The Role of MicroRNAs in Stress and Psychiatric Disorders

Post by Laura Maile

Why study stress?

We all experience stress at some point in our lives. Stress induces a normal physiological response in the body and brain important for adaptation and continued survival. Ongoing or major stressful events, however, are a significant risk factor for the development of psychiatric disorders such as major depressive disorder, generalized anxiety disorder, and posttraumatic stress disorder. There is also evidence that individual responses to stress can be influenced by our environment, previous life experience, and individual genetic differences. The mechanisms involved in individual differences in response to stress are not fully understood, though recent findings indicate that epigenetics may play a role.  

What is epigenetics?

Epigenetics is the process of altering the expression of genes without changing the genetic code itself. In order for genes to be expressed, the transcriptional machinery must be able to access the DNA, which is folded around histones and other proteins, making up chromatin. The remodeling of chromatin allows access to the DNA to allow transcription (i.e., gene expression) to occur. Epigenetic changes, such as histone modifications, DNA methylation, and posttranscriptional regulation by microRNAs, are a part of this dynamic process that control which genes are expressed. If you think of your genome like a library, the DNA sequence is the collection of books, while epigenetics is the unique system that decides which books are open for reading (gene expression) and which are kept closed (gene suppression).

How do microRNAs work?

MicroRNA is a type of non-coding RNA that can affect the expression of DNA by binding with an mRNA with a matching sequence, preventing that mRNA from being translated into protein and thus reducing protein expression. In our library analogy, microRNA is like the librarian who puts certain books on display and hides others in the back, controlling which books (genes) get read. It is estimated that over 60% of human protein-encoding genes are targeted by microRNA, with each microRNA targeting potentially hundreds of mRNA sequences. When microRNA targets and silences a target mRNA, it does so only for a small proportion, giving it the ability to fine-tune gene expression and regulate the body’s responses to environmental changes, including those that induce stress. This means microRNA plays a dynamic role in epigenetics as we encounter and respond to the environment and events around us.   

How does microRNA impact stress response?

Changes in expression levels of microRNAs have been reported both in animal models of chronic stress and in post-mortem brains of patients with psychiatric disorders. These changes have been identified in brain areas known to be involved in the response to stress. Animal models of chronic stress are often used as a model of depression, mimicking both behavioral changes and cellular and molecular changes associated with major depressive disorder. Rodent models of chronic stress can lead to decreased expression of microRNAs like miR-9, while ketamine, a drug used in the treatment of major depression, can both alleviate the depressive behavior and return the altered microRNA levels back to normal. Additionally, clinical studies have shown either increases or decreases in the levels of different microRNAs in the CSF and blood serum of patients with major depressive disorder. Other studies that work to control the activity of specific microRNAs indicate that silencing these microRNAs in stress-related brain structures can rescue depressive-like behaviors in rodents.  

There are also specific types of microRNAs involved in stress. The miR-34 family, a group of microRNAs, has been shown to be related to chronic stress and the stress response in rodents. The involvement of miR-34 was also linked to the trans-generational effects of stress, where exposure to stress in a female rat could impact the anxiety-like behavior in her offspring. Further, miR-124 — another microRNA whose expression has been linked to the effects of several models of chronic stress and early life stress — can impact both the expression of receptors in the brain related to the stress response and depressive-like behaviors that result from stress.  

Controlling the expression of microRNAs can impact not only behavior but cellular and structural changes in the brain induced by rodent models of depression. MicroRNAs have been shown to play a role in influencing structural changes associated with psychiatric disorders, like changes in gray matter density, the number of dendritic spines, and synaptic changes between neurons.  

MicroRNAs not only affect protein expression and function within cells but they can also be incorporated into exosomes that migrate into the extracellular space. Exosomes are extracellular vesicles that play a role in communication between cells and are contained in almost all bodily fluids, making them a useful diagnostic target. Evidence shows a link between microRNA expression in exosomes and chronic stress and major depressive disorder.  Exosomes also have potential as a therapeutic tool for drug delivery since they can cross the blood-brain barrier. 

What does the future look like?

Research has revealed a strong link between microRNAs and their epigenetic modifications and psychiatric disorders. Despite this link, evidence is often contradictory, indicating the need for continued research in this complex field. MicroRNAs have the potential to serve as biomarkers in the diagnosis of disease and help in the measurement of drug efficacy in the treatment of those diseases. Tools have recently been developed to leverage the detection of microRNAs in tissues to aid in the diagnosis of cancer. There is potential for this type of tool to be used in the diagnosis and treatment of psychiatric diseases as well, though none have been developed yet. Continued research is necessary to advance the use of microRNAs as effective diagnostic and therapeutic tools.  

References +

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