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Corticotropin-Releasing Factor From Rodents to Primates: Translational Hope Expresses Itself, Pun Intended

  • George F. Koob
    Correspondence
    Address correspondence to: George F. Koob, National Institute on Alcohol Abuse and Alcoholism, 5635 Fishers Lane, Room 2001, Suite 2000, Rockville, MD 20852.
    Affiliations
    National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland
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      Corticotropin-releasing factor (CRF) is a neuropeptide in the brain and body that coordinates hormonal, sympathetic, and behavioral responses to stressors. Since its discovery in 1981 (
      • Bale T.L.
      • Vale W.W.
      CRF and CRF receptors: Role in stress responsivity and other behaviors.
      ), literally thousands of articles have been published that support its role in these three functional domains. CRF controls corticotropin secretion and in turn glucocorticoid activation in the face of acute stressor exposure via its actions as a releasing factor in the paraventricular nucleus of the hypothalamus. Vale and colleagues first demonstrated that CRF initiates the hypothalamic-pituitary-adrenal (HPA) axis neuroendocrine stress response by binding CRF1 receptors on anterior pituitary corticotropes to release adrenocorticotropic hormone (
      • Bale T.L.
      • Vale W.W.
      CRF and CRF receptors: Role in stress responsivity and other behaviors.
      ). CRF controls sympathetic activation via its actions as a neurotransmitter in the brainstem (
      • Kovács K.J.
      CRH: The link between hormonal-, metabolic- and behavioral responses to stress.
      ), and CRF via CRF1 receptors controls behavioral responses to stressors, from activation to freezing, anxiety-like responses, and fear conditioning via its actions as a neurotransmitter in the extended amygdala [for review, see Zorrilla et al. (
      • Zorrilla E.P.
      • Logrip M.L.
      • Koob G.F.
      Corticotropin releasing factor: A key role in the neurobiology of addiction.
      )]. CRF and CRF1 receptors are widely distributed in stress-responsive brain regions, including the neocortex, central extended amygdala, medial septum, hippocampus, thalamus, cerebellum, and autonomic midbrain and hindbrain nuclei (
      • Bale T.L.
      • Vale W.W.
      CRF and CRF receptors: Role in stress responsivity and other behaviors.
      ). CRF in the gastrointestinal system plays a key role in modulating gastrointestinal motility and as such may play a key role in stress-related physiological disorders, such as irritable bowel syndrome (
      • Taché Y.
      • Brunnhuber S.
      From Hans Selye’s discovery of biological stress to the identification of corticotropin-releasing factor signaling pathways: Implication in stress-related functional bowel diseases.
      ). In human psychiatric disorders, CRF has been implicated in anxiety and depressive disorders and addiction, again largely based on preclinical animal models (
      • Zorrilla E.P.
      • Logrip M.L.
      • Koob G.F.
      Corticotropin releasing factor: A key role in the neurobiology of addiction.
      ) and correlational measures of CRF in cerebrospinal fluid and postmortem brains (
      • Kalin N.H.
      • Fox A.S.
      • Kovner R.
      • Riedel M.K.
      • Fekete E.M.
      • Roseboom P.H.
      • et al.
      Overexpressing corticotropin-releasing factor in the primate amygdala increases anxious temperament and alters its neural circuit.
      ). Much of the preclinical work that implicates endogenous CRF in biological function has relied on both peptide and small-molecule antagonists. In rodents, CRF antagonists have profound effects in blocking physiological and behavioral responses to stressors (
      • Bale T.L.
      • Vale W.W.
      CRF and CRF receptors: Role in stress responsivity and other behaviors.
      ,
      • Zorrilla E.P.
      • Logrip M.L.
      • Koob G.F.
      Corticotropin releasing factor: A key role in the neurobiology of addiction.
      ).
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      References

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        Corticotropin releasing factor: A key role in the neurobiology of addiction.
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        Neuropsychopharmacology. 2006; 31: 1822-1831

      Linked Article

      • Overexpressing Corticotropin-Releasing Factor in the Primate Amygdala Increases Anxious Temperament and Alters Its Neural Circuit
        Biological PsychiatryVol. 80Issue 5
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          Nonhuman primate models are critical for understanding mechanisms underlying human psychopathology. We established a nonhuman primate model of anxious temperament (AT) for studying the early-life risk to develop anxiety and depression. Studies have identified the central nucleus of the amygdala (Ce) as an essential component of AT’s neural substrates. Corticotropin-releasing factor (CRF) is expressed in the Ce, has a role in stress, and is linked to psychopathology. Here, in young rhesus monkeys, we combined viral vector technology with assessments of anxiety and multimodal neuroimaging to understand the consequences of chronically increased CRF in the Ce region.
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