Circadian Regulation of Hippocampal-Dependent Memory: Circuits, Synapses, and Molecular Mechanisms

Abstract

Circadian modulation of learning and memory efficiency is an evolutionarily conserved phenomenon, occurring in organisms ranging from invertebrates to higher mammalian species, including humans. While the suprachiasmatic nucleus (SCN) of the hypothalamus functions as the master mammalian pacemaker, recent evidence suggests that forebrain regions, including the hippocampus, exhibit oscillatory capacity. This finding, as well as work on the cellular signaling events that underlie learning and memory, has opened promising new avenues of investigation into the precise cellular, molecular, and circuit-based mechanisms by which clock timing impacts plasticity and cognition. In this review, we examine the complex molecular relationship between clock timing and memory, with a focus on hippocampal-dependent tasks. We evaluate how the dysregulation of circadian timing, both at the level of the SCN and at the level of ancillary forebrain clocks, affects learning and memory. Further, we discuss experimentally validated intracellular signaling pathways (e.g., ERK/MAPK and GSK3β) and potential cellular signaling mechanisms by which the clock affects learning and memory formation. Finally, we examine how long-term potentiation (LTP), a synaptic process critical to the establishment of several forms of memory, is regulated by clock-gated processes.

Melatonin modulates daytime‐dependent synaptic plasticity and learning efficiency

“…(5, 6) Several reports demonstrated that performance of mice in acquisition, recall, and extinction of hippocampus‐based memory is better during daytime than nighttime, even under conditions of constant darkness (for review see ). The rhythm in hippocampal spatial learning was severely affected in mice as they lack the WT‐specific improvement of memory formation during daytime.…”

“…Since 1973, learning and memory have been known to be modulated through time‐of‐day‐dependent mechanisms . Ever since, the presence of a circadian rhythm in memory acquisition, consolidation, and retrieval has been demonstrated in numerous species, ranging from invertebrates ( Aplysia ; fruit fly), to vertebrates (Zebrafish; rodents) including the human (for review see Refs ). However, despite these widespread and common observations in circadian gating of memory formation, the mechanisms underlying time‐of‐day‐dependent dynamics in learning efficiency are far from being understood.…”

“…In mammals, a central structure for long‐term memory (LTM) formation is the hippocampus, with the plasticity of long‐term potentiation (LTP) mirroring hippocampal LTM . It is well described that hippocampal learning efficiency depends on the time‐of‐day . Notably, this temporal coordination depends on the integrity of the SCN that shows a higher activity during daytime, independent of whether an animal is day‐ or night‐active .…”

“…Notably, this temporal coordination depends on the integrity of the SCN that shows a higher activity during daytime, independent of whether an animal is day‐ or night‐active . Despite this, in night‐active laboratory mice, disparate findings for the time‐of‐day window for eased learning are reported . This raises the question, if additional factors are involved in shaping the time‐of‐day‐dependent efficiency in memory formation.…”

“…13,15 It is well described that hippocampal learning efficiency depends on the time-of-day. 10,[16][17][18][19] Notably, this temporal coordination depends on the integrity of the SCN 20 that shows a higher activity during daytime, independent of whether an animal is day-or night-active. 21 Despite this, in night-active laboratory mice, disparate findings for the time-of-day window for eased learning are reported.…”