The CBP KIX domain regulates long-term memory and circadian activity

Abstract

Background CREB-dependent transcription necessary for long-term memory is driven by interactions with CREB-binding protein (CBP), a multi-domain protein that binds numerous transcription factors potentially affecting expression of thousands of genes. Identifying specific domain functions for multi-domain proteins is essential to understand processes such as cognitive function and circadian clocks. We investigated the function of the CBP KIX domain in hippocampal memory and gene expression using CBPKIX/KIX mice with mutations that prevent phospho-CREB (Ser133) binding. Results We found that CBPKIX/KIX mice were impaired in long-term memory, but not learning acquisition or short-term memory for the Morris water maze. Using an unbiased analysis of gene expression in the dorsal hippocampus after training in the Morris water maze or contextual fear conditioning, we discovered dysregulation of CREB, CLOCK, and BMAL1 target genes and downregulation of circadian genes in CBPKIX/KIX mice. Given our finding that the CBP KIX domain was important for transcription of circadian genes, we profiled circadian activity and phase resetting in CBPKIX/KIX mice. CBPKIX/KIX mice exhibited delayed activity peaks after light offset and longer free-running periods in constant dark. Interestingly, CBPKIX/KIX mice displayed phase delays and advances in response to photic stimulation comparable to wildtype littermates. Thus, this work delineates site-specific regulation of the circadian clock by a multi-domain protein. Conclusions These studies provide insight into the significance of the CBP KIX domain by defining targets of CBP transcriptional co-activation in memory and the role of the CBP KIX domain in vivo on circadian rhythms. Graphical abstract

Endoplasmic reticulum chaperone genes encode effectors of long-term memory

“…Notably, these ligand-independent “orphan” receptors are robustly up-regulated in the hippocampus within minutes after learning ( 3 , 4 ). The learning-dependent expression of the Nr4a genes is regulated by histone acetylation, which is driven by recruitment of adenosine 3′,5′-monophosphate (cAMP) response element–binding protein (CREB)–binding protein (CBP) ( 9 ) to CREB response elements in the promoters of these genes ( 10 , 11 ). Blocking the expression or inactivating the transactivation function of Nr4a factors is sufficient to impair long-term memory ( 4 , 7 ) and synaptic plasticity ( 12 ), whereas transgenic or pharmacological activation enhances long-term memory ( 13 , 14 ).…”

NEUROeSTIMator: Using Deep Learning to Quantify Neuronal Activation from Single-Cell and Spatial Transcriptomic Data

“…Per1 , a target of our model, is a circadian regulator gene upregulated by neuronal activity 29 . It has been demonstrated that disrupted activity-dependent binding of CREB to CREB-binding protein (CBP) impairs long-term memory in mice and blunts the transcriptional upregulation of immediate early genes and circadian rhythm genes 30 . Together with our results, this suggests a subset of the activity response is allocated to a group of genes regulating circadian rhythm, and our model extracts this information from the transcriptome to predict expression levels of activity-dependent genes.…”

4’-demethylnobiletin-rich fermented Citrus reticulata (ponkan) attenuated the disturbance in clock gene expression and locomotor activity rhythms caused by high-fat diet feeding

“…Indeed, synRas mice, in which endogenous Ras activity continues to be regulated and ERK phosphorylation level is upregulated, were found to be more sensitive to light than wild-type mice, because synRas mice showed higher phosphorylation levels of CREB in the SCN induced by light pulses than wild-type mice, especially during the early subjective night period (Serchov et al 2016). Moreover, CBP KIX/KIX mice that do not show stimulus-induced activation of CREB, showed lower locomotor activity levels at the beginning of the active period (Chatterjee et al 2020). Taken together, these results suggest that FCR modified the HFD feeding-induced locomotor activity level decrease at of the time LD switching via the activation of the ERK/ CREB signaling.…”