CREB binding and activity in brain: regional specificity and induction by electroconvulsive seizure

Area of Science:

• Neuroscience
• Molecular Biology
• Genomics

Background:

• Cyclic adenosine monophosphate response element binding protein (CREB) is a transcription factor crucial for neurobiological processes like cell differentiation, survival, and plasticity.
• Dysregulation of CREB-mediated transcription is linked to central nervous system (CNS) disorders, including depression, anxiety, addiction, and cognitive decline.
• The precise CREB-regulated genes and the spatiotemporal dynamics of CREB function in the brain are not fully understood.

Purpose of the Study:

• To identify CREB-regulated genes and binding sites in the rat brain using a combination of microarray and chromatin immunoprecipitation.
• To investigate the regional differences in CREB occupancy and activity across the frontal cortex, hippocampus, and striatum.
• To determine the impact of electroconvulsive therapy (ECT) on CREB binding and activity in the brain.

Main Methods:

• Chromatin immunoprecipitation sequencing (ChIP-seq) and microarray analysis were employed to map CREB-DNA interactions in rat brain.
• CREB occupancy and activity were compared in the frontal cortex, hippocampus, and striatum before and after a rodent model of electroconvulsive therapy.
• Analysis focused on identifying genomic loci enriched with CREB binding sites and associated transcripts.

Main Results:

• Over 860 CREB binding sites were identified in the rat brain.
• CREB-occupied transcripts were found to extensively interact, promoting cell proliferation, plasticity, and resiliency.
• Significant regional variations in CREB occupancy and activity were observed, contributing to diverse neurobiological outputs.
• Electroconvulsive seizure rapidly enhanced CREB occupancy and/or phosphorylation at specific promoters, indicating its role in temporal transcriptome regulation.

Conclusions:

• The findings provide a mechanistic understanding of how CREB integrates regional and temporal cues to control brain transcription patterns.
• CREB was identified as a key mediator of the biological responses to electroconvulsive seizure.
• This study offers global mechanistic insights into CREB's involvement in psychiatric and cognitive functions.