Circadian expression of Fabp7 mRNA is disrupted in Bmal1 KO mice

Gerstner, Jason R.; Paschos, Georgios K.

doi:10.1186/s13041-020-00568-7

Cited by 15 publications

(8 citation statements)

References 18 publications

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“…These results support activation of astrocytes as a general feature of CNS model systems with knockout of Bmal1, since a modest upregulation of Fabp7 transcripts in the hypothalamus of global Bmal1 knockout mice was recently reported (Gerstner & Paschos, 2020), whereas the relation between a knockout of BMAL1 and activation of GFAP-positive astrocyte has been previously reported both in vitro and in vivo (Lananna et al, 2018;Musiek et al, 2013).…”

Section: Gfap-and Fabp7-positive Cells Are Abundant In the Cerebral C...supporting

confidence: 83%

Diurnal proteome profile of the mouse cerebral cortex: Conditional deletion of the Bmal1 circadian clock gene elevates astrocyte protein levels and cell abundance in the neocortex and hippocampus

Bering

Gadgaard

Vorum

et al. 2023

Glia

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Circadian oscillators, defined by cellular 24 h clock gene rhythms, are found throughout the brain. Cerebral cortex‐specific conditional knockout of the clock gene Bmal1 (Bmal1 CKO) leads to depressive‐like behavior, but the molecular link from clock gene to altered behavior is unknown. Further, diurnal proteomic data on the cerebral cortex are currently unavailable. With the aim of determining the diurnal proteome profile and downstream targets of the cortical circadian clock, we here performed a proteomic analysis of the mouse cerebral cortex. Proteomics identified approximately 2700 proteins in both the neocortex and the hippocampus. In the neocortex, 15 proteins were differentially expressed (>2‐fold) between day and night, mainly mitochondrial and neuronal plasticity proteins. Only three hippocampal proteins were differentially expressed, suggesting that daily protein oscillations are more prominent in the neocortex. The number of differentially expressed proteins was reduced in the Bmal1 CKO, suggesting that daily rhythms in the cerebral cortex are primarily driven by local clocks. The proteome of the Bmal1 CKO cerebral cortex was dominated by upregulated proteins expressed in astrocytes, including GFAP (4‐fold) and FABP7 (>20‐fold), in both the neocortex and hippocampus. These findings were confirmed at the transcript level. Cellular analyses of astrocyte components revealed an increased number of GFAP‐positive cells in the Bmal1 CKO cerebral cortex. Further, BMAL1 was found to be expressed in both GFAP‐ and FABP7‐positive astrocytes of control animals. Our data show that Bmal1 is required for proper cellular composition of the cerebral cortex, suggesting that increased cortical astrocyte activity may induce behavioral changes.

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Section: Gfap-and Fabp7-positive Cells Are Abundant In the Cerebral C...supporting

confidence: 83%

Diurnal proteome profile of the mouse cerebral cortex: Conditional deletion of the Bmal1 circadian clock gene elevates astrocyte protein levels and cell abundance in the neocortex and hippocampus

Bering

Gadgaard

Vorum

et al. 2023

Glia

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“…It regulates fatty acid uptake in astrocytes, sleep (Gerstner et al, 2017) and drug seeking under stressful conditions (Hamilton et al, 2018). Fabp7 is rhythmically expressed throughout the brain (Schnell et al, 2014) and is similarly upregulated in Arntl and Nr1d1 knock-out mice (Schnell et al, 2014;Gerstner and Paschos, 2020). Fabp7 could be upregulated in Npas2 mutants because of the downregulation of Nr1d1, which represses Fabp7 (Schnell et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Circadian-Dependent and Sex-Dependent Increases in Intravenous Cocaine Self-Administration inNpas2Mutant Mice

