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Severe stress switches CRF action in the nucleus accumbens from appetitive to aversive

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Stressors motivate an array of adaptive responses ranging from ‘fight or flight’ to an internal urgency signal facilitating long-term goals1. However, traumatic or chronic uncontrollable stress promotes the onset of major depressive disorder, in which acute stressors lose their motivational properties and are perceived as insurmountable impediments2. Consequently, stress-induced depression is a debilitating human condition characterized by an affective shift from engagement of the environment to withdrawal3. An emerging neurobiological substrate of depression and associated pathology is the nucleus accumbens, a region with the capacity to mediate a diverse range of stress responses by interfacing limbic, cognitive and motor circuitry4. Here we report that corticotropin-releasing factor (CRF), a neuropeptide released in response to acute stressors5 and other arousing environmental stimuli6, acts in the nucleus accumbens of naive mice to increase dopamine release through coactivation of the receptors CRFR1 and CRFR2. Remarkably, severe-stress exposure completely abolished this effect without recovery for at least 90 days. This loss of CRF’s capacity to regulate dopamine release in the nucleus accumbens is accompanied by a switch in the reaction to CRF from appetitive to aversive, indicating a diametric change in the emotional response to acute stressors. Thus, the current findings offer a biological substrate for the switch in affect which is central to stress-induced depressive disorders.

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Figure 1: Cellular localization of CRF peptide, CRFR1 and CRFR2 in the nucleus accumbens.
Figure 2: CRF increases dopamine release in the nucleus accumbens through coactivation of CRFR1 and CRFR2.
Figure 3: CRF in the nucleus accumbens promotes appetitive behaviour.
Figure 4: Stress exposure abolishes the CRF-mediated increase in evoked dopamine release and subsequent appetitive behaviours.

Change history

  • 17 October 2012

    The spelling of an author name (J.R.S.) was corrected.


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This work was supported by National Institutes of Health grants F31-MH086269 (J.C.L.), F32-DA026273 (M.J.W.), R01-DA009082 (E.J.V.B.), R01-DA030074 (C.C.), R01-MH079292 and R01-DA016782 (P.E.M.P.), the National Science Foundation (N.G.H.) and NARSAD (P.E.M.P.). We thank C. Zietz, M. Miyatake and P. Groblewski for assisting with histological verification of cannula placement, H. Gill for help with data analysis, D. Messinger for breeding and genotyping mice and N. Stella for use of a microscope. We thank M. Darvas and R. Palmiter for providing Thfs/fs;DbhTh/+ mice. We thank R. Sapolsky, J. Day, S. Sesack, M. Soden, C. Walker and E. Horne for useful suggestions and insights.

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Authors and Affiliations



Author Contributions J.C.L. performed immunohistochemistry. J.C.L. and N.G.H. carried out fast-scan cyclic-voltammetry experiments. J.C.L., M.J.W. and J.S.S. performed the behavioural experiments. B.A.S.R. and E.J.V.B. provided transmission electron microscopy data. J.C.L., M.J.W., C.C. and P.E.M.P. developed the conceptual and experimental framework, and J.C.L. and P.E.M.P. wrote the paper.

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Correspondence to Paul E. M. Phillips.

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Lemos, J., Wanat, M., Smith, J. et al. Severe stress switches CRF action in the nucleus accumbens from appetitive to aversive. Nature 490, 402–406 (2012).

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