Phasic locus coeruleus activity enhances trace fear conditioning by increasing dopamine release in the hippocampus.

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.

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.

Septo-hippocampal dynamics and the encoding of space and time.

Encoding an event in memory requires neural activity to represent multiple dimensions of behavioral experience in space and time. Recent experiments have explored the influence of neural dynamics regulated by the medial septum on the functional encoding of space and time by neurons in the hippocampus and associated structures. This review addresses these dynamics, focusing on the role of theta rhythm, the differential effects of septal inactivation and activation on the functional coding of space and time by individual neurons, and the influence on phase coding that appears as phase precession. We also discuss data indicating that theta rhythm plays a role in timing the internal dynamics of memory encoding and retrieval, as well as the behavioral influences of these neuronal manipulations with regard to memory function.

Amnesia for context fear is caused by widespread disruption of hippocampal activity.

The hippocampus plays an essential role in the formation and retrieval of episodic memories in humans and contextual memories in animals. However, amnesia is not always observed when this structure is compromised. To determine why this is the case, we compared the effects of several different circuit manipulations on memory retrieval and hippocampal activity. Mice were first trained on context fear conditioning and then optogenetic and chemogenetic tools were used to alter activity during memory retrieval. We found that retrieval was only impaired when manipulations caused widespread changes (increases or decreases) in hippocampal activity. Widespread increases occurred when pyramidal cells were excited and widespread decreases were found when GABAergic neurons were stimulated. Direct hyperpolarization of excitatory neurons only moderately reduced activity and did not produce amnesia. Surprisingly, widespread decreases in hippocampal activity did not prevent retrieval if they occurred gradually prior to testing. This suggests that intact brain regions can express contextual memories if they are given adequate time to compensate for the loss of the hippocampus.

Acute Disruption of the Dorsal Hippocampus Impairs the Encoding and Retrieval of Trace Fear Memories.

A major function of the hippocampus is to link discontiguous events in memory. This process can be studied in animals using Pavlovian trace conditioning, a procedure where the conditional stimulus (CS) and unconditional stimulus (US) are separated in time. While the majority of studies have found that trace conditioning requires the dorsal segment of the hippocampus, others have not. This variability could be due to the use of lesion and pharmacological techniques, which lack cell specificity and temporal precision. More recent studies using optogenetic tools find that trace fear acquisition is disrupted by decreases in dorsal CA1 (dCA1) activity while increases lead to learning enhancements. However, comparing these results is difficult given that some studies manipulated the activity of CA1 pyramidal neurons directly and others did so indirectly (e.g., via stimulation of entorhinal cortex inputs). The goal of the current experiments, therefore, was to compare the effects of direct CA1 excitation and inhibition on the encoding and expression of trace fear memories. Our data indicates that stimulation of ArchT in dCA1 pyramidal neurons reduces activity and impairs both the acquisition and retrieval of trace fear. Unlike previous work, direct stimulation of CA1 with ChR2 increases activity and produces deficits in trace fear learning and expression. We hypothesize that this is due to the artificial nature of optogenetic stimulation, which could disrupt processing throughout the hippocampus and in downstream structures.