From Circuits to Chromatin: The Emerging Role of Epigenetics in Mental Health

Abstract

A central goal of neuroscience research is to understand how experiences modify brain circuits to guide future adaptive behavior. In response to environmental stimuli, neural circuit activity engages gene regulatory mechanisms within each cell. This activity-dependent gene expression is governed, in part, by epigenetic processes that can produce persistent changes in both neural circuits and the epigenome itself. The complex interplay between circuit activity and neuronal gene regulation is vital to learning and memory, and, when disrupted, is linked to debilitating psychiatric conditions, such as substance use disorder. To develop clinical treatments, it is paramount to advance our understanding of how neural circuits and the epigenome cooperate to produce behavioral adaptation. Here, we discuss how new genetic tools, used to manipulate neural circuits and chromatin, have enabled the discovery of epigenetic processes that bring about long-lasting changes in behavior relevant to mental health and disease.

Keywords: activity-dependent gene regulation; epigenome; lncRNA; memory engram; substance use disorder.

Figure 1.

Epigenetic mechanisms regulate cell type-specific gene expression involved in memory storage. Histone modifications, such as acetylation and methylation, regulate gene expression in response to experience (e.g., Mews et al., 2017). Newly developed sequencing technology enables the study of gene expression at the single-cell level and allows insight into the enormous heterogeneity of gene activity profiles within defined neuronal populations. For example, snRNA-seq performed on hippocampal brain tissue enables cluster analysis that groups individual single-cell transcriptomes by subregion and cell type. This approach can identify sets of marker genes whose expression distinguishes any such cluster. Shown is a projection of individual cells following global dimensionality reduction that congregate into clusters representing the hippocampal subregions CA1, CA2, and CA3, the subiculum (SUB1-SUB3), the dentate gyrus (DG), and GABAergic interneurons (GABA). Epigenetic mechanisms also act at the synapse, where microRNAs and lncRNAs regulate the localized translation and stability of mRNA transcripts that encode proteins central to synaptic plasticity (Park et al., 2017; Madugalle et al., 2020).

Figure 2.

Single-nucleus RNA-seq reveals cell-specific transcriptional response to cocaine. a, Global dimensionality reduction clustering (UMAP) of 15,631 individual NAc nuclei identifies 16 transcriptionally distinct cell classes of the rat NAc, including MSNs expressing Drd1 and Drd2 mRNA. b, Circos plot of differentially expressed genes 1 h after cocaine administration, analyzed within each cell type. Cocaine differentially expressed genes are most abundant in Drd1-MSNs, followed by astrocytes. c, UMAP plot from a in gray with the representative expression of Fosb, a cocaine-responsive immediate-early gene. Fosb mRNA expression is increased in a small fraction of “activated” Drd1-MSNs. Data from Savell et al. (2020).

Figure 3.

Alcohol metabolism and gut microbiome affect epigenetic regulation in the brain. Alcohol is metabolized in the liver to acetate, which is released into circulation and enters the brain. In neurons, acetate is used by ACSS2 to generate acetyl-CoA, boosting histone acetylation, and gene expression involved in memory (Mews et al., 2019). SCFA metabolites are produced by bacterial fermentation of fiber. The three most abundant of these (acetate, butyrate, and propionate) have been shown to regulate the catalytic activity of HAT and HDAC enzymes that influence gene expression and behavior (Kiraly et al., 2016). Created with www.BioRender.com.