Influence of the locus coeruleus on fear learning and threat processing in the ventral hippocampus

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Abstract The locus coeruleus (LC) and ventral hippocampus (vHPC) both influence our response to threatening stimuli. Research to date has focused primarily on the contribution each of these structures makes to fear learning and anxiety. However, few studies have examined the interactions that occur between the LC and vHPC during threat processing. The LC is typically thought to provide a salience signal to the HPC and other brain regions, that enhances plasticity and facilitates memory formation. However, the LC and vHPC have also been shown to drive innate anxiety-related behaviors in stressful situations. To resolve this apparent discrepancy, we will test the novel idea that fear learning and innate anxiety are both controlled by distinct oscillations in the LC (phasic vs tonic firing) that are transmitted to the vHPC when a threat is encountered. Acute, fear-inducing stimuli have been shown to produce large, transient responses in the LC and the vHPC. For example, aversive footshock produces phasic activity in both structures that can persist for up to several seconds after the stimulus has terminated. As phasic LC responses are typically associated with focused attention and the encoding of salient stimuli, we hypothesize that phasic activity in the LC promotes fear learning by enhancing shock processing in the vHPC. In contrast, situations that induce anxiety, such as open, unsheltered environments, produce smaller, but longer lasting increases in tonic activity in the LC. Consequently, we hypothesize that the LC elicits anxiety-related behaviors when a potential threat is encountered by inducing tonic firing in the vHPC. To test these ideas, we will use a multidisciplinary approach that combines in vivo fiber photometry with cell-type specific optogenetics to simultaneously monitor vHPC activity while manipulating LC neurons during fear conditioning and situations that provoke anxiety. Follow-up studies will build on these results by using in vivo calcium imaging to determine the effects of tonic and phasic LC firing on the activity of shock-responsive and anxiety-responsive cells in the vHPC.