et al. 2020

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Substance use disorder (SUD) is associated with disruptions in circadian rhythms. The circadian transcription factor neuronal PAS domain protein 2 (NPAS2) is enriched in reward-related brain regions and regulates reward, but its role in SU is unclear. To examine the role of NPAS2 in drug taking, we measured intravenous cocaine self-administration (acquisition, dose-response, progressive ratio, extinction, cue-induced reinstatement) in wild-type (WT) and Npas2 mutant mice at different times of day. In the light (inactive) phase, cocaine self-administration, reinforcement, motivation and extinction responding were increased in all Npas2 mutants. Sex differences emerged during the dark (active) phase with Npas2 mutation increasing self-administration, extinction responding, and reinstatement only in females as well as reinforcement and motivation in males and females. To determine whether circulating hormones are driving these sex differences, we ovariectomized WT and Npas2 mutant females and confirmed that unlike sham controls, ovariectomized mutant mice showed no increase in self-administration. To identify whether striatal brain regions are activated in Npas2 mutant females, we measured cocaine-induced DFosB expression. Relative to WT, DFosB expression was increased in D11 neurons in the nucleus accumbens (NAc) core and dorsolateral (DLS) striatum in Npas2 mutant females after dark phase self-administration. We also identified potential target genes that may underlie the behavioral responses to cocaine in Npas2 mutant females. These results suggest NPAS2 regulates reward and activity in specific striatal regions in a sex and time of day (TOD)-specific manner. Striatal activation could be augmented by circulating sex hormones, leading to an increased effect of Npas2 mutation in females.

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“…Alongside sleep disturbance, another mechanism that may influence FABP7-signaling in AD is disruption of the circadian system. Circadian expression of Fabp7 is regulated by the core-clock gene BMAL1 ( Gerstner and Paschos, 2020 ) and the circadian transcriptional repressor REV-ERBα (NR1D1) ( Vanderheyden et al, 2021 ) and exhibits time-of-day changes at the tripartite synapse ( Gerstner et al, 2012b ). Many studies in humans and in animal models have shown a link between the circadian clock and AD ( Weldemichael and Grossberg, 2010 ; Cermakian et al, 2011 ; Musiek and Holtzman, 2016 ; Homolak et al, 2018 ; Wu et al, 2019 ; Lananna and Musiek, 2020 ; Carter et al, 2021 ; Fusilier et al, 2021 ; Nassan and Videnovic, 2022 ).…”

Section: Alzheimer’s Disease Fabp7 and The Circadian Clockmentioning

confidence: 99%

A Dichotomous Role for FABP7 in Sleep and Alzheimer’s Disease Pathogenesis: A Hypothesis

et al. 2022

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Fatty acid binding proteins (FABPs) are a family of intracellular lipid chaperone proteins known to play critical roles in the regulation of fatty acid uptake and transport as well as gene expression. Brain-type fatty acid binding protein (FABP7) is enriched in astrocytes and has been implicated in sleep/wake regulation and neurodegenerative diseases; however, the precise mechanisms underlying the role of FABP7 in these biological processes remain unclear. FABP7 binds to both arachidonic acid (AA) and docosahexaenoic acid (DHA), resulting in discrete physiological responses. Here, we propose a dichotomous role for FABP7 in which ligand type determines the subcellular translocation of fatty acids, either promoting wakefulness aligned with Alzheimer’s pathogenesis or promoting sleep with concomitant activation of anti-inflammatory pathways and neuroprotection. We hypothesize that FABP7-mediated translocation of AA to the endoplasmic reticulum of astrocytes increases astrogliosis, impedes glutamatergic uptake, and enhances wakefulness and inflammatory pathways via COX-2 dependent generation of pro-inflammatory prostaglandins. Conversely, we propose that FABP7-mediated translocation of DHA to the nucleus stabilizes astrocyte-neuron lactate shuttle dynamics, preserves glutamatergic uptake, and promotes sleep by activating anti-inflammatory pathways through the peroxisome proliferator-activated receptor-γ transcriptional cascade. Importantly, this model generates several testable hypotheses applicable to other neurodegenerative diseases, including amyotrophic lateral sclerosis and Parkinson’s disease.

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Circadian expression of Fabp7 mRNA is disrupted in Bmal1 KO mice

Cited by 15 publications

References 18 publications

Diurnal proteome profile of the mouse cerebral cortex: Conditional deletion of the Bmal1 circadian clock gene elevates astrocyte protein levels and cell abundance in the neocortex and hippocampus

Diurnal proteome profile of the mouse cerebral cortex: Conditional deletion of the Bmal1 circadian clock gene elevates astrocyte protein levels and cell abundance in the neocortex and hippocampus

Circadian-Dependent and Sex-Dependent Increases in Intravenous Cocaine Self-Administration inNpas2Mutant Mice

A Dichotomous Role for FABP7 in Sleep and Alzheimer’s Disease Pathogenesis: A Hypothesis

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