Review: Winner of the 2003 Frank Beach Award in Behavioral NeuroendocrinologySensitivity to stress: Dysregulation of CRF pathways and disease development☆
Introduction
Stress-related mood disorders, including anxiety and depression, have become pervasive in our world today. Depressive disorders currently affect over 10% of the American population, and are the most common form of mental illness in America. Examination of the genetic predisposition for the development of mood disorders has proven extremely difficult. The hurdle in such research stems both from the complex nature of the underlying neurobiology as well as a glaring lack of good animal models in which the neurocircuits and genes involved in mood disorder development can be more clearly elucidated. While a rodent is certainly not a human, a great portion of what we do understand today regarding antidepressant/anxiolytic drug mechanisms, and the genes involved have come from studies conducted in these animals. From these studies, new therapeutic targets have been developed. However, even the most effective antidepressant drugs only provide a beneficial improvement 18% above that found with placebo. While we have obtained a great deal of information from decades of research, much is still not understood. This review will discuss recent work in the area of stress sensitivity and corticotropin-releasing factor (CRF) pathway dysregulation related to development of mood disorders, and will provide evidence supporting a new mouse model of elevated stress sensitivity.
Strong evidence links stress, and the sensitivity of the individual to stressful encounters, to the development of mood disorders. The stress response is essential for adaptation, maintenance of homeostasis, and survival. However, chronic stress can accelerate disease processes, cause neural degeneration, and lead to depression or other affective disorders (Nestler et al., 2002). Understanding the neuroendocrinology of stress and its impacts on emotionality can elucidate the underlying neurocircuitry involved in the susceptibility to disease (see review in (Carrasco and Van de Kar, 2003)). Dysregulation of the hypothalamic–pituitary–adrenal (HPA) stress axis and CRF signaling have been associated with development of mood disorders (Arborelius et al., 1999, Holsboer, 1999, Nemeroff, 1988, Nemeroff, 1992, Reul and Holsboer, 2002). It is clear that the delicate balance of the CRF system is critical for maintenance of mental and physical soundness.
Section snippets
CRF family members
Corticotropin-releasing factor (CRF), first characterized in 1981 (Vale et al., 1981), belongs to a growing family of ligands and receptors. This family of neuropeptides and receptors was initially shown to be an important regulator of the endocrine stress response, and is now known to be involved in diverse roles necessary for homeostasis maintenance and important in rapid mobilization of resources and behaviors for responses to stress. These ligands include CRF, urocortinI (UcnI), UcnII, and
Overview of CRF regulation of the HPA stress axis
Stress can be operationally defined as that which produces a homeostatic perturbation resulting in a physiological response (endocrine and/or autonomic). During a stress response, CRF activates the hypothalamic–pituitary–adrenal (HPA) axis via CRFR1 on anterior pituitary corticotropes to stimulate the release of adrenal corticotropic hormone (ACTH). ACTH then enters the blood stream and acts at MC2 receptors in the adrenal gland cortex to stimulate the synthesis and releases of glucocorticoids.
CRF dysregulation in anxiety development
CRF regulation has been proposed to have an involvement in the development of anxiety and mood disorders. Studies have found that dysregulation of CRF or its family members in stress responsivity can lead to the onset of anxiety-like behaviors and depression. Evidence from research and clinical investigations demonstrates that such disorders encompass a profound neurocircuitry failure. The central nucleus of the amygdala, locus coeruleus, ventral tegmental area and the dorsal raphe nucleus are
CRF dysregulation in depression development
Mental health disorders can have an enormous impact on quality of life issues. Depressive disorders currently affect nearly 19 million American adults and are the most common form of mental illness in America (Nestler et al., 2002). Evidence from research and clinical investigations demonstrates that the development of depression encompasses a profound neurocircuitry failure. The brain regions involved in this dysregulation may include the hypothalamus, hippocampus, amygdala, and striatum (
Conclusions
A vast body of evidence has demonstrated the importance of the CRF family in regulation of organismal homeostasis. This review has focused on the involvement of CRF ligands and receptors in development of stress-related mood disorders, with supporting evidence from behavioral, physiological, molecular and biochemical studies. By mapping the changes in expression patterns and levels in these mice, we can compile greater details regarding the brain regions involved in stress regulation in
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Based on the Frank A. Beach Award lecture presented at the 33rd Annual Meeting of the Society for Neuroscience.