ReviewThe central corticotropin releasing factor system during development and adulthood
Introduction
Corticotropin releasing factor (CRH) is mediator of endocrine, autonomic, and immune responses to stress (Vale et al., 1981, Owens and Nemeroff, 1991, De Souza, 1995, Holsboer and Barden, 1996, Brunson et al., 2001a). CRH has also been implicated in the modulation of a wide range of behaviors including anxiety, as well as in arousal, motor function (Dunn and Berridge, 1990), and learning and memory (Blank et al., 2002, Fenoglio et al., 2006a). In these capacities as a central neurotransmitter in distinct brain regions, CRH is involved in both normal brain function as well as in pathological conditions including anxiety, depression (Nemeroff and Vale, 2005) dementia (Behan et al., 1995, Brunson et al., 2001b, Rehman, 2002) and addiction (Koob, 2006).
Several groups have demonstrated release of endogenous CRH from neurons within amygdala (Merali et al., 1998, Herringa et al., 2006) hippocampus (Chen et al., 2004b, Chen et al., 2006a), locus coeruleus (Curtis and Valentino, 1994, Kirby et al., 2000) and cerebellum (King et al., 1997). However, much remains to be determined about the nature of the endogenous CRH-CRH receptor unit: how is the peptide released? From which neurons? From dendrites or axon terminals? How does the peptide reach its receptors? Is CRH transported by volume transmission or is there a specific ‘CRH synapse’? (Chen et al., 2004b). Where are the receptors located? What happens down-stream of CRH receptor activation? What is the role of the CRH-binding protein in the central CRH system? Clearly, many questions about the CRH system remain unanswered. Here we focus on the available information and delineate the central CRH system, highlighting the functions of this peptide within the central nervous system (CNS) both in the adult and the developing organism. The data suggests that during development, CRH has additional roles that influence long-lasting plasticity within the CNS.
Section snippets
CRH neuroanatomy
CRH mRNA and protein are widely but specifically distributed throughout the CNS (Merchenthaler et al., 1982, Swanson et al., 1983, Keegan et al., 1994, Arborelius et al., 1999, Chen et al., 2001a). A major site of CRH-containing cell bodies is the parvocellular portion of the hypothalamic paraventricular nucleus where CRH acts as neurohormone (Sawchenko and Swanson, 1985, Swanson and Simmons, 1989). CRH-expressing axons originating in these neurons project to the median eminence, where CRH is
Developmental neuroanatomy and regulation of CRH in rodent brain: hypothalamus
In view of the essential role of the stress response for normal function of the organism, a coordinate, progressive development of the stress circuit is required. Several studies in humans have demonstrated that early-life trauma, such as childhood abuse or neglect, has lasting effects on parameters of the neuroendocrine stress circuit, and conveys major risk for the development of mood and anxiety disorders (Agid et al., 2000, Welberg and Seckl, 2001, Charney and Manji, 2004, Nemeroff, 2004).
Developmental neuroanatomy and regulation of CRH in rodent brain: hippocampus
While hypothalamic CRH plays a neuroendocrine role, activated upon physiological stressors (also referred to as ‘reactive’ and ‘physical’), in higher brain centers CRH is an important mediator of psychological stressors (also termed ‘anticipated’ and ‘emotional’; Herman and Cullinan, 1997). These stressors activate higher-order limbic pathways that contribute to the central stress circuit (Herman and Cullinan, 1997) which includes the amygdala (McGaugh et al., 1996, Hatalski et al., 1998, Dayas
Developmental neuroanatomy and regulation of CRH in rodent brain: amygdala
The central nucleus of the amygdala is a key regulator of the stress response (Gray and Bingaman, 1996). CRH-expressing neurons are found in the amygdala nuclei which are key components of the limbic stress circuit (Merali et al., 2004, Herman et al., 2005). Stress triggers the release of endogenous CRH in central nucleus of the amygdala, because administration of CRH antagonist into amygdala can attenuate stress-induced behaviors (Roozendaal et al., 2002). CRH mRNA levels within the amygdala
Developmental neuroanatomy and regulation of CRH receptors in rodent brain
Within the brain CRH is synthesized and released into synaptic spaces where it can activate its receptors; therefore, the actions of this neuronal effector may be modulated via alteration of CRH receptor expression or binding capacity. Thus the developmental pattern of expression of CRH receptors, their regulation and binding properties through development provide useful information regarding modulation of age-specific roles of CRH in different brain areas.
General conclusions
CRH is a key contributor to the repertoire of factors regulating the mammalian response to stress, complementing the actions of glucocorticoids and sympathetic neurotransmitters. In the spatial domain, because the peptide is released from local neurons, it can mediate rapidly the effects of acute stress on specific neuronal populations. Thus, local CRH release in amygdala (Roozendaal et al., 2002) or hippocampus (Chen et al., 2004b, Chen et al., 2006a) can activate selected neuronal populations
Acknowledgment
The authors thank Joy Calara for the excellent editorial assistance. This research is supported by NIH grants MH73136 and NS 28912.
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