Review
The central corticotropin releasing factor system during development and adulthood

https://doi.org/10.1016/j.ejphar.2007.11.066Get rights and content

Abstract

Corticotropin releasing factor (CRH) has been shown to contribute critically to molecular and neuroendocrine responses to stress during both adulthood and development. This peptide and its receptors are expressed in the hypothalamus, as well as in limbic brain areas including amygdala and hippocampus. This is consistent with roles for CRH in mediating the influence of stress on emotional behavior and cognitive function. The expression of CRH and of its receptors in hypothalamus, amygdala and hippocampus is age-dependent, and is modulated by stress throughout life (including the first postnatal weeks). Uniquely during development, the cardinal influence of maternal care on the central stress response governs the levels of central CRH expression, and may alter the ‘set-point’ of CRH-gene sensitivity to stress in a lasting manner.

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.

References (161)

  • BrunsonK.L. et al.

    Corticotropin-releasing hormone (CRH) downregulates the function of its receptor (CRF1) and induces CRF1 expression in hippocampal and cortical regions of the immature rat brain

    Exp. Neurol.

    (2002)
  • ChenY. et al.

    Rapid phosphorylation of the CRE binding protein precedes stress-induced activation of the corticotropin releasing hormone gene in medial parvocellular hypothalamic neurons of the immature rat

    Mol. Brain Res.

    (2001)
  • ChenY. et al.

    Hippocampal corticotropin releasing hormone: pre-and postsynaptic location and release by stress

    Neuroscience

    (2004)
  • CosteS.C. et al.

    Animal models of CRH excess and CRH receptor deficiency display altered adaptations to stress

    Peptides

    (2001)
  • CurtisA.L. et al.

    Corticotropin-releasing factor neurotransmission in locus coeruleus: a possible site of antidepressant action

    Brain Res. Bull.

    (1994)
  • DeakT. et al.

    Long-term changes in mineralocorticoid and glucocorticoid receptor occupancy following exposure to an acute stressor

    Brain Res.

    (1999)
  • De SouzaE.B.

    Corticotropin-releasing factor receptors: physiology, pharmacology, biochemistry and role in central nervous system and immune disorders

    Psychoneuroendocrinology

    (1995)
  • DunnA.J. et al.

    Physiological and behavioral responses to corticotropin-releasing factor administration: is CRF a mediator of anxiety or stress responses?

    Brain Res. Rev.

    (1990)
  • Eghbal-AhmadiM. et al.

    The developmental profile of the corticotropin releasing factor receptor (CRF2) in rat brain predicts distinct age-specific functions

    Dev. Brain Res.

    (1998)
  • EhlersC.L. et al.

    Corticotropin releasing factor produces increases in brain excitability and convulsive seizures in rats

    Brain Res.

    (1983)
  • FenoglioK.A. et al.

    Hippocampal neuroplasticity induced by early-life stress: functional and molecular aspects

    Front. Neuroendocrinol.

    (2006)
  • FrancisD.D. et al.

    The role of corticotropin-releasing factor-norepinephrine systems in mediating the effects of early experience on the development of behavioral and endocrine responses to stress

    Biol. Psychiatry

    (1999)
  • GillesE.E. et al.

    Abnormal corticosterone regulation in an immature rat model of continuous chronic stress

    Pediatr. Neurol.

    (1996)
  • GonzalezG.A. et al.

    Cyclic AMP stimulates somatostatin gene transcription by phosphorylation of CREB at serine 133

    Cell

    (1989)
  • HatalskiC.G. et al.

    Neuronal activity and stress differentially regulate hippocampal and hypothalamic corticotropin-releasing hormone expression in the immature rat

    Neuroscience

    (2000)
  • HermanJ.P. et al.

    Neurocircuitry of stress: central control of the hypothalamo-pituitary-adrenocortical axis

    Trends Neurosci.

    (1997)
  • HermanJ.P. et al.

    Limbic system mechanisms of stress regulation: hypothalamo-pituitary-adrenocortical axis

    Prog. Neuropsychopharmacol. Biol. Psychiatry

    (2005)
  • HerringaR.J. et al.

    Corticotropin-releasing factor (CRF), but not corticosterone, increases basolateral amygdala CRF-binding protein

    Brain Res.

    (2006)
  • HollrigelG.S. et al.

    The pro-convulsant actions of corticotropin-releasing hormone in the hippocampus of infant rats

    Neuroscience

    (1998)
  • ImakiT. et al.

    Corticotropin-releasing factor up-regulates its own receptor mRNA in the paraventricular nucleus of the hypothalamus

    Mol. Brain Res.

    (1996)
  • IxartG. et al.

    Evidence for basal and stress-induced release of corticotropin releasing factor in the push-pull cannulated median eminence of conscious free-moving rats

    Neurosci. Lett.

