title: 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.
authors.affiliation: Department of Neuroscience, Ohio State University, Columbus, OH, USA.
authors.forename: Kaiden H
authors.initials: KH
authors.lastname: Price
authors.affiliation: Department of Neuroscience, Ohio State University, Columbus, OH, USA.
authors.forename: Heather
authors.initials: H
authors.lastname: Dziema
authors.affiliation: Department of Neuroscience, Ohio State University, Columbus, OH, USA.
authors.forename: Sydney
authors.initials: S
authors.lastname: Aten
authors.affiliation: Department of Neuroscience, Ohio State University, Columbus, OH, USA.
authors.forename: Jacob
authors.initials: J
authors.lastname: Loeser
authors.affiliation: Department of Neuroscience, Ohio State University, Columbus, OH, USA.
authors.forename: Frances E
authors.initials: FE
authors.lastname: Norona
authors.affiliation: Division of Pharmacology, Ohio State University, Columbus, OH, USA.
authors.forename: Kari
authors.initials: K
authors.lastname: Hoyt
authors.affiliation: Department of Neuroscience, Ohio State University, Columbus, OH, USA. Electronic address: obrietan.1@osu.edu.
authors.forename: Karl
authors.initials: K
authors.lastname: Obrietan
mesh_terms: D056930:ARNTL Transcription Factors / Q000172:deficiency* / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics / Q000378:metabolism; D057906:Circadian Clocks / Q000502:physiology*; D005106:Exploratory Behavior / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D019417:Hindlimb Suspension; D007858:Learning / Q000502:physiology*; D018782:Maze Learning; D008568:Memory / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D016548:Prosencephalon / Q000378:metabolism*; D017384:Sequence Deletion / Q000235:genetics*; D013493:Suprachiasmatic Nucleus / Q000378:metabolism
chemical_list: D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse; D049452:Green Fluorescent Proteins; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2
keywords: BMAL1; Brain and muscle Arnt-like protein-1; Circadian; Learning; Memory