Locus Coeruleus and Dopamine-Dependent Memory Consolidation

Abstract

Most everyday memories including many episodic-like memories that we may form automatically in the hippocampus (HPC) are forgotten, while some of them are retained for a long time by a memory stabilization process, called initial memory consolidation. Specifically, the retention of everyday memory is enhanced, in humans and animals, when something novel happens shortly before or after the time of encoding. Converging evidence has indicated that dopamine (DA) signaling via D₁/D₅ receptors in HPC is required for persistence of synaptic plasticity and memory, thereby playing an important role in the novelty-associated memory enhancement. In this review paper, we aim to provide an overview of the key findings related to D₁/D₅ receptor-dependent persistence of synaptic plasticity and memory in HPC, especially focusing on the emerging evidence for a role of the locus coeruleus (LC) in DA-dependent memory consolidation. We then refer to candidate brain areas and circuits that might be responsible for detection and transmission of the environmental novelty signal and molecular and anatomical evidence for the LC-DA system. We also discuss molecular mechanisms that might mediate the environmental novelty-associated memory enhancement, including plasticity-related proteins that are involved in initial memory consolidation processes in HPC.

Figure 1

Two distinct novelty systems. There are two types of novelty: “environmental novelty” (e.g., new environment with objects never seen before) and “reward-associated novelty” (e.g., new reward in an unexpected location). They are associated with release of dopamine (DA) in the hippocampus (HPC) but might be processed by different systems with different time windows. (a) The locus coeruleus- (LC-) HPC system mediates environmental novelty which modulates the retention of memory with a broad time window (~1 hr). (b) The ventral tegmental area- (VTA-) HPC system might mediate reward-associated novelty which modulates the memory with a narrow time window.

Figure 2

Hippocampal projections from LC neurons and increased LC neuron activity by environmental novelty. (a) Immunofluorescence of DβH in HPC. (a) is reproduced from [88]. (b) TH⁺ axons in the dorsal HPC originate from LC-TH⁺ neurons. Quantification shows stronger TH⁺ projections from LC than from VTA in CA1, CA3, and DG. ^∗∗∗p < 0.001 , paired t-test. (b) is reproduced from [22]. (c) Response to novelty and its habituation in LC neurons. (c) is reproduced from [96]. (d) LC-TH⁺ neurons show strong response to environmental novelty that habituates over 5 min. (d) is reproduced from [22].

Figure 3

Noncanonical release of DA from LC-TH⁺ axons in HPC. (a) LC electorical stimulation-induced increase of NA (top) and DA (bottom) in the medial prefrontal cortex. (a) is reproduced from [106]. (b) LC electorical stimulation-mediated D₁/D₅ receptor-sensitive facilitation of CA3–CA1 LTD in vivo. (b) is reproduced from [52]. (c) TH knockdown in LC prevents D₁/D₅ receptor-mediated enhancement of excitatory transmission in HPC. (c) is reproduced from [20]. (d) Optogenetic activation of LC-TH⁺ neurons enhances persistence of memory in a manner consistent with release of DA in HPC ^∗p < 0.05 versus chance, t-test. (d) is reproduced from [22]. (e) Optogenetic activation of LC-TH⁺ axons in HPC produces an increase in DA release in the dorsal HPC. ^∗p < 0.05, t-test. (e) is reproduced from [23].

Figure 4

Identification of key PRPs (plasticity-related proteins) by using optogenetics and translational profiling. (a) The critical test session would include (i) a behavioural condition that enhances memory (novelty), (ii) optogenetic activation of LC neurons (LC on), and (iii) LC activation with D₁/D₅ receptor blocker (LC on with D₁/D₅-R blocker) that might block the relevant synthesis of PRPs mediated by DAergic signaling in key target neurons. These conditions are compared to a home cage condition. (b) The TRAP technology, involving cell type-specific expression of green fluorescent protein- (GFP-) tagged ribosomal protein and GFP immunoprecipitation, enables the selective isolation of “translated mRNAs” in genetically defined neurons. (c) BONCAT (bioorthogonal noncanonical amino acid tagging) technology, involving labelling of newly synthesized proteins by AHA (azidohomoalanine), which can be later tagged for isolation and identification by mass spectrometry. (d) Candidate PRPs would be identified through the Venn diagram overlap of experimental conditions. (e) Optogenetic inhibition of a candidate PRP using “miniSOG,” a genetically encoded singlet oxygen generator [168]. After light illumination, singlet oxygen (¹O₂) is generated by miniSOG leading to the inactivation of fusion protein of interest.