Research reportModulation of learning and memory by the targeted deletion of the circadian clock gene Bmal1 in forebrain circuits
Introduction
Work in a wide array of organisms (from Aplysia to humans) has clearly established that learning and memory are modulated by a circadian timekeeper [1], [2], [3], [4], [5]. For example, in rodent models, learning tasks such as spatial memory and context and cued fear conditioning vary as a function of circadian time [6], [7], [8]. Paralleling these findings, a large number of studies have shown that recall deficits occur as a function of the time of day, indicating that the memory recall process (which is independent of memory formation and acquisition) is also gated by a circadian-dependent process [1], [9], [10], [11]. The connection between circadian timing and learning and memory is supported by cellular-based approaches that have shown that underlying physiological properties of the hippocampus are modulated by the clock. Along these lines, clock timing modulates long-term potentiation magnitude in subregions of the hippocampus that include area CA1 (cornu ammonis 1) and the GCL (granule cell layer) [12], [13], [14]. Likewise, evoked GCL response properties vary as a function of the circadian cycle [15], and pyramidal cell responsiveness to a range of transmitters (i.e., serotonin, norepinephrine, and acetylcholine) is modulated by the clock [16]. Further, the circadian clock has also been reported to exert control over GABAergic inhibition in the forebrain, a physiological effect that is independent of sleep history (including sleep deprivation [17]). Clearly, circadian variations in electrophysiological signatures of forebrain neurons (both excitatory and inhibitory) could have profound effects on the function of circuits that underlie cognition.
With respect to learning and memory, the functional significance of the master clock located in the suprachiasmatic nucleus (SCN) of the hypothalamus has been described, but the role of the forebrain clock(s) is not clear. Interestingly, all forebrain regions express the essential clock genes required to generate circadian oscillations [18], [19], [20], [21], [22], [23], [24], and, indeed, several studies have shown that limbic structures and the cortex exhibit low-level rhythmicity [20], [21], [22], [23], [24]. Moreover, the activation state of cell signaling pathways involved in learning and memory (such as cAMP/PKA and ERK/MAPK) exhibit daily oscillations in the hippocampus [25]. Further, within the hippocampus, CREB, a transcription factor involved in learning and memory, displays a circadian oscillation in its Serine-133 phosphorylated state [25], [26], and germline Period1 deletion has been shown to abrogate this rhythm [27]. These findings raise an interesting question: in addition to the SCN, could a critical “time cue” also emanate from the forebrain?
Here, we addressed the role of forebrain clock timing in the modulation of cognition. Using a targeted gene knockout strategy, we show that the disruption of Bmal1 in forebrain excitatory neurons has a detrimental effect on time-of-day regulated learning and memory. These findings suggest that forebrain oscillators work in a coordinated manner with the SCN to shape key aspects of learning and memory as a function of circadian time.
Section snippets
Transgenic mice
Three transgenic mouse lines were obtained from Jackson Laboratories. B6.129S4(Cg)-Arntltm1Weit/J (commonly referred to as Bmal1(fl/fl) mice) are homozygous for a floxed allele of the Bmal1 gene. B6.Cg-Tg(Camk2a-cre)T29-1Stl/J mice (commonly referred to as the CaMKII-CRE mouse line) express CRE recombinase driven by the CaMKIIa promoter. B6.129S4-Gt(ROSA)26Sortm1Sor/J (here referred to as the ROSA26-β-gal line), express the β-galactosidase gene via the CRE-mediated deletion of a floxed stop
Conditional forebrain deletion of Bmal1
To disrupt the canonical core clock transcriptional feedback loop in excitatory neurons of the cortex and limbic system, we employed a targeted gene disruption strategy to disrupt the expression of the Bmal1 gene. BMAL1 forms a heterodimeric transcription factor with CLOCK (and NPAS2), binding to the Ebox element and facilitating the transcription of core clock genes (e.g., Per and Cry) as well as clock-controlled output genes. Hence, BMAL1 is considered a lynchpin of the clock. Indeed, the
Discussion
A rich literature across diverse species has demonstrated that the circadian timing system modulates the efficiency of learning and memory [7], [8], [62], [63]. In mammals, much of the neuroanatomical work logically has focused on the contribution of the SCN clock to the generation of rhythms in cognition [64], [65], [66], [67] . Here, we sought to move this question from the SCN to ancillary oscillator populations in the forebrain. A rationale for this was based on studies over the past
Conflict of interest
The authors have no conflict of interest to declare.
Acknowledgements
This work was supported by the National Institutes of Health (Grant code: MH103361, NS066345, NS091302) and the National Science Foundation (Grant code: 1354612). We thank Andrew Fischer for assistance with optokinetic assays.
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