Melatonin modulates daytime‐dependent synaptic plasticity and learning efficiency

Abstract

Mechanisms of hippocampus‐related memory formation are time‐of‐day‐dependent. While the circadian system and clock genes are related to timing of hippocampal mnemonic processes (acquisition, consolidation, and retrieval of long‐term memory [LTM]) and long‐term potentiation (LTP), little is known about temporal gating mechanisms. Here, the role of the neurohormone melatonin as a circadian time cue for hippocampal signaling and memory formation was investigated in C3H/He wildtype (WT) and melatonin receptor‐knockout (MT1/2-false/-) mice. Immunohistochemical and immunoblot analyses revealed the presence of melatonin receptors on mouse hippocampal neurons. Temporal patterns of time‐of‐day‐dependent clock gene protein levels were profoundly altered in MT1/2-false/- mice compared to WT animals. On the behavioral level, WT mice displayed better spatial learning efficiency during daytime as compared to nighttime. In contrast, high error scores were observed in MT1/2-false/- mice during both, daytime and nighttime acquisition. Day‐night difference in LTP, as observed in WT mice, was absent in MT1/2-false/- mice and in WT animals, in which the sympathetic innervation of the pineal gland was surgically removed to erase rhythmic melatonin synthesis. In addition, treatment of melatonin‐deficient C57BL/6 mice with melatonin at nighttime significantly improved their working memory performance at daytime. These results illustrate that melatonin shapes time‐of‐day‐dependent learning efficiency in parallel to consolidating expression patterns of clock genes in the mouse hippocampus. Our data suggest that melatonin imprints a time cue on mouse hippocampal signaling and gene expression to foster better learning during daytime.

MT1 and MT2 melatonin receptors are expressed in nonoverlapping neuronal populations

“…Immunohistochemical analysis showed that MT1 and MT2 expression patterns partially overlap, with MT1 being expressed predominantly in the CA1 hippocampal subfield and MT2 in the CA3/CA4 subfields . Our present results allow unambiguous identification of MT2‐expressing cells in the hippocampus, and apparent absence of MT1, and should facilitate experimental studies on the mechanism of MLT action on memory …”

“…44 Our present results allow unambiguous identification of MT2-expressing cells in the hippocampus, and apparent absence of MT1, and should facilitate experimental studies on the mechanism of MLT action on memory. [76][77][78][79][80][81] The moderate MLT receptor immunoreactivity in the rat dorsal raphe nucleus suggested the possible involvement of MT1 receptors in the pathogenesis of depression. 44 This is supported by a study which demonstrated behavioral changes mimicking the symptoms of melancholic depression in MLT receptor knockout mice.…”

Regulation and function of extra‐SCN circadian oscillators in the brain

“…Interestingly, expression peak times correlate with the species' temporal niche . Melatonin can reset hippocampal clocks but pinealectomy does not markedly affect clock protein rhythmicity …”

Melatonin Relations with Energy Metabolism as Possibly Involved in Fatal Mountain Road Traffic Accidents

“…Daily repeating phenomena, thus, coordinate widespread functions like temperature control [59][60][61], cardiovascular performance [62], autonomic [63], and endocrine regulations [49,64,65], as well as, behavior [52,53,66,67]. Biological oscillators, thus, effectively contribute to sustain homeostasis [30,68] and related functions like preconditioning (hormesis) and learning [69][70][71][72][73][74]. Even everyday coupling of rhythms between subjects has a neurophysiological substrate [75].…”