scholarly journals CREB is Required in Excitatory Neurons in the Forebrain to Sustain Wakefulness

2020 ◽  
Author(s):  
Mathieu E. Wimmer ◽  
Cui Rosa ◽  
Jennifer M. Blackwell ◽  
Ted Abel
Keyword(s):  
Cyclic Amp ◽  
Intracellular Signaling ◽  
Target Genes ◽  
Nrem Sleep ◽  
Creb Phosphorylation ◽  
Element Binding Protein ◽  
Cyclic Amp Response Element ◽  
Phosphorylated Creb ◽  
And Control ◽  
Activity Dependent

AbstractThe molecular and intracellular signaling processes that control sleep and wake states remain largely unknown. A consistent observation is that the cyclic-AMP response element binding protein (CREB), an activity-dependent transcription factor, is differentially activated during sleep and wakefulness. CREB is phosphorylated by the cyclic AMP/protein kinase A (cAMP/PKA) signaling pathway as well as other kinases, and phosphorylated CREB (pCREB) promotes transcription of target genes. Genetic studies in flies and mice suggest that CREB signaling influences sleep/wake states by promoting and stabilizing wakefulness. However, it remains unclear where in the brain CREB is required to drive wakefulness. In rats, CREB phosphorylation increases in the cerebral cortex during wakefulness and decreases during sleep, but it is not known if this change is functionally relevant to the maintenance of wakefulness. Here, we used the cre/lox system to conditionally delete CREB in the forebrain and in the locus coereleus (LC), two regions known to be important for the production of arousal and wakefulness. We used polysomnography to measure sleep/wake levels and sleep architecture in conditional CREB mutant mice and control littermates. We found that forebrain-specific deletion of CREB decreased wakefulness and increased non-rapid eye movement (NREM) sleep. Mice lacking CREB in the forebrain were unable sustain normal periods of wakefulness. On the other hand, deletion of CREB from LC neurons did not change sleep/wake levels or sleep/wake architecture. Taken together, these results suggest that CREB is required in neurons within the forebrain but not in the LC to promote and stabilize wakefulness.

scholarly journals Cyclic AMP response element-binding protein is required in excitatory neurons in the forebrain to sustain wakefulness

SLEEP ◽  
2020 ◽  
Author(s):  
Mathieu E Wimmer ◽  
Rosa Cui ◽  
Jennifer M Blackwell ◽  
Ted Abel
Keyword(s):  
Cyclic Amp ◽  
Intracellular Signaling ◽  
Target Genes ◽  
Binding Protein ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Response Element ◽  
Creb Phosphorylation ◽  
Element Binding Protein ◽  
And Control

Abstract The molecular and intracellular signaling processes that control sleep and wake states remain largely unknown. A consistent observation is that the cyclic adenosine monophosphate (AMP) response element-binding protein (CREB), an activity-dependent transcription factor, is differentially activated during sleep and wakefulness. CREB is phosphorylated by the cyclic AMP/protein kinase A (cAMP/PKA) signaling pathway as well as other kinases, and phosphorylated CREB promotes the transcription of target genes. Genetic studies in flies and mice suggest that CREB signaling influences sleep/wake states by promoting and stabilizing wakefulness. However, it remains unclear where in the brain CREB is required to drive wakefulness. In rats, CREB phosphorylation increases in the cerebral cortex during wakefulness and decreases during sleep, but it is not known if this change is functionally relevant to the maintenance of wakefulness. Here, we used the Cre/lox system to conditionally delete CREB in the forebrain (FB) and in the locus coeruleus (LC), two regions known to be important for the production of arousal and wakefulness. We used polysomnography to measure sleep/wake levels and sleep architecture in conditional CREB mutant mice and control littermates. We found that FB-specific deletion of CREB decreased wakefulness and increased non-rapid eye movement sleep. Mice lacking CREB in the FB were unable to sustain normal periods of wakefulness. On the other hand, deletion of CREB from LC neurons did not change sleep/wake levels or sleep/wake architecture. Taken together, these results suggest that CREB is required in neurons within the FB but not in the LC to promote and stabilize wakefulness.

Genetic Evidence for a Role of CREB in Sustained Cortical Arousal

2003 ◽  
Vol 90 (2) ◽  
pp. 1152-1159 ◽  
Author(s):  
Laurel A. Graves ◽  
Kevin Hellman ◽  
Sigrid Veasey ◽  
Julie A. Blendy ◽  
Allan I. Pack ◽  
...  
Keyword(s):  
Rem Sleep ◽  
Nrem Sleep ◽  
Genetic Alterations ◽  
Memory Storage ◽  
Cortical Arousal ◽  
Element Binding Protein ◽  
Cyclic Amp Response Element ◽  
Phosphorylated Creb ◽  
Activity Dependent

The cyclic AMP-response element binding protein (CREB) is an activity-dependent transcription factor important for synaptic plasticity and memory storage. Levels of phosphorylated CREB within the cortex are higher in waking than in sleep, suggesting that CREB plays a role in sleep/wake regulation in mammals. We tested the hypothesis that CREB is critical for sleep/wake regulation by examining behavioral state parameters in mice lacking the α and Δ isoforms of CREB. Over 24 h, time spent awake was significantly decreased in CREB αΔ mutant mice by approximately 100 min, and time spent in nonrapid eye movement sleep (NREM) sleep was increased correspondingly. Wake and REM sleep periods were shorter in CREB αΔ mice, and CREB αΔ mice had decreased levels of θ-activity during wake and REM sleep, consistent with an impairment in the ability to maintain an activated electroencephalogram. These results suggest that the CREB protein contributes to the mechanisms by which wakefulness is maintained and demonstrate that specific genetic alterations in species as diverse as Drosophila and mice produce similar phenotypes in arousal and wakefulness.

scholarly journals Role of hippocampal activity-induced transcription in memory consolidation

2016 ◽  
Vol 27 (6) ◽  
pp. 559-573 ◽  
Author(s):  
Andrew L. Eagle ◽  
Paula A. Gajewski ◽  
Alfred J. Robison
Keyword(s):  
Memory Consolidation ◽  
Target Genes ◽  
Serum Response Factor ◽  
Future Research ◽  
Hippocampal Activity ◽  
Element Binding Protein ◽  
Cyclic Amp Response Element ◽  
Meta Analyses ◽  
And Function ◽  
Activity Dependent

AbstractExperience-dependent changes in the strength of connections between neurons in the hippocampus (HPC) are critical for normal learning and memory consolidation, and disruption of this process drives a variety of neurological and psychiatric diseases. Proper HPC function relies upon discrete changes in gene expression driven by transcription factors (TFs) induced by neuronal activity. Here, we describe the induction and function of many of the most well-studied HPC TFs, including cyclic-AMP response element binding protein, serum-response factor, AP-1, and others, and describe their role in the learning process. We also discuss the known target genes of many of these TFs and the purported mechanisms by which they regulate long-term changes in HPC synaptic strength. Moreover, we propose that future research in this field will depend upon unbiased identification of additional gene targets for these activity-dependent TFs and subsequent meta-analyses that identify common genes or pathways regulated by multiple TFs in the HPC during learning or disease.

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