Our brains are more likely to remember activities or incidents that stand out from typical day-to-day experiences. For instance, if your phone is stolen on the way to work, you will have a stronger memory of this experience compared to other uneventful commutes. These are known as salient events and can be emotional, surprising, or even just out of the ordinary.

During salient events, an area of the brain known as the hippocampus receives chemicals called neuromodulators from other parts of the brain. These neuromodulators enhance the formation of the memory by modifying how neurons connect together in the hippocampus.

One of the regions that signals to the hippocampus – called the locus coeruleus – was thought to enhance memory by releasing the neuromodulator norepinephrine. Recent studies indicate that the locus coeruleus also releases a second neuromodulator called dopamine. However, it remained unclear what causes the locus coeruleus to release dopamine, and what effect this neuromodulator has on the hippocampus.

To investigate these questions, Wilmot et al. recorded and manipulated the activity of the locus coeruleus in the brains of mice experiencing salient, fearful events. The mice were exposed to a sound and, a few seconds later, a shock to the foot to illicit the formation of an aversive salient memory. If the next day, the mice responded to just the sound as if they were expecting a shock, this indicated they had remembered the aversive experience.

Wilmot et al. observed that neurons in the locus coeruleus were active during the salient event, resulting in increased dopamine in the hippocampus. When the activity of these neurons was forcefully increased during relatively non-salient events, such as a quiet tone and a very mild shock, the animals still showed strong memory formation. Finally, blocking the action of dopamine in the hippocampus substantially affected memory formation, whereas blocking the action of norepinephrine did not have the same effect.

These findings suggest that the locus coeruleus enhances the memory of salient events by increasing the levels of dopamine in the hippocampus not norepinephrine, as was previously thought. Developing a better understanding of how the locus coeruleus regulates memory may lead to improved treatments for various neurological disorders, like Alzheimer’s disease, which are associated with neuromodulators taking on different roles in the hippocampus.

The locus coeruleus (LC) supports an array of cognitive processes by modulating brain-wide arousal states and responding to salient events in the environment. LC neurons accomplish this via two distinct modes of activity: tonic and phasic. Changes in the frequency of tonic activity are associated with corresponding changes in psychological state. Low tonic activity (~0–2 Hz) is associated with drowsiness or sleep and increasing levels of tonic activity (~3–10 Hz) are associated with increased arousal, progressing from exploration and task engagement to agitation and anxiety states (Aston-Jones and Cohen, 2005). Bouts of phasic activity (~10–20 Hz) are most often observed during intermediate levels of tonic activity in response to salient environmental events (Aston-Jones et al., 1999). When locked to task-relevant events, these phasic responses are associated with improved cognitive performance across a variety of tasks (Aston-Jones and Cohen, 2005 for review).

A large body of research supports the idea that the LC is critically involved in memory formation. Monoamine depletion in the LC, noradrenergic and dopaminergic antagonism in multiple brain regions, and direct inhibition of the LC all impair memory across a number of tasks (Giustino and Maren, 2018; Lisman and Grace, 2005; Selden et al., 1990; Uematsu et al., 2017; Wagatsuma et al., 2018). Conversely, LC stimulation as well as dopamine and norepinephrine agonism can enhance memory (Bach et al., 1999; Kempadoo et al., 2016; Packard and White, 1991; Packard and White, 1989; Sara and Devauges, 1988). Although the LC is typically thought to modulate neural activity via the release of norepinephrine, several recent studies have suggested that it may also release dopamine into the hippocampus (HPC) and other cortical regions (Devoto and Flore, 2006; Smith and Greene, 2012). In some cases, it appears that dopamine release from LC into the HPC may be more important for memory than norepinephrine (Kempadoo et al., 2016; Takeuchi et al., 2016; Wagatsuma et al., 2018).

However, studies examining the effect of LC on HPC-dependent memory have generally not distinguished between tonic and phasic LC activity or between dopamine and norepinephrine signaling. In some cases, this distinction is prevented by the use of temporally imprecise manipulations like lesions and drug infusions. In others, it is difficult to determine the importance of time-locked phasic firing because of the use of spatial memory tasks that are commonly used to assess hippocampus (HPC)-dependent memory. Because space is a temporally diffuse stimulus, it is difficult to know the exact moments during spatial learning when phasic responses might be important. This does not rule out the possibility that phasic LC activity and dopamine signaling is important for spatial learning, but the lack of experimental control over the animals’ sampling of the relevant stimuli makes this possibility opaque to examination. Studies that have used discrete reward learning tasks to examine dopamine function in the HPC have also not typically distinguished between tonic and phasic release.

To address these issues, we used a trace fear conditioning task in which animals learn an association between a neutral and aversive stimulus that are separated in time. Because trace fear conditioning (a) requires intact hippocampal activity (Chowdhury et al., 2005; Raybuck and Lattal, 2014; Wilmot et al., 2019) and (b) involves learning about discrete, well-controlled stimuli, it is ideally suited to characterize the rapid temporal dynamics of LC activity and LC-HPC communication during learning and examine their role in long term memory formation. Here, we used fiber photometry and optogenetics to make temporally precise observations and manipulations of LC activity during learning in a trace fear conditioning task. We extend this data by providing direct evidence that LC activity increases both dopamine and norepinephrine content in the HPC and by showing that dopamine release is important for trace fear memory formation, but the release of norepinephrine is not.

