Recent evidence suggests that some functions of the hippocampus (HPC) may be segregated along its transverse axis. For instance, the HPC receives spatial input from the medial entorhinal cortex (MEC) and postrhinal cortex, while it receives odor/object-related information from the lateral entorhinal cortex (LEC) and perirhinal cortex. Although these inputs are mixed in dentate gyrus and CA3, they remain segregated in the entorhinal cortex projections to CA1. The proximal (next to CA2) and distal (next to subiculum) segments of CA1 receive direct projections from MEC and LEC, respectively. This suggests that information processing may be functionally distinct along the proximo-distal axis of CA1. In our study, we examined how proximodistal segments of CA1 are involved in processing object-related information. First, we quantified c-Fos expression in proximal and distal CA1 of mice that were either exposed to a novel context, novel objects in a familiar context, or a familiar context without objects. Consistent with previous reports, we found that novel context exposure increased c-fos activity in proximal CA1 while exposure to novel objects resulted in higher c-fos levels in distal CA1 compared to control mice. Second, we examined the role of catecholamines in regulating activity of proximodistal CA1 neurons during object exploration. Catecholaminergic lesions in the hippocampus reduced c-Fos activity in both segments of CA1 and impaired performance of the hippocampal-dependent object location memory (OLM) task. Finally, we monitored calcium activity of proximodistal CA1 via fiber photometry while animals performed the OLM task. We observed differential activity in proximodistal CA1 during exploration of stationary and displaced objects. Overall, our results are consistent with the framework of the parallel circuits within the hippocampus; proximal CA1 is important for determining the animal’s location in space, while distal CA1 is involved in processing information about the content of an experience.

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.

Trace fear conditioning (TFC) is a variant of Pavlovian conditioning in which the CS and US are separated by a temporal gap (aka trace interval). The hippocampus is commonly assumed to facilitate this type of learning by maintaining a memory of the CS until the US occurs. Prior work from our lab and others has demonstrated that optogenetic inhibition of CA1 during the tone and trace interval impairs the acquisition of TFC. However, there is currently little to no evidence that individual hippocampal neurons reliably maintain a memory of the CS during the trace interval. Here, we used fiber photometry to record bulk calcium activity in CA1 as mice underwent TFC. Similar to previous work, we found that the footshock US produced a large and prolonged increase in CA1 activity. To determine if this activity was important for learning, we optogenetically silenced CA1 after footshock and found that trace fear memory was significantly impaired. In contrast, silencing CA1 for an equivalent period during the intertrial interval had no effect, indicating that immediate, but not delayed post-shock activity is essential for memory formation. However, this was only true for new learning, as post-shock silencing on the second day of training did not disrupt a previously formed trace fear memory. Similar patterns of activity in CA1 have been observed in spatial studies when a reward US is encountered on a maze. In that case, reward induces replay during sharp wave-ripples that travel backwards in time to reactivate the path leading to food. We hypothesize that something similar may happen during TFC: the aversive US activates CA1 and causes it to replay the sequence of events that lead to footshock. This allows the animal to associate the aversive outcome with predictive stimuli that occurred tens of seconds earlier. Implications for models of trace conditioning and hippocampal function are discussed.