Table of Contents
Introduction to Psychosis and Histone Modifications
Psychosis is characterized by a disconnection from reality, often manifesting through delusions and hallucinations, which can significantly impair an individual’s insight (1). The terms delusions refer to strongly held beliefs that contradict reality, while hallucinations involve perceiving things that are not present (2). Understanding the neural and biological underpinnings of psychosis is critical for developing effective interventions. One area of increasing interest is the role of epigenetic mechanisms, particularly histone modifications, in influencing neurodevelopmental processes related to psychotic disorders.
Histone modifications are post-translational alterations on histone proteins that regulate gene expression without changing the underlying DNA sequence (3). These modifications, often referred to as histone marks, can affect chromatin structure and function, impacting transcriptional activity and cellular plasticity (4). The dynamics of histone marks are influenced by various internal and external cues, making them vital for understanding the neurodevelopmental trajectories that may lead to psychosis (5).
Research has shown that specific histone marks are associated with either activation or repression of gene transcription, thereby influencing neurodevelopment (6). For instance, H3K4me3 is typically found at active promoter regions, while H3K27me3 is associated with transcriptional silencing (7). The interplay between these marks is crucial in determining the expression levels of genes involved in neurodevelopment and, ultimately, the susceptibility to psychotic disorders.
Key Histone Marks and Their Role in Gene Expression
Histone marks play a central role in modulating gene expression through various mechanisms. The most studied histone marks include:
| Histone Mark | Primary Location | Function |
|---|---|---|
| H3K4me1 | Enhancers | Fine-tunes enhancer activity and recruits transcription factors (8) |
| H3K4me3 | Promoters | Promotes gene transcription and is associated with active chromatin (9) |
| H3K9me3 | Heterochromatin | Silences gene expression and stabilizes chromatin structure (10) |
| H3K27me3 | Promoters | Represses gene expression through Polycomb repressive complexes (11) |
| H3K36me3 | Gene bodies | Prevents run-away transcription by interacting with histone deacetylases (12) |
| H3K27ac | Enhancers and promoters | Activates transcription by increasing chromatin accessibility (13) |
| H3K9ac | Promoters | Facilitates transcription initiation and elongation (14) |
The regulatory effects of these histone marks can be context-dependent, influenced by the specific cellular environment and the presence of other transcriptional regulators (15). This intricate regulation underscores the importance of histone modifications in the context of neurodevelopment and psychiatric disorders, including psychosis.
Neurodevelopmental Impacts of PM2.5 Exposure on the Brain
Emerging evidence highlights the neurotoxic effects of environmental pollutants, particularly particulate matter (PM2.5), on brain development and function (16). PM2.5 is a complex mixture of tiny particles suspended in the air, which can penetrate deep into the lungs and enter systemic circulation, potentially affecting neurological health (17). Studies have indicated that exposure to PM2.5 during critical periods of neurodevelopment can disrupt normal brain maturation, leading to long-term cognitive and behavioral deficits (18).
Recent research utilizing data from the Adolescent Brain Cognitive Development Study (ABCD Study®) has demonstrated that specific sources of PM2.5, such as biomass burning, are associated with alterations in cortical microstructure development in adolescents (19). This study assessed the impact of PM exposure on neurite development, revealing significant correlations between environmental pollutants and neurodevelopmental outcomes. These findings highlight the pressing need to consider environmental factors, such as air pollution, in the context of neurodevelopmental disorders, including psychosis.
Evolutionary Conservation of Hippocampal Structure Across Species
The hippocampus is a critical brain region involved in memory formation and spatial navigation, and its structure is highly conserved across species, including humans, macaques, and rodents (20). Comparative studies of hippocampal morphology and function provide valuable insights into the evolutionary adaptations that underlie cognitive processes. Recent findings indicate that while the overall organization of the hippocampus is similar, there are notable species-specific differences in cellular composition and function.
Research utilizing single-nucleus RNA sequencing (snRNA-seq) has identified distinct cell populations within the hippocampus, revealing evolutionary conservation and divergence in hippocampal cellular architecture (21). For example, studies have shown that the expression of key markers, such as SLC1A3 and GFAP, are conserved across species, highlighting their role in maintaining hippocampal function (22). However, variations in gene expression patterns and cellular interactions have been observed, suggesting that while the hippocampal structure is conserved, its functional adaptations may differ among species (23).
These findings underscore the importance of cross-species comparisons in understanding the neural mechanisms underlying cognitive function and the potential implications for neurodevelopmental disorders, including psychosis.
