GR-owing Up Stressed: Implications for Anxiety and Addiction

Abstract

f e w n s a s d s a d c d t s E arly life adversity is known to have profound effects on the development and function of neural circuits that control emotional behaviors (1). The result in humans is a greatly nhanced predisposition to develop depression and anxiety disorers or addiction throughout the individual’s lifetime. Rodent modls of chronic stress have begun to identify the critical periods of arly life adversity along with the brain circuits and molecules that ontrol pathologic behaviors relevant to these psychiatric disorers. In this issue, Wei et al. (2) provides new evidence for a critical indow before weaning, whereby increased levels of glucocortioid receptors (GRs) in the forebrain lead to lifelong increases in xploratory-based anxiety behavior and cocaine-induced locomoor sensitization. Associated with these behavioral changes are vast ifelong transcriptional changes in the dentate gyrus of the hipocampus (hipp) and, to a lesser extent, the nucleus accumbens NAc), brain structures critically involved in stress disorders and ddiction. These data highlight the potential importance of develpmental experience in controlling normal brain function and beavior in adulthood. Glucocorticoids are powerful regulators of brain plasticity mechnisms and can produce profound and irreversible changes in brain ircuitry when an individual is exposed to extremely high levels of tress or even more moderate stress during critical phases of develpment. In response to stress, glucocorticoids are known to act ithin multiple brain structures through the GR, which upon actiation, can translocate to the nucleus and act as a transcription actor to induce gene expression. During prolonged stress, GRependent mechanisms switch from protective to maladaptive hrough a switch in transcriptional targets that can promote denritic atrophy and hypertrophy and even neuronal loss (3). It is this witch that is thought to underlie the development of psychiatric isorders such as anxiety, depression, and addiction. Thus, much ecent effort has focused on defining the type, duration, quality, nd developmental timing of stressful experience in promoting tressand addiction-related behaviors. This is not to say that stress s always bad. It is quite clear that even in the face of extreme stress, ost humans and animals are resilient and can maintain normal sychologic and physical function. However, when organisms are xposed to chronic elevations in glucocorticoids early on, they do ot develop normal coping resources and this leads to a greatly ncreased risk for developing psychiatric disorders throughout dulthood. In the article by Wei et al. (2), the authors provide mechanistic vidence that a critical window of GR overexpression during early ife is sufficient to increase anxiety and addiction liability later in life. he authors used a transgenic mouse line with a tetracycline-reguated promoter that can be turned on or off to tightly control GR verexpression throughout the animal’s lifetime. By doing so, they ere able to define the developmental timing of such GR-depen-