Modulation of learning and memory by the targeted deletion of the circadian clock gene Bmal1 in forebrain circuits

Abstract

A large body of literature has shown that the disruption of circadian clock timing has profound effects on mood, memory and complex thinking. Central to this time keeping process is the master circadian pacemaker located within the suprachiasmatic nucleus (SCN). Of note, within the central nervous system, clock timing is not exclusive to the SCN, but rather, ancillary oscillatory capacity has been detected in a wide range of cell types and brain regions, including forebrain circuits that underlie complex cognitive processes. These observations raise questions about the hierarchical and functional relationship between the SCN and forebrain oscillators, and, relatedly, about the underlying clock-gated synaptic circuitry that modulates cognition. Here, we utilized a clock knockout strategy in which the essential circadian timing gene Bmal1 was selectively deleted from excitatory forebrain neurons, whilst the SCN clock remained intact, to test the role of forebrain clock timing in learning, memory, anxiety, and behavioral despair. With this model system, we observed numerous effects on hippocampus-dependent measures of cognition. Mice lacking forebrain Bmal1 exhibited deficits in both acquisition and recall on the Barnes maze. Notably, loss of forebrain Bmal1 abrogated time-of-day dependent novel object location memory. However, the loss of Bmal1 did not alter performance on the elevated plus maze, open field assay, and tail suspension test, indicating that this phenotype specifically impairs cognition but not affect. Together, these data suggest that forebrain clock timing plays a critical role in shaping the efficiency of learning and memory retrieval over the circadian day.

Physiological and cognitive consequences of a daily 26h photoperiod in a primate(M. murinus)

“…It is well documented that a strong link exists between circadian clock and cerebral performances. Through its link with the hippocampus (Borgs et al, 2009; Chiang et al, 2017; Schnell et al, 2014, Snider et al, 2018), the circadian system influences mood, learning, time-place association and memory in laboratory mice (Albrecht, 2017; Cain et al, 2004; Legates et al, 2012; Ruby et al, 2008), and the involvement of clock genes is well established (Snider et al, 2016; Van der Zee et al, 2008; Wang et al, 2009). Furthermore, numerous data indicate that circadian disorganization (jet-lag, phase shifts, aging alterations, sleep impairments, shift work…) invariably leads to impaired cognitive performances which suggests that clock resynchronization indirectly impacts cognitive capacities (Antoniadis et al, 2000; Chellappa et al, 2018; Gibson et al, 2010; Krishnan and Lyons, 2015; Loh et al, 2010; Rouch et al, 2005).…”

GSK3 activity regulates rhythms in hippocampal clock gene expression and synaptic plasticity

“…The circadian molecular clock is important for hippocampal processes such as spatial memory, time–place association, contextual memory, and synaptic plasticity (Jager et al, ; Snider et al, ; Van der Zee et al, ; Wang et al, ); however, the underlying mechanisms of this circadian regulation is less clear. Hippocampal processes such as spatial learning and memory and synaptic plasticity are dependent upon activation of GSK3 (Hernandez et al, ; Hooper et al, ; Liu et al, ; Peineau et al, ).…”

“…Finally, Bmal1−/− mice display initial hyperactivity and impaired intrasession and intersession habituation to a novel environment, suggesting a deficit in short‐ and long‐term contextual memory formation (Kondratova, Dubrovsky, Antoch, & Kondratov, ). More recently, mice with forebrain‐specific Bmal1 knockout were shown to have impaired Barnes maze performance and novel object location memory (Snider et al, ). These findings indicate that the circadian clock is involved in learning and memory processes, including synaptic plasticity.…”

Interacting influences of aging and Alzheimer's disease on circadian rhythms

“…Loss of clock gene expression has functional consequences beyond impairments in circadian timekeeping; the effects most relevant to AD include cognitive deterioration and neurodegeneration (Jilg et al., ; Kondratov et al., ; Rawashdeh et al., ; Snider et al., ; Wang et al., ). For example, global (germline) deletion of Per1 or Per2 in mice impairs spatial learning or cued fear conditioning, respectively, as well as hippocampal long‐term potentiation, a basic cellular substrate underlying learning and memory (Jilg et al., ; Wang et al., ).…”