Age-Related Changes in Neurogenesis and Cellular Dynamics
Aging is associated with significant changes in neurogenesis, the process by which new neurons are generated from neural stem cells (NSCs). In the hippocampus, neurogenesis is believed to play a crucial role in learning and memory (24). Research has shown that neurogenic decline occurs with age, leading to reduced hippocampal plasticity and impairments in cognitive function (25).
Recent studies have identified distinct stages of neurogenesis, from quiescent radial glia-like cells (RGLs) to intermediate progenitor cells (IPCs) and ultimately to mature neurons (26). Analysis of transcriptomic data has revealed age-related shifts in the abundance and function of these cell populations, with RGLs showing a decline in their proliferation and differentiation capacity as aging progresses (27).
Furthermore, age-related changes in cellular interactions and signaling pathways have been implicated in the decline of neurogenesis. For instance, elevated proinflammatory signaling in microglia and oligodendrocytes has been observed during aging, contributing to a neuroinflammatory environment that may hinder neurogenic processes (28). The identification of these age-related alterations provides valuable insights into the mechanisms underlying cognitive decline and the potential for therapeutic interventions to promote neurogenesis in aging populations (29).
Implications for Neurodegenerative Disease Research and Treatment
The understanding of histone marks, environmental impacts on neurodevelopment, and age-related changes in neurogenesis has significant implications for neurodegenerative disease research and treatment. The interplay between genetic, epigenetic, and environmental factors highlights the complexity of neurodevelopmental and neurodegenerative disorders, including psychosis and Alzheimer’s disease.
Research into the role of histone modifications in regulating gene expression offers potential therapeutic avenues for targeting epigenetic mechanisms to enhance neurogenesis and cognitive function (30). Moreover, addressing environmental factors, such as PM exposure, may provide strategies for mitigating neurodevelopmental risks associated with psychiatric disorders (31).
As the field of neuroscience continues to evolve, integrating findings from various domains—including genetics, epigenetics, neurodevelopment, and environmental influences—will be essential for developing comprehensive treatment approaches for neurodegenerative diseases and improving patient outcomes.
Frequently Asked Questions (FAQ)
What is psychosis?
Psychosis is a mental health condition characterized by a disconnection from reality, often involving hallucinations and delusions.
How do histone marks affect gene expression?
Histone marks are modifications on histone proteins that regulate gene expression by altering chromatin structure and recruiting transcription factors.
What is PM2.5 and its impact on neurodevelopment?
PM2.5 refers to fine particulate matter that can penetrate the lungs and affect overall health, including neurodevelopment, leading to cognitive and behavioral issues.
Why is the study of the hippocampus important?
The hippocampus is crucial for memory and learning, and understanding its structure and function can provide insights into cognitive processes and disorders.
How does aging affect neurogenesis?
Aging leads to a decline in neurogenesis, reducing the generation of new neurons and affecting cognitive function and plasticity in the hippocampus.
References
- Introduction to Psychosis and Histone Modifications. (2023). Retrieved from https://pubmed.ncbi.nlm.nih.gov/11879018/
- Amygdala Function, Blood Flow, and Functional Connectivity in Nonclinical Schizotypy. (2023). Retrieved from https://pubmed.ncbi.nlm.nih.gov/11879494/
- Sex Differences in the Relationship Between Cortical Thickness and Sensory Motor Symptoms in Adults on the Autism Spectrum. (2023). Retrieved from https://pubmed.ncbi.nlm.nih.gov/11879536/
- Tau and MAP6 establish labile and stable domains on microtubules. (2025). Retrieved from https://doi.org/10.1016/j.isci.2025.111785
- Air pollution from biomass burning disrupts early adolescent cortical microarchitecture development. (2024). Retrieved from https://doi.org/10.1016/j.envint.2024.108769
- The Relationship Among Range Adaptation, Social Anhedonia, and Social Functioning: A Combined Magnetic Resonance Spectroscopy and Resting-State fMRI Study. (2023). Retrieved from https://pubmed.ncbi.nlm.nih.gov/11879587/
- Cross-Species Insights from Single-Nucleus Sequencing Highlight Aging-Related Hippocampal Features in Tree Shrew. (2023). Retrieved from https://pubmed.ncbi.nlm.nih.gov/11879083/
- Neuroscience of Schizotypy: A Translational Perspective From Phenotype to Genetics and Brain Networks. (2023). Retrieved from https://pubmed.ncbi.nlm.nih.gov/11879548/
- The complexity of human subjective experience during binocular rivalry. (2023). Retrieved from https://pubmed.ncbi.nlm.nih.gov/11879079/
- The Relationship Among Range Adaptation, Social Anhedonia, and Social Functioning: A Combined Magnetic Resonance Spectroscopy and Resting-State fMRI Study. (2023). Retrieved from https://pubmed.ncbi.nlm.nih.gov/11879548/
