Locus coeruleus (LC) projections to the hippocampus play a critical role in learning and memory. However, the precise timing of LC-hippocampus communication during learning and which LC-derived neurotransmitters are important for memory formation in the hippocampus are currently unknown. 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 and other cortical regions. In some cases, it appears that dopamine release from LC into the hippocampus may be more important for memory than norepinephrine. Here, we extend these data by characterizing the phasic responses of the LC and its projections to the dorsal hippocampus during trace fear conditioning in mice. We find that the LC and its projections to the hippocampus respond to task-relevant stimuli and that amplifying these responses with optogenetic stimulation can enhance long-term memory formation. We also demonstrate that LC activity increases both norepinephrine and dopamine content in the dorsal hippocampus and that the timing of hippocampal dopamine release during trace fear conditioning is similar to the timing of LC activity. Finally, we show that hippocampal dopamine is important for trace fear memory formation, while norepinephrine is not.
Keywords: dopamine; fear conditioning; hippocampus; locus coeruleus; memory; mouse; neuroscience; norepinephrine.
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.
© 2023, Wilmot et al.