, projecting to te hippocampus from the medial septum, or excitatory connections, projecting to hippocampal area CA1 from area CA3. Using this fast acting neural silencing technique, we will test the proposed functional roles of these projections in the context of the hippocampal dependent memory task: delayed non-match to position (DNMP). Simultaneously, we will seek to characterize the influences of these pathways on the theta and gamma rhythms of the hippocampus. These studies will serve to expand our understanding of 1) how these pathways may subserve healthy episodic memory function and 2) the role that dysfunction of these pathways may play in conditions such as post-traumatic stress disorder (PTSD), addiction, schizophrenia, and Alzheimer's disease.
The research proposed here will explore how memories are stored and retrieved, the ways memories are forgotten, and the roles that coordinated activity in the brain play in these functions. The results of this study will have direct relevance to the stud and development of clinical therapies for post-traumatic stress disorder (PTSD), addiction, schizophrenia, and Alzheimer's disease.