Early Life Stress- and Drug-Induced Histone Modifications Within the Ventral Tegmental Area

Abstract

Psychiatric illnesses are a major public health concern due to their prevalence and heterogeneity of symptom presentation resulting from a lack of efficacious treatments. Although dysregulated dopamine (DA) signaling has been observed in a myriad of psychiatric conditions, different pathophysiological mechanisms have been implicated which impede the development of adequate treatments that work across all patient populations. The ventral tegmental area (VTA), a major source of DA neurons in the brain reward pathway, has been shown to have altered activity that contributes to reward dysregulation in mental illnesses and drug addiction. It has now become better appreciated that epigenetic mechanisms contribute to VTA DA dysfunction, such as through histone modifications, which dynamically regulate transcription rates of critical genes important in synaptic plasticity underlying learning and memory. Here, we provide a focused review on differential histone modifications within the VTA observed in both humans and animal models, as well as their relevance to disease-based phenotypes, specifically focusing on epigenetic dysregulation of histones in the VTA associated with early life stress (ELS) and drugs of abuse. Locus-and cell-type-specific targeting of individual histone modifications at specific genes within the VTA presents novel therapeutic targets which can result in greater efficacy and better long-term health outcomes in susceptible individuals that are at increased risk for substance use and psychiatric disorders.

Impact of Early Life Stress on Reward Circuit Function and Regulation

“…Direct comparison of rodent and human reward circuitry development in the neonatal periods is lacking, although it is suggested that rodent brain development is shifted relative to human development such that the first week of rodent life is approximately aligns with the last trimester of human gestation ( 16 , 88 ). While a majority of rodent models of ELS begin ELS in the first few days after birth ( 86 , 89 ), some shift stress to start around P9-10 ( 82 , 90 , 91 ). Each of these models of ELS have been documented to alter pups' plasma corticosterone levels acutely ( 85 , 92 , 93 ), although the long-term impact on basal and stress-induced corticosterone appear to depend on type and timing of stress (reviewed in ( 86 ).…”

“…Post-translational modifications to histone protein tails – including acetylation, methylation, and other modifications – can increase or decrease compaction, and repress or allow gene expression, respectively. 24-h maternal deprivation at P9 ELS has been shown to alter histone acetylation in VTA, which is directly linked to altered GABAergic function in VTA and increased dopaminergic excitability, and which is restored by histone deacetylase inhibitor treatment ( 90 , 91 , 141 , 177 ). ELS (combined maternal separation and limited nesting material from P10-17) also broadly altered levels of post-translational histone modifications in NAc across postnatal development in a sex-specific manner ( 178 ).…”

The Histone Modifications of Neuronal Plasticity

“…Increasing evidence has confirmed that at least 12 types of specific modifications occur to the N-terminal amino acid residues of histones, which affect the nucleosomes bind to DNA and the three-dimensional structure of chromosomes, and regulate gene expression. The patterns of histone modification are the following way: acetylation (lysine), methylation (lysine and arginine), phosphorylation (serine and threonine), sumoylation (lysine), ubiquitylation (lysine), ADP ribosylation, butyrylation, citrullination, crotonylation, formylation, proline isomerization, propionylation, serotonylation, and dopaminylation (glutamine) [ 4 , 5 ]. The nomenclature of histone modification is as follows, such as H3K9me3, H3 refers to the core histone protein, K refers to the amino acid, the number 9 indicates the position of lysine residue from the N-terminal end of the amino acid tail of histone protein, and me3 refers to the type of modification on the lysine residue [ 6 ].…”

A cross-species assay demonstrates that reward responsiveness is enduringly impacted by adverse, unpredictable early-life experiences

“…Sensitivity to reward is modulated by prior experiences, particularly during early developmental periods [1][2][3][4][5][6][7][8][9][10][11]. In the United States, over 30% of children experience some type of early-life adversity (ELA) related to poverty, trauma, and chaotic environments [12] and these events have been associated with poor cognitive and emotional health [13][14][15][16].…”