The locus coeruleus and its interaction with the hippocampus are known to be critical for hippocampus-dependent memory formation (Compton et al., 1995; Kempadoo et al., 2016; Lemon et al., 2009; Takeuchi et al., 2016; Wagatsuma et al., 2018). However, due to the predominant use of spatial memory tasks in which the learned information is experienced diffusely in time, the precise temporal dynamics of learning-related LC and LC-HPC activity remain poorly understood. In these experiments, we used trace fear conditioning to examine the contribution of precisely timed phasic LC and LC-HPC activity to long-term memory formation.

In the first experiment, we demonstrated that the LC exhibits responses to both neutral and aversive stimuli. This data is consistent with previous reports (Aston-Jones and Bloom, 1981; Hirata and Aston-Jones, 1994; Rasmussen and Jacobs, 1986). Given their relatively short duration and the fact that they are elicited specifically by salient sensory stimuli, we refer to these responses as ‘phasic responses’. However, because of the comparatively slow dynamics of fluorescent sensors relative to electrophysiology, we cannot rule out the possibility that these responses are somehow different in nature from previously reported phasic LC responses. Thus, some care must be taken in conflating the characteristics and/or function of the relatively short-lasting responses presented here and the extremely fast phasic responses to very brief (μs to ms) sensory stimuli reported previously. Our data also demonstrate that the size of the LC phasic response is modulated by the intensity, or salience, of sensory stimuli. This relationship between salience and LC response magnitude was particularly pronounced for the aversive foot-shock. Across all intensities, LC responses were larger to the aversive stimuli than to neutral auditory stimuli, suggesting that the LC may encode some information about the emotional valence of stimuli in addition to the simple sensory salience – though to determine this conclusively would require equating the salience of stimuli across the somatosensory and auditory modalities while varying the emotional valence, which may not be possible, especially in a rodent model. These data are consistent with previous work suggesting a role for LC in signaling salience (Foote et al., 1980; Grant et al., 1988; Vazey et al., 2018) and extend them by providing a parametric characterization of LC responses to stimuli of varying intensities.

We also found that phasic LC responses change with learning. First, consistent with a role for LC in signaling salience or novelty, LC responses to a neutral auditory stimulus habituate across repeated exposure to a stimulus, as demonstrated previously (Hervé-Minvielle and Sara, 1995). Additionally, we demonstrated that the LC response to the same auditory stimulus is larger when the stimulus is associated with an aversive outcome. Previous work has shown that LC neurons can respond more to conditioned than non-conditioned stimuli (Aston-Jones et al., 1994; Bouret and Sara, 2004; Uematsu et al., 2017); however, to our knowledge, this is the first demonstration of increased LC responding to the CS in a trace conditioning task where the CS and US are separated by an extended interval. This may indicate some level of top-down influence over the LC by the hippocampus or prefrontal cortex, as both of these regions are required for learning in this task (Gilmartin and Helmstetter, 2010; Wilmot et al., 2019).

Our results also confirmed that the direct projections from the LC to the dHPC are phasically activated by all learning-relevant stimuli during trace conditioning. This data provides support for the idea that phasic LC input to the hippocampus is involved in memory formation. We did not observe obvious changes in tonic LC-HPC activity in our data, although these changes may be more subtle and occur over longer time scales that would be difficult to detect using fiber photometry. The presence of the same responses in the LC-HPC axon terminals that were seen in LC cell bodies fits with the canonical view of the LC as a largely homogenous structure whose neurons’ axons are highly collateralized. However, it was important to test whether LC-HPC projections respond during trace conditioning directly, as more recent work suggests the LC may be composed of many distinct ‘modules’ of neurons that project to separate regions and it is not yet known whether these modules exhibit different response properties (Schwarz and Luo, 2015; Uematsu et al., 2017). Because we only recorded from LC projections to the HPC, our data could be consistent with either a homogenous or modular LC organization. Future work could distinguish between these possibilities by recording LC projections in an array of downstream targets.

We also sought to determine whether LC stimulation results in the release of dopamine and/or norepinephrine into the HPC. Using DREADDs, we were able to show that direct LC stimulation drives increases in both dopamine and norepinephrine in the HPC, consistent with a number of recent studies indicating their co-release from LC terminals in the hippocampus and neocortex (Devoto and Flore, 2006; Kempadoo et al., 2016; Smith and Greene, 2012; Takeuchi et al., 2016; Wagatsuma et al., 2018). Due to the low number of VTA/SN fibers in dorsal HPC, it is likely that the large increase in dopamine during LC stimulation is due to direct release from LC terminals. However, it is also possible that HPC dopamine is increased indirectly via LC projections to dopaminergic midbrain regions, although there are several problems for this argument (Guiard et al., 2008). First, recent studies have shown that activation of LC terminals in the dorsal hippocampus induces the release of dopamine (Kempadoo et al., 2016). Second, inactivation of LC but not VTA terminals in the dorsal hippocampus decreases dopamine release in this region (Gálvez-Márquez et al., 2022). Therefore, while it is not possible to completely rule out increased hippocampal dopamine via a LC-midbrain-HPC circuit based on our studies, direct release of dopamine from LC terminals in HPC is more likely.

