Doctor of Philosophy (PhD)
Faculty of Science
Diano F. Marrone
The locus coeruleus (LC) responds to salience cues, including novelty, and sends a major noradrenergic projection to the hippocampal formation (HF). Novelty-associated LC activation may help to sculpt contextual representations in the HF, but modulatory influence of norepinephrine (NE) over HF representations remains poorly understood. One possible mechanism is that NE provides a “reset” signal causing the HF to recruit distinct neural populations, thereby providing a molecular switch to dictate if hippocampal circuits should generate new representations or update existing ones to incorporate novel information. This hypothesis suggests that NE release should cause the HF to recruit a unique population even in the presence of the same stimuli an animal has just experienced, a phenomenon referred to as “global remapping”. The compartmental expression of immediate early genes (i.e. arc & zif268) allowed us to test this by mapping the activity history of individual neurons as animals engaged in spatial processing following LC-NE manipulation.
Recruitment of new neurons is part of the memory encoding process involved in separating memories. Tasks involving memory retrieval require reactivation of representations formed during encoding. If those representations “remapped” (i.e. a new cellular ensemble was recruited, rather than reactivation of the cells comprising the previously formed representation), this should theoretically result in a retrieval error. Therefore, switching the system back to a state of encoding would prove maladaptive in situations where retrieval is necessary to perform a task, unless new information was at hand. We hypothesize that NE resets the system causing the HF to move from a state of retrieval back to encoding when it is necessary, when novel information needs to be incorporated. This hypothesis suggests the effect of modulating NE on memory critically depends on the stage of training. To further understand how NE modulation of hippocampal circuits affects spatial memory, we tested whether infusions of the β-adrenergic agonist isoproterenol would impair working and reference memory retrieval (i.e., switching the system back to encoding when it is maladaptive) and in contrast, promote cognitive flexibility thus improving reversal learning (i.e., switching the system back to encoding when it is adaptive).
Grella, Stephanie L., "Testing the Network Reset Hypothesis: Noradrenergic Modulation of Hippocampal Representations" (2018). Theses and Dissertations (Comprehensive). 2016.