Generation Mechanisms of Memory-Related Internal Sequences in the Hoppocampal CA1 Region - Project Summary/Abstract Episodic memory is the memory that allows us to mentally re-experience specific episodes from our personal past. During memory encoding, the continuous stream of experience is segmented into individual episodes, where each episode encodes a sequence of events ordered in time. Yet, how neural circuits perform computations to segment experience and encode sequentially occurring events remains unknown. Revealing the circuit-level mechanisms behind these computations is essential for understanding episodic memory in both health and disease. In the hippocampus, a brain area essential for episodic memory, neurons are sequentially activated as an animal travels through an environment. The sequential firing of these so-called place cells repeats each time the animal revisits the same path, as if the animal’s previous experience of traversing the path is recollected. However, rich sensory cues are present in every environment, making it difficult to assess how much of the spiking activity in the place cell sequence is independent of direct sensory inputs. Reversibly toggle sensory inputs on and off during locomotion has made it possible to isolate the sequential activity produced by the internal computation (internally generated sequences (IGSs)) from that driven by sensory inputs. These IGSs that occurred during locomotion coincide with the performance of memory tasks, suggesting that they are memory-related sequential activity patterns. Interestingly, IGSs reoccur in each trial of a memory task and sometimes appear following spontaneous locomotion onset, implying that hippocampus can identify behavior- level boundaries and encode specific segments of experience. Revealing the neural circuits that underlie the expression of IGSs within a segment of experience such as a single behavior trial will provide new insight into how continuous experience is segmented and selectively encoded. The objective of this study is to elucidate the circuit-level mechanisms that evoke IGSs, and test the hypothesis that distinct types of interneurons in hippocampal CA1 coordinately modulate the state of the pyramidal neuron population thus gating IGS expression. Accomplished in three aims, we will employ a multidisciplinary approach encompassing the use of in vivo functional recordings, cell-type specific chemogenetic and optogenetic perturbations, and behavioral analysis to identify the behavioral conditions required for IGSs to occur, and determine how two distinct types of interneurons coordinate to signal the start of integration and control the window of integration, thus gating the occurrence of IGS. Completion of these aims will contribute to novel insights into how neural circuits operate to segment experience and encode episodic memory, and what can go wrong under pathological conditions such as dementia and Alzheimer’s disease where impaired episodic memory profoundly impacts the patients’ quality of life.
