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

Lemos JC, Wanat MJ, Smith JS, Reyes BA, Hollon NG, Van Bockstaele EJ, Chavkin C, Phillips PE - Nature (2012)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington 98195, USA.

ABSTRACT
Stressors motivate an array of adaptive responses ranging from 'fight or flight' to an internal urgency signal facilitating long-term goals. 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 impediments. Consequently, stress-induced depression is a debilitating human condition characterized by an affective shift from engagement of the environment to withdrawal. 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 circuitry. Here we report that corticotropin-releasing factor (CRF), a neuropeptide released in response to acute stressors and other arousing environmental stimuli, 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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Cellular localization of CRF peptide, CRF R1 and CRF R2 in the nucleus accumbensa, Immunoreactivity for CRF peptide (top), CRF R1 (middle) or CRF R2 (bottom) is shown in red and for tyrosine hydroxylase (TH) is shown in green. The arrows highlight examples of co-localization (yellow in the merged images). Scale bar = 10 μm. b, Transmission electron microscopy photomicrographs demonstrating CRF receptors (labeled with immunogold particles; arrows) present on both TH positive (immunoperoxidase labeled) and TH negative profiles. Top scale bar = 0.5 μm; bottom scale bars = 1 μm.
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Figure 1: Cellular localization of CRF peptide, CRF R1 and CRF R2 in the nucleus accumbensa, Immunoreactivity for CRF peptide (top), CRF R1 (middle) or CRF R2 (bottom) is shown in red and for tyrosine hydroxylase (TH) is shown in green. The arrows highlight examples of co-localization (yellow in the merged images). Scale bar = 10 μm. b, Transmission electron microscopy photomicrographs demonstrating CRF receptors (labeled with immunogold particles; arrows) present on both TH positive (immunoperoxidase labeled) and TH negative profiles. Top scale bar = 0.5 μm; bottom scale bars = 1 μm.

Mentions: CRF initiates neuroendocrine signaling in the hypothalamic-pituitary-adrenal axis, and also regulates neurotransmission directly via two receptor subtypes, CRF R1 and CRF R2, which are distributed widely throughout the brain7,8. In the nucleus accumbens, CRF facilitates cue-elicited motivation9 and social bonding10, behaviors thought to be mediated by dopamine transmission11,12. Therefore, we sought evidence for CRF-dopamine interactions in the nucleus accumbens, first using fluorescent immunohistochemistry. Dense CRF immunoreactivity was present throughout the rostro-caudal axis of the nucleus accumbens core and lateral shell and in the most rostral portion of the medial shell in sparsely located large cell bodies (cholinergic interneurons, see Supplementary Fig. 1) and fiber terminals that were interdigitated with tyrosine-hydroxylase (TH) immunoreactive fibers that are indicative of dopamine-containing axons (Fig. 1a). Immunoreactivity for the CRF R1 receptor displayed punctate staining with co-localization of TH immunoreactivity on fiber segments in addition to localization on cell bodies within the nucleus accumbens (Fig. 1b and Supplementary Fig. 2). CRF R2 immunoreactivity had a more diffuse, but still, punctate pattern of staining, similar to that in other regions13, with some co-localization with TH-immunoreactivity (Fig. 1c and Supplementary Fig. 3). Expression of CRF receptors on subcellular profiles in the nucleus accumbens, including TH-positive terminals, was confirmed at higher spatial resolution using transmission electron microscopy (Fig. 1d; quantified in Supplementary Table 1). Together, these data indicate that the localization of CRF and its receptors in the nucleus accumbens is well suited for modulation of dopamine release.


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

Lemos JC, Wanat MJ, Smith JS, Reyes BA, Hollon NG, Van Bockstaele EJ, Chavkin C, Phillips PE - Nature (2012)

Cellular localization of CRF peptide, CRF R1 and CRF R2 in the nucleus accumbensa, Immunoreactivity for CRF peptide (top), CRF R1 (middle) or CRF R2 (bottom) is shown in red and for tyrosine hydroxylase (TH) is shown in green. The arrows highlight examples of co-localization (yellow in the merged images). Scale bar = 10 μm. b, Transmission electron microscopy photomicrographs demonstrating CRF receptors (labeled with immunogold particles; arrows) present on both TH positive (immunoperoxidase labeled) and TH negative profiles. Top scale bar = 0.5 μm; bottom scale bars = 1 μm.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3475726&req=5

Figure 1: Cellular localization of CRF peptide, CRF R1 and CRF R2 in the nucleus accumbensa, Immunoreactivity for CRF peptide (top), CRF R1 (middle) or CRF R2 (bottom) is shown in red and for tyrosine hydroxylase (TH) is shown in green. The arrows highlight examples of co-localization (yellow in the merged images). Scale bar = 10 μm. b, Transmission electron microscopy photomicrographs demonstrating CRF receptors (labeled with immunogold particles; arrows) present on both TH positive (immunoperoxidase labeled) and TH negative profiles. Top scale bar = 0.5 μm; bottom scale bars = 1 μm.
Mentions: CRF initiates neuroendocrine signaling in the hypothalamic-pituitary-adrenal axis, and also regulates neurotransmission directly via two receptor subtypes, CRF R1 and CRF R2, which are distributed widely throughout the brain7,8. In the nucleus accumbens, CRF facilitates cue-elicited motivation9 and social bonding10, behaviors thought to be mediated by dopamine transmission11,12. Therefore, we sought evidence for CRF-dopamine interactions in the nucleus accumbens, first using fluorescent immunohistochemistry. Dense CRF immunoreactivity was present throughout the rostro-caudal axis of the nucleus accumbens core and lateral shell and in the most rostral portion of the medial shell in sparsely located large cell bodies (cholinergic interneurons, see Supplementary Fig. 1) and fiber terminals that were interdigitated with tyrosine-hydroxylase (TH) immunoreactive fibers that are indicative of dopamine-containing axons (Fig. 1a). Immunoreactivity for the CRF R1 receptor displayed punctate staining with co-localization of TH immunoreactivity on fiber segments in addition to localization on cell bodies within the nucleus accumbens (Fig. 1b and Supplementary Fig. 2). CRF R2 immunoreactivity had a more diffuse, but still, punctate pattern of staining, similar to that in other regions13, with some co-localization with TH-immunoreactivity (Fig. 1c and Supplementary Fig. 3). Expression of CRF receptors on subcellular profiles in the nucleus accumbens, including TH-positive terminals, was confirmed at higher spatial resolution using transmission electron microscopy (Fig. 1d; quantified in Supplementary Table 1). Together, these data indicate that the localization of CRF and its receptors in the nucleus accumbens is well suited for modulation of dopamine release.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington 98195, USA.

ABSTRACT
Stressors motivate an array of adaptive responses ranging from 'fight or flight' to an internal urgency signal facilitating long-term goals. 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 impediments. Consequently, stress-induced depression is a debilitating human condition characterized by an affective shift from engagement of the environment to withdrawal. 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 circuitry. Here we report that corticotropin-releasing factor (CRF), a neuropeptide released in response to acute stressors and other arousing environmental stimuli, 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.

Show MeSH
Related in: MedlinePlus