Glucocorticoids have long been recognized for their role in regulating the availability of energetic resources, particularly during stress. Furthermore, bidirectional connections between glucocorticoids and the physiology and function of mitochondria have been discovered over the years. However, the precise mechanisms by which glucocorticoids act on mitochondria have only recently been explored. Glucocorticoids appear to regulate mitochondrial transcription via activation of glucocorticoid receptors (GRs) with elevated circulating glucocorticoid levels following stress. While several mechanistic questions remain, GR and other nuclear transcription factors appear have the capacity to substantially alter mitochondrial transcript abundance. The regulation of mitochondrial transcripts by stress and glucocorticoids will likely prove functionally relevant in many stress-sensitive tissues including the brain.

Transposable elements make up a much larger portion of the genome than protein-coding genes, yet we know relatively little about their function in the human genome. However, we are beginning to more fully understand their role in brain development, neuroinflammation, and adaptation to environmental insults such as stress. For instance, glucocorticoid receptor activation regulates transposable elements in the brain following acute stress. Early life is a period of substantial brain development during which transposable elements play a role. Environmental exposures and experiences during early life that promote abnormal regulation of transposable elements may lead to a cascade of events that ultimately increase susceptibility to disorders later in life. Recent attention to transposable elements in psychiatric illness has begun to clarify associations indicative of dysregulation of different classes of transposable elements in stress-related and neurodevelopmental illness. Though individual susceptibility or resiliency to psychiatric illness has not been explained by traditional genetic studies, the wide inter-individual variability in transposable element composition in the human genome make TEs attractive candidates to elucidate this differential susceptibility. In this review, we discuss evidence that regulation of transposable elements in the brain are stage-specific, sensitive to environmental factors, and may be impacted by early life perturbations. We further present evidence of associations with stress-related and neurodevelopmental psychiatric illness from a developmental perspective.

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