Locus Coeruleus Contributions to Hippocampus-Dependent Memory Formation

The locus coeruleus (LC) exerts its neuromodulatory effects via two distinct modes of activity: tonic and phasic. Tonic activity refers to extended periods of low to moderate firing (1-10Hz) that are thought to mediate relatively long-lasting changes in brain state by setting brain-wide noradrenergic tone. This type of activity is particularly important for regulating the overall level of arousal, which can, in turn, affect many psychological and physiological processes. Phasic activity refers to brief bouts of elevated firing rate (10-20Hz), usually in response to a specific environmental event. Phasic LC responses to task-related events are generally associated with improved performance across a variety of cognitive domains including perception, attention, and decision making. However, the role of precisely timed phasic LC responses in memory formation is relatively understudied. In particular, the role of phasic LC activity in hippocampus-dependent memory formation is unknown. In Part 1 of this dissertation, we characterize a trace fear conditioning task that requires mice to associate a tone and shock that are separated in time by 20 seconds. Using optogenetics, we show that this task requires intact hippocampal activity during both learning and memory retrieval. In Part 2, we characterize the phasic responses of the LC and its projections to the dorsal hippocampus during trace fear conditioning. We find learning related changes in these responses that are consistent with a role for LC in signaling the learned salience of environmental stimuli. We go on to show that amplifying these phasic responses can lead to enhancements in long-term memory. We also demonstrate that LC stimulation increases both norepinephrine and dopamine content in the dorsal hippocampus. Somewhat unexpectedly, we find that only the release of dopamine is needed to enhance memory formation. The implications of these findings for LC function and dopamine release in the hippocampus during aversive learning are discussed