Circadian Rhythms in Fear Conditioning: An Overview of Behavioral, Brain System, and Molecular Interactions

Abstract

The formation of fear memories is a powerful and highly evolutionary conserved mechanism that serves the behavioral adaptation to environmental threats. Accordingly, classical fear conditioning paradigms have been employed to investigate fundamental molecular processes of memory formation. Evidence suggests that a circadian regulation mechanism allows for a timestamping of such fear memories and controlling memory salience during both their acquisition and their modification after retrieval. These mechanisms include an expression of molecular clocks in neurons of the amygdala, hippocampus, and medial prefrontal cortex and their tight interaction with the intracellular signaling pathways that mediate neural plasticity and information storage. The cellular activities are coordinated across different brain regions and neural circuits through the release of glucocorticoids and neuromodulators such as acetylcholine, which integrate circadian and memory-related activation. Disturbance of this interplay by circadian phase shifts or traumatic experience appears to be an important factor in the development of stress-related psychopathology, considering these circadian components are of critical importance for optimizing therapeutic approaches to these disorders.

Figure 1

Overview of circadian fear memory system interactions. (a) On the behavioral level, fear memory strength is higher when fear conditioning and its retrieval took place during the inactive, light phase [51], while extinction memory is facilitated when training and testing took place during the dark, active phase [54]. On evolutionary aspects, this may relate to the increased significance of aversive events occurring during the inactive phase, when the animal usually retires to the nest. Further, the increased probability of posttraining sleep, which is required for memory consolidation, may strengthen fear memory acquired during the inactive phase. (b) On the brain circuit level, fear and extinction memory strength are determined by an interaction of the amygdala, hippocampus, and medial prefrontal cortex (mPFC). While cue associations are stored in the lateral and basolateral nuclei of the amygdala (LA/BLA), contextual information is processed by the hippocampal formation (DG: dentate gyrus; CA: Cornu ammonis, 1–3) [13, 16]. For extinction of fear memory, the infralimbic cortex (IL) is important in inhibiting conditioned responses, mediated trough the central amygdala (CeA) [22]. The expression of clock genes such as period (PER) 2 displays a circadian rhythm with different phase settings within the LA/BLA (light orange) and hippocampal subregions (light green) versus the CeA (dark orange) and IL (blue) [–82]. Adrenalectomy (AdX) abolishes the circadian expression pattern of PER2 only in the CeA and the IL [80, 82], which correspond to circadian rhythms of corticosterone (CORT) plasma levels [95] depicted in the lower graph. In addition, fear memory consolidation strength is modulated by serotonin (5HT) and acetylcholine (ACh), which show circadian variations in amygdala and/or hippocampal tissue levels as well [112, 117]. (c) On the molecular level, it has been shown in hippocampal neurons that different components of the MAPK pathway display a circadian activation profile, with peaks during the light phase for the second messenger cAMP (dark red), the kinase ERK1/2 (light green), the transcription factor CREB (dark green), and the protein translation initiation factor eIF4E (light red) [90, 91, 93]. Moreover, the nuclear translocation of p90RSK, a kinase that activates CREB and modulates translation, is regulated by the clock protein PER1, thereby modulating transcriptional activation of CREB-dependent downstream proteins [90]. PER1 expression levels are further regulated by corticosterone signaling, adding a further level of stress and circadian systems interactions [96].