A wide body of evidence suggests that LC activation enhances memory acquisition (Kempadoo et al., 2016), consolidation (LaLumiere et al., 2003; Novitskaya et al., 2016; Takeuchi et al., 2016), and retrieval (Murchison et al., 2004; Sara and Devauges, 1988). Here, we extended this data by showing that precisely timed phasic activation of the locus coeruleus enhances memory formation. Specifically, our data indicate that phasic LC activation can enhance memory formation when the relevant stimuli are not salient enough to produce significant learning on their own.

There are multiple possibilities as to the mechanism underlying this enhancement. First, both dopamine (Frey et al., 1990; Lisman et al., 2011) and norepinephrine (Bliss et al., 1983; Hu et al., 2007; Stanton and Sarvey, 1985) enhance synaptic plasticity in the hippocampus and in other structures important for trace fear conditioning, including the prefrontal cortex and amygdala (Bissière et al., 2003; Huang et al., 2000; Tully et al., 2007). Given our data showing that dopamine, and not norepinephrine, is required for trace fear memory formation, the most direct possibility is that the release of dopamine from the LC enhances learning-related plasticity in regions supporting trace fear conditioning. Our finding that systemic β-adrenergic receptor antagonism has no effect on trace fear memory formation was surprising in light of previous work demonstrating memory impairments after infusions of adrenergic antagonists into the hippocampus or amygdala (Giustino and Maren, 2018 for review). However, our data is consistent with recent findings from several other groups (Kempadoo et al., 2016; Murchison et al., 2004; Takeuchi et al., 2016; Wagatsuma et al., 2018). In particular, the work of Thomas et al. used several different methods to demonstrate that β-adrenergic receptors in the dHPC are required for the retrieval of context fear but not learning or memory consolidation (Murchison et al., 2004). Based on this previous work and our data showing learning-related activity in LC-HPC projections, we believe that LC release of dopamine into the hippocampus is at least partially responsible for our observed effects. However, future work manipulating this projection directly would be required to make this conclusion.

The LC may also assert its effect on memory formation indirectly via its influence over sensory processing, attention, or valence processing, all of which are affected by phasic LC activity (Aston-Jones and Cohen, 2005; Bouret and Sara, 2004; McCall et al., 2015; Vazey et al., 2018). Under this hypothesis, the LC could facilitate memory by enhancing the responses of neural populations involved in processing, attending, or assigning valence to the learning-relevant stimuli. For example, in our optogenetic experiment (Figure 4) phasic LC stimulation may have enhanced stimulus detection and allowed the relatively weak stimuli that were used to capture the animals’ attention and produce learning when they otherwise would not. Distinguishing between these plasticity and cognitive modulation accounts of LC-driven memory enhancements would be difficult as many of the same cellular mechanisms are likely involved in both processes. Indeed, it is likely that LC enhancements of plasticity and cognitive function both contribute to its effects on memory.

Data and code used in this study are available at https://github.com/jhwilmot/Wilmot-et-al.-2023-Data (copy archived at Wilmot, 2024). Up-to-date code for fiber photometry processing and analysis are available at https://github.com/kpeez/fiberphotopy (copy archived at Puhger, 2024).

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Author details

1. Jacob H Wilmot

   1. Department of Psychology, University of California, Davis, Davis, United States
   2. Center for Neuroscience, University of California, Davis, Davis, United States

   Contribution

   Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Visualization, Writing – original draft, Writing – review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-5408-732X

2. Cassiano RAF Diniz

   Center for Neuroscience, University of California, Davis, Davis, United States

   Contribution

   Investigation, Writing – review and editing

   Competing interests

   No competing interests declared

3. Ana P Crestani

   Center for Neuroscience, University of California, Davis, Davis, United States

   Contribution

   Investigation, Writing – review and editing

   Competing interests

   No competing interests declared

4. Kyle R Puhger

   1. Department of Psychology, University of California, Davis, Davis, United States
   2. Center for Neuroscience, University of California, Davis, Davis, United States

   Contribution

   Software, Writing – review and editing

   Competing interests

   No competing interests declared

5. Jacob Roshgadol

   1. Center for Neuroscience, University of California, Davis, Davis, United States
   2. Department of Biomedical Engineering, University of California, Davis, Davis, United States

   Contribution

   Investigation, Writing – review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-3541-0715

6. Lin Tian

   Department of Biochemistry and Molecular Medicine, University of California, Davis, Davis, United States

   Contribution

   Resources, Writing – review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-7012-6926

7. Brian Joseph Wiltgen

   1. Department of Psychology, University of California, Davis, Davis, United States
   2. Center for Neuroscience, University of California, Davis, Davis, United States

   Contribution

   Conceptualization, Supervision, Funding acquisition, Writing – original draft, Writing – review and editing

   For correspondence

   bjwiltgen@ucdavis.edu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-3811-5183

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