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The importance of understanding the biological mechanisms of trauma

Adverse life events, especially early in life, have consistently been shown to strongly increase the risk for psychiatric disorders, including mood and anxiety disorders but also psychoses. Severe forms of early adverse life events such as childhood abuse or neglect have been associated with the highest rates of increased risk. Nonetheless, other forms of early adverse experiences, such as parental loss, bullying, or low socioeconomic status in childhood, were also shown to increase risk for a number of psychiatric disorders (1, 2). Finally, the possible effects of adversity even extend to the prenatal period, as stress or mood and anxiety disorders of the mother are also risk factors for psychiatric disorders in the offspring (3). Next to genetic predisposition, and for many disorders even to a greater extent, adverse life events are thus the strongest predisposing factors for psychiatric diseases. Understanding how such environmental factors moderate risk is therefore an important step in better understanding psychiatric pathology. A series of studies have shown that exposure to adverse life events, especially when occurring in childhood, can lead to lasting biological changes that impact the function of several key systems. Lasting structural changes have been reported in a number of brain regions that on the one hand include the cortical regions relevant for processing the trauma information (e.g., visual cortex with witnessing domestic violence) but also key areas in emotion processing, such as the anterior cingulate cortex as well the hippocampus (4). Such structural changes may be adaptive in the face of expected future adversity and seem to extend to all individuals exposed to adversity, regardless of psychopathology. Differences in additional compensatory mechanisms of these changes may thus determine risk or resilience to psychiatric illness. Another set of consistent findings are alterations of the endocrine stress axis following trauma exposure as well as lasting changes in immune and metabolic systems (5, 6). Given these consistent biological alterations following trauma exposure, a number of researchers propose that exposure to early adversity could be used to identify biologically distinct, possibly transdiagnostically relevant subtypes of psychiatric disorders. Indeed, exposure to childhood trauma has been associated with worse treatment outcome and long-term prognosis and could thus guide treatment choices. One of the main questions is what are the mechanisms that lead to these adversity-related biological changes. One molecular mechanism that has come into focus for mediating such long-term environmental effects is epigenetics (7). Epigenetics describes mechanisms of how genomic information is regulated without changing the DNA sequence. These mechanisms include the post-translational modification of histone proteins as well as chemical modifications of single nucleotides (most commonly in the form of DNA methylation or hydroxymethylation at cytosine residues), which alter the chromatin structure, and thus the accessibility of the DNA to transcriptional regulators. In the broader sense, these mechanisms also include the regulation of transcription and translation by non-coding RNAs. A number of studies have now shown that exposure to early adversity can lead to such lasting epigenetic changes. One of the mediators of these changes is the glucocorticoids receptor which is activated by stress and functions as a transcription factor but can also induce lasting epigenetic changes at its binding sites (7). Adversity-related epigenetic changes are observed in brain tissue, but also in peripheral tissue, further supporting the organism-wide impact of early adversity. Via these mechanisms, the environment can thus have a lasting impact on gene transcription and thereby cell function and could underlie the biological changes observed following trauma exposure. An important question that remains unresolved to date is the mapping of differential sensitive periods across brain circuits but also different organ systems to adversity exposure and how this interferes with normal development and leads to differential risk profiles for psychiatric but also medical disorders. The risk conveyed by early adversity is likely moderated by genetic factors as well as additional environmental exposure as similar levels of trauma exposure do not always lead to the same level of psychopathology. A number genetic variants or polygenic risk scores that interact with early adversity have been described, some with relatively consistent findings, such as for example for polymorphisms in the promoter of the serotonin transporter gene, the CRHR1 and the FKBP5 gene (7). All of these variants have not only been show to interact with adversity to predict psychopathology, but also intermediate phenotypes, such as structural or functional brain changes or endocrine responses. One possible molecular mechanism for mediating such gene 9 environment interactions is again epigenetics with genetic variants moderating the long-term epigenetic consequences of environmental exposure. This can be either directly by genetic variants located in environmentally sensitive transcriptional regulator regions of target genes or indirectly by influencing the regulation of response systems, such as the stress hormone system, which then in turn can have an epigenetic impact on downstream targets. The field of epigenetics thus provides a possible molecular framework of how genetic and environmental factors interact and shape the risk for psychiatric disorders. Understanding the impact of adversity on a molecular, cellular, and systemic level could have import consequences for the prevention, diagnostics, and treatment of psychiatric disorders. While animal studies can deliver important mechanistic insight for trauma research, there are a number of aspects that cannot be modeled satisfactorily. These include aspects of specific types of abuse such as sexual and emotional abuse but also a detailed mapping of sensitive periods for specific brain circuits and regions with distinct developmental trajectories in humans. Studies in human are therefore of great importance