The hippocampal formation is essential for the formation and maintenance of new long-term memories. The process of memory consolidation, where new potential memories that are still labile enter long term storage, is thought to involve bidirectional flows of information between the hippocampus and neocortex. Understanding how our different emotions and motivations might guide memory consolidation so as to bias the learning of salient information is a major objective of systems neuroscience research. The locus coeruleus (LC) is involved in both emotion and memory. LC cells release norepinephrine (NE) in various brain regions, including the hippocampus and neocortex, during states of high emotional arousal. Disruption of the activity of the LC cells themselves or inhibiting the receptors for NE in the hippocampus can suppress memory formation. Conversely, enhancing NE signaling in the hippocampus can improve memory. These results have pointed to a clear role for NE in sending emotional signals to the hippocampus, where it can boost access of highly salient information to long term memory storage. However, LC NE signaling is more elaborate during cognitive tasks. The cells shift rapidly between tonic and phasic firing modes, transitions that have been shown to predict accurate performance on signal detection tasks. While critically defining the LC systems' importance in hippocampal coding and memory formation, previous causal studies did not have the temporal resolution to capture the function of the LC's tonic and phasic firing shifts. Moreover, it is not known even how gross alterations in NE signaling alters hippocampal neuronal ensemble coding of information. In this proposal, therefore, LC neurons' precise firing patterns will be measured during a cued spatial memory task that is known to engage hippocampal-cortical interactions. Then, based on the timing of the phasic events, the release of NE triggered by phasic bursts of firing of the LC cells will be inhibited using optogenetics, while leaving the baseline firing intact, and the impact on the coding of the experience in the hippocampus will be measured. The changes in hippocampal coding will be measured by obtaining simultaneous recordings from hundreds of neurons simultaneously in the hippocampus during memory performance. Understanding how the LC can influence memory processes in the hippocampus has far-reaching implications for memory related pathologies, especially Alzheimer's disease (AD). Profound loss of LC NE neurons and NE levels occurs in the early stages of AD. The function of the LC inputs to the hippocampus in memory and hippocampal coding can now be elucidated by controlling neural activity at temporal resolution of neural activity variation. NE is an especially promising novel target for treating AD since pharmacological agents targeting the NE receptors are in wide use for mood disorders and cardiovascular disease so repurposing these drugs to help AD patients would be an imminent possibility.
Memory deficits, especially in Alzheimer's disease, debilitate millions of people around the world. One often overlooked aspect of the disease is the consistent degradation of a class of cells that is involved in arousal, motivation and memory, called the Locus Coeruleus. In this proposal, I describe experiments that can provide a deeper understanding into how the Locus Coeruleus impacts memory formation through its action on information processing in the hippocampus and potentially reveal new promising targets to enhance memory via pharmacotherapy.
