Locus coeruleus and dopaminergic consolidation of everyday memory

Abstract

Summary The retention of episodic-like memory is enhanced, in humans and animals, when something novel happens shortly before or after encoding. Using an everyday memory task in mice, we sought the neurons mediating this dopamine-dependent novelty effect, previously thought to originate exclusively from the tyrosine hydroxylase-expressing (TH+) neurons in the ventral tegmental area (VTA). We report that neuronal firing in the locus coeruleus (LC) is especially sensitive to environmental novelty, LC-TH+ neurons project more profusely than VTA-TH+ neurons to the hippocampus, optogenetic activation of LC-TH+ neurons mimics the novelty effect, and this novelty-associated memory enhancement is unaffected by VTA inactivation. Surprisingly, two effects of LC-TH+ photoactivation are sensitive to hippocampal D1/D5 receptor blockade and resistant to adrenoceptors blockade – memory enhancement and long lasting potentiation of synaptic transmission in CA1 ex vivo. Thus, LC-TH+ neurons can mediate post-encoding memory enhancement in a manner consistent with possible co-release of dopamine in hippocampus.

Locus coeruleus input to hippocampal CA3 drives single-trial learning of a novel context

“…S3B). These results demonstrate the release of dopamine elicited by the activation of LC neurons under physiological conditions, as supported by recent gain-of-function stimulation studies (8,12), and reveal the importance of LC projections to hippocampal CA3 in single-trial learning.…”

“…We applied this protocol of CFC with preexposure as it allows clear separation of the encoding of a novel context from contextual recall and CS-US association and precise temporal regulation of optogenetic inhibition. In this way, it is also possible to avoid rebound effects that were observed in LC neurons expressing light-sensitive opsins (8). Freezing deficits in the conditioned context were present in the Arch group with inhibition of LC-CA3 input during the entire context-preexposure session ( Fig.…”

“…It was recently shown that optogenetic stimulation of the LC can enhance the retention of everyday memories in a familiar environment (8). Interestingly, it is known that activity in the LC switches from tonic firing at low frequency to phasic burst firing when novel stimuli occur, and the intensity of the burst firing wears off when the novelty of the experience wanes (8)(9)(10)(11). Another source of neuromodulation in the hippocampus is the ventral tegmental area (VTA), which also responds to novelty.…”

“…Another source of neuromodulation in the hippocampus is the ventral tegmental area (VTA), which also responds to novelty. However, studies have shown that VTA projections to dorsal hippocampus are scarce, whereas LC projections are abundant (8,12,13). In addition, dopamine, which is the most prominently implicated neuromodulator in novelty signaling (14), was demonstrated to be released from the LC, along with norepinephrine in the cortex (15) and in the hippocampus (8,12,16).…”

The Object Space Task shows cumulative memory expression in both mice and rats

“…Such learning incentives activate the neuromodulatory systems, a fact often not considered in studies using these tasks (MartinSoelch, Linthicum et al 2007). Neuromodulation is known to have a major effect on the memory system (Redondo and Morris 2011;Takeuchi, Duszkiewicz et al 2016;Genzel, Rossato et al 2017). Therefore, this makes these tasks difficult to compare with most, more neutral paradigms used in human research.…”