Animals utilize a repertoire of defensive behaviors to avoid predators and other noxious stimuli. Successful implementation of these behaviors depends on both the external environment and the internal state of the animal as the brain makes a series of computations to integrate and use such information. Memory systems in particular play a highly influential role in mediating defensive strategies based on previous experiences. These events are encoded in the brain as a form of episodic memory and recruit the hippocampus. Yet, how hippocampal cell populations (i.e., engram ensembles) that drive memory expression modulate downstream neural systems to properly gate defensive behaviors is unknown. To address this, we use activity-dependent labeling strategies to leverage optical control over a hippocampal engram ensemble that encodes the information of a fearful experience (i.e., hippocampal CFC [Contextual Fear Conditioning] engram). Our first experiment aimed to test for the behavioral flexibility of a hippocampal CFC engram, where we use optogenetics to artificially reactivate this fear memory-bearing ensemble across environments that differed in size. We quantified freezing behavior, which is a passive defensive behavior that is commonly associated with negative affective states in rodents, such as fear, and found that environment size influenced the amount of light-induced freezing. From there, our second experiment utilized whole-organ immunohistochemistry, light-sheet microscopy, and graph theoretical analyses to identify regions of interest that were preferentially engaged during hippocampal CFC engram reactivation. Our manipulations conferred positive correlations in brain-wide endogenous cFos expression, induced alterations in network topology, and recruited regions spanning putative memory and defense systems as hubs in respective networks. Lastly, our third experiment aimed to test for the necessity of a hub region for generating light-induced freezing when a hippocampal CFC engram was reactivated in a small arena. Our preliminary results suggest that the lateral hypothalamic area could be one of many regions important for integrating information to generate light-induced freezing, but future work is required to further tease out its role. Overall, by identifying and manipulating the circuits supporting memory function, as well as their corresponding brain-wide activity patterns, it is thereby possible to resolve systems-level biological mechanisms mediating memory’s capacity to modulate behavioral states.
| Identifer | oai:union.ndltd.org:bu.edu/oai:open.bu.edu:2144/49424 |
| Date | 23 October 2024 |
| Creators | Dorst, Kaitlyn Elizabeth |
| Contributors | Ramirez, Steve |
| Source Sets | Boston University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
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