Unveiling Transcriptional and Epigenetic Mechanisms Within Engram Cells: Insights into Memory Formation and Stability.

Memory traces for behavioral experiences, such as fear conditioning or taste aversion, are believed to be stored through biophysical and molecular changes in distributed neuronal ensembles across various brain regions. These ensembles are known as engrams, and the cells that constitute them are referred to as engram cells. Recent advancements in techniques for labeling and manipulating neural activity have facilitated the study of engram cells throughout different memory phases, including acquisition, allocation, long-term storage, retrieval, and erasure. In this chapter, we will explore the application of next-generation sequencing methods to engram research, shedding new light on the contribution of transcriptional and epigenetic mechanisms to engram formation and stability.

CBP Is Required for Establishing Adaptive Gene Programs in the Adult Mouse Brain.

Environmental factors and life experiences impinge on brain circuits triggering adaptive changes. Epigenetic regulators contribute to this neuroadaptation by enhancing or suppressing specific gene programs. The paralogous transcriptional coactivators and lysine acetyltransferases CREB binding protein (CBP) and p300 are involved in brain plasticity and stimulus-dependent transcription, but their specific roles in neuroadaptation are not fully understood. Here we investigated the impact of eliminating either CBP or p300 in excitatory neurons of the adult forebrain of mice from both sexes using inducible and cell type-restricted knock-out strains. The elimination of CBP, but not p300, reduced the expression and chromatin acetylation of plasticity genes, dampened activity-driven transcription, and caused memory deficits. The defects became more prominent in elderly mice and in paradigms that involved enduring changes in transcription, such as kindling and environmental enrichment, in which CBP loss interfered with the establishment of activity-induced transcriptional and epigenetic changes in response to stimulus or experience. These findings further strengthen the link between CBP deficiency in excitatory neurons and etiopathology in the nervous system.SIGNIFICANCE STATEMENT How environmental conditions and life experiences impinge on mature brain circuits to elicit adaptive responses that favor the survival of the organism remains an outstanding question in neurosciences. Epigenetic regulators are thought to contribute to neuroadaptation by initiating or enhancing adaptive gene programs. In this article, we examined the role of CREB binding protein (CBP) and p300, two paralogous transcriptional coactivators and histone acetyltransferases involved in cognitive processes and intellectual disability, in neuroadaptation in adult hippocampal circuits. Our experiments demonstrate that CBP, but not its paralog p300, plays a highly specific role in the epigenetic regulation of neuronal plasticity gene programs in response to stimulus and provide unprecedented insight into the molecular mechanisms underlying neuroadaptation.

Transcriptome and epigenome analysis of engram cells: Next-generation sequencing technologies in memory research.

Transcription and epigenetic changes are integral components of the neuronal response to stimulation and have been postulated to be drivers or substrates for enduring changes in animal behavior, including learning and memory. Memories are thought to be deposited in neuronal assemblies called engrams, i.e., groups of cells that undergo persistent physical or chemical changes during learning and are selectively reactivated to retrieve the memory. Despite the research progress made in recent years, the identity of specific epigenetic changes, if any, that occur in these cells and subsequently contribute to the persistence of memory traces remains unknown. The analysis of these changes is challenging due to the difficulty of exploring molecular alterations that only occur in a relatively small percentage of cells embedded in a complex tissue. In this review, we discuss the recent advances in this field and the promise of next-generation sequencing (NGS) and epigenome editing methods for overcoming these challenges and address long-standing questions concerning the role of epigenetic mechanisms in memory encoding, maintenance and expression.