    (1987)
  • KalinN.H. et al.

    Restraint stress increases corticotropin-releasing hormone mRNA content in the amygdala and paraventricular nucleus

    Brain Res.

    (1994)
  • KingJ.S. et al.

    The distribution of corticotropin-releasing factor (CRF), CRF binding sites and CRF1 receptor mRNA in the mouse cerebellum

    Prog. Brain Res.

    (1997)
  • KorosiA. et al.

    Chronic ether stress-induced response of urocortin 1 neurons in the Edinger–Westphal nucleus in the mouse

    Brain Res.

    (2005)
  • KorosiA. et al.

    Distribution and expression of CRF receptor 1 and 2 mRNAs in the CRF over-expressing mouse brain

    Brain Res.

    (2006)
  • KoziczT. et al.

    Urocortin expression in the Edinger–Westphal nucleus is down-regulated in transgenic mice over-expressing neuronal corticotropin-releasing factor

    Neuroscience

    (2004)
  • LevineS.

    The pituitary-adrenal system and the developing brain

    Prog. Brain Res.

    (1970)
  • LevineS.

    The ontogeny of the hypothalamic-pituitary-adrenal axis. The influence of maternal factors

    Ann. N.Y. Acad. Sci.

    (1994)
  • AkanaS.F. et al.

    Chronic cold in adrenalectomized, corticosterone (B)-treated rats: facilitated corticotropin responses to acute restraint emerge as B increases

    Endocrinology

    (1997)
  • AkanaS.F. et al.

    Feedback and facilitation in the adrenocortical system: unmasking facilitation by partial inhibition of the glucocorticoid response to prior stress

    Endocrinology

    (1992)
  • AldenhoffJ.B. et al.

    Corticotropin releasing factor decreases postburst hyperpolarizations and excites hippocampal neurons

    Science

    (1983)
  • AltmanJ. et al.

    The development of the rat hypothalamus

    Adv. Anat. Embryol. Cell Biol.

    (1986)
  • ArboreliusL. et al.

    The role of corticotropin-releasing factor in depression and anxiety disorders

    J. Endocrinol.

    (1999)
  • Avishai-ElinerS. et al.

    Down-regulation of hypothalamic corticotropin-releasing hormone messenger ribonucleic acid (mRNA) precedes early-life experience-induced changes in hippocampal glucocorticoid receptor mRNA

    Endocrinology

    (2001)
  • Avishai-ElinerS. et al.

    Altered regulation of gene and protein expression of hypothalamic-pituitary-adrenal axis components in an immature rat model of chronic stress

    J. Neuroendocrinol.

    (2001)
  • BaleT.L. et al.

    Mice deficient for corticotropin-releasing hormone receptor-2 display anxiety-like behaviour and are hypersensitive to stress

    Nat. Genet.

    (2000)
  • BaramT.Z. et al.

    Corticotropin-releasing hormone-induced seizures in infant rats originate in the amygdala

    Ann. Neurol.

    (1992)
  • BaramT.Z. et al.

    Development neurobiology of the stress response: multilevel regulation of corticotropin-releasing hormone function

    Ann. N.Y. Acad. Sci.

    (1997)
  • BehanD.P. et al.

    Displacement of corticotropin releasing factor from its binding protein as a possible treatment for Alzheimer's disease

    Nature

    (1995)
  • BlankT. et al.

    Priming of long-term potentiation in mouse hippocampus by corticotropin-releasing factor and acute stress: implications for hippocampus-dependent learning

    J. Neurosci.

    (2002)
  • Cited by (90)

    • CRHR1 endocytosis: Spatiotemporal regulation of receptor signaling

      2023, Progress in Molecular Biology and Translational Science
    • Resource scarcity but not maternal separation provokes unpredictable maternal care sequences in mice and both upregulate Crh-associated gene expression in the amygdala

      2022, Neurobiology of Stress
      Citation Excerpt :

      For example, LBN in females, but not males, increased the expression of CrhBP and CrhR1 at PD16, four days following the end of the LBN manipulation. While the unique developmental roles of the receptors and CrhBP are still being established, evidence supports that heightened expression in the neonate amygdala is indicative of a transition from a hypo-functional to a hyper-functional amygdala and supports accelerated aversive learning (Moriceau and Sullivan 2004, 2006; Moriceau et al., 2004, 2006; Vazquez et al., 2006; Korosi and Baram 2008). Further, it has been postulated that CrhR1 and CrhR2 play opposing roles whereby the former is anxiogenic and the latter is anxiolytic, mediating stress recovery (Reul and Holsboer 2002), and both receptors are altered by a variety of early-life experiences (Vazquez et al., 2006; Wang et al., 2011; Eghbal-Ahmadi et al., 1997).

    View all citing articles on Scopus
    View full text