Stress and glucocorticoid receptor-dependent mechanisms in long-term memory: from adaptive responses to psychopathologies

A proper response against stressors is critical for survival. In mammals, the stress response is primarily mediated by secretion of glucocorticoids via the hypothalamic-pituitary-adrenocortical (HPA) axis and release of catecholamines through adrenergic neurotransmission. Activation of these pathways results in a quick physical response to the stress and, in adaptive conditions, mediates long-term changes in the brain that lead to the formation of long-term memories of the experience. These long-term memories are an essential adaptive mechanism that allows an animal to effectively face similar demands again. Indeed, a moderate stress level has a strong positive effect on memory and cognition, as a single arousing or moderately stressful event can be remembered for up to a lifetime. Conversely, exposure to extreme, traumatic, or chronic stress can have the opposite effect and cause memory loss, cognitive impairments, and stress-related psychopathologies such as anxiety disorders, depression and post-traumatic stress disorder (PTSD). While more effort has been devoted to the understanding of the negative effects of chronic stress, much less has been done thus far on the identification of the mechanisms engaged in the brain when stress promotes long-term memory formation. Understanding these mechanisms will provide critical information for use in ameliorating memory processes in both normal and pathological conditions. Here, we will review the role of glucocorticoids and glucocorticoid receptors (GRs) in memory formation and modulation. Furthermore, we will discuss recent findings on the molecular cascade of events underlying the effect of GR activation in adaptive levels of stress that leads to strong, long-lasting memories. Our recent data indicate that the positive effects of GR activation on memory consolidation critically engage the brain-derived neurotrophic factor (BDNF) pathway. We propose and will discuss the hypothesis that stress promotes the formation of strong long-term memories because the activation of hippocampal GRs after learning is coupled to the recruitment of the growth and pro-survival BDNF/cAMP response element-binding protein (CREB) pathway, which is well-know to be a general mechanism required for long-term memory formation. We will then speculate about how these results may explain the negative effects of traumatic or chronic stress on memory and cognitive functions.