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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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CRF in the nucleus accumbens promotes appetitive behaviora, Mean (+ s.e.m.) mean times spent in CRF-paired chamber than the vehicle paired chambers before and after conditioning, n = 7 (top) and representative post-conditioning activity trace (bottom). b, Place preference (time in CRF-paired chamber – time in vehicle paired chamber post conditioning) for intra-nucleus accumbens injections of 500 ng CRF bilateral, 500 ng unilateral or 5 ng bilateral, n = 7-10 (left). Place preference for 500 ng CRF (unilateral) in sham or 6-OHDA treated mice, n = 10 (right). c, Time spent in the center of an open field before and during presentation of a novel object (placed in center of field) following bilateral intra-accumbens infusion of the CRF-receptor antagonist α-helical CRF (500 ng) or its vehicle, n = 10. Data on bar graphs are mean + s.e.m.; ns p > 0.05, * p < 0.05, ** p < 0.01, *** p < 0.001; § p < 0.05 for interaction.
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Figure 3: CRF in the nucleus accumbens promotes appetitive behaviora, Mean (+ s.e.m.) mean times spent in CRF-paired chamber than the vehicle paired chambers before and after conditioning, n = 7 (top) and representative post-conditioning activity trace (bottom). b, Place preference (time in CRF-paired chamber – time in vehicle paired chamber post conditioning) for intra-nucleus accumbens injections of 500 ng CRF bilateral, 500 ng unilateral or 5 ng bilateral, n = 7-10 (left). Place preference for 500 ng CRF (unilateral) in sham or 6-OHDA treated mice, n = 10 (right). c, Time spent in the center of an open field before and during presentation of a novel object (placed in center of field) following bilateral intra-accumbens infusion of the CRF-receptor antagonist α-helical CRF (500 ng) or its vehicle, n = 10. Data on bar graphs are mean + s.e.m.; ns p > 0.05, * p < 0.05, ** p < 0.01, *** p < 0.001; § p < 0.05 for interaction.

Mentions: If this ability for CRF to positively regulate dopamine in the nucleus accumbens has specific motivational relevance to the behaving animal, we would predict that it would cause conditioned place preference when restricted to the nucleus accumbens, even though centrally administered CRF elicits robust conditioned place aversion16. Therefore, we used a balanced place-conditioning apparatus consisting of two visually distinct test chambers separated by a smaller neutral compartment. On day 1, mice were allowed to freely roam the apparatus, and the time they spent in each chamber was recorded. On days 2 and 3, mice received CRF bilaterally into the nucleus accumbens (500 ng per side in 200 nl artificial cerebrospinal fluid; cannulae placements shown in Supplementary Fig. 6) or vehicle infusions and then were isolated in one of the test chambers for 30 minutes. Four hours later they received the alternative infusion and were isolated in the other test chamber for 30 minutes. On day 4, mice were again allowed free access to the apparatus. Mice exhibited a significant preference for the CRF-paired context, demonstrating that intra-accumbens CRF (500 ng) was an appetitive stimulus to these animals (conditioning by drug, F1,12 = 6.435, p < 0.001 two-way repeated-measures ANOVA, Fig. 3a). Similarly, unilateral infusions of CRF (500 ng/200 nl) also produced conditioned place preference (conditioning by drug, F1,12 = 11.77, p < 0.001 two-way repeated-measures ANOVA; Fig. 3b and Supplementary Fig. 7a). This dose of CRF is within the range that produces selective effects in vivo11, but it is difficult to ascertain the steady-state concentration at receptors as CRF undergoes both radial diffusion and active clearance17. Nonetheless, even at a lower dose of CRF (5 ng/ 200 nl), conditioned place preference was observed (conditioning by drug, F1,14 = 5.415, p < 0.05, two-way repeated measures ANOVA; Fig. 3b and Supplementary Fig. 7b). Taken together, these data indicate that CRF acts in the nucleus accumbens to produce a positive affective state.


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)

CRF in the nucleus accumbens promotes appetitive behaviora, Mean (+ s.e.m.) mean times spent in CRF-paired chamber than the vehicle paired chambers before and after conditioning, n = 7 (top) and representative post-conditioning activity trace (bottom). b, Place preference (time in CRF-paired chamber – time in vehicle paired chamber post conditioning) for intra-nucleus accumbens injections of 500 ng CRF bilateral, 500 ng unilateral or 5 ng bilateral, n = 7-10 (left). Place preference for 500 ng CRF (unilateral) in sham or 6-OHDA treated mice, n = 10 (right). c, Time spent in the center of an open field before and during presentation of a novel object (placed in center of field) following bilateral intra-accumbens infusion of the CRF-receptor antagonist α-helical CRF (500 ng) or its vehicle, n = 10. Data on bar graphs are mean + s.e.m.; ns p > 0.05, * p < 0.05, ** p < 0.01, *** p < 0.001; § p < 0.05 for interaction.
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Figure 3: CRF in the nucleus accumbens promotes appetitive behaviora, Mean (+ s.e.m.) mean times spent in CRF-paired chamber than the vehicle paired chambers before and after conditioning, n = 7 (top) and representative post-conditioning activity trace (bottom). b, Place preference (time in CRF-paired chamber – time in vehicle paired chamber post conditioning) for intra-nucleus accumbens injections of 500 ng CRF bilateral, 500 ng unilateral or 5 ng bilateral, n = 7-10 (left). Place preference for 500 ng CRF (unilateral) in sham or 6-OHDA treated mice, n = 10 (right). c, Time spent in the center of an open field before and during presentation of a novel object (placed in center of field) following bilateral intra-accumbens infusion of the CRF-receptor antagonist α-helical CRF (500 ng) or its vehicle, n = 10. Data on bar graphs are mean + s.e.m.; ns p > 0.05, * p < 0.05, ** p < 0.01, *** p < 0.001; § p < 0.05 for interaction.
Mentions: If this ability for CRF to positively regulate dopamine in the nucleus accumbens has specific motivational relevance to the behaving animal, we would predict that it would cause conditioned place preference when restricted to the nucleus accumbens, even though centrally administered CRF elicits robust conditioned place aversion16. Therefore, we used a balanced place-conditioning apparatus consisting of two visually distinct test chambers separated by a smaller neutral compartment. On day 1, mice were allowed to freely roam the apparatus, and the time they spent in each chamber was recorded. On days 2 and 3, mice received CRF bilaterally into the nucleus accumbens (500 ng per side in 200 nl artificial cerebrospinal fluid; cannulae placements shown in Supplementary Fig. 6) or vehicle infusions and then were isolated in one of the test chambers for 30 minutes. Four hours later they received the alternative infusion and were isolated in the other test chamber for 30 minutes. On day 4, mice were again allowed free access to the apparatus. Mice exhibited a significant preference for the CRF-paired context, demonstrating that intra-accumbens CRF (500 ng) was an appetitive stimulus to these animals (conditioning by drug, F1,12 = 6.435, p < 0.001 two-way repeated-measures ANOVA, Fig. 3a). Similarly, unilateral infusions of CRF (500 ng/200 nl) also produced conditioned place preference (conditioning by drug, F1,12 = 11.77, p < 0.001 two-way repeated-measures ANOVA; Fig. 3b and Supplementary Fig. 7a). This dose of CRF is within the range that produces selective effects in vivo11, but it is difficult to ascertain the steady-state concentration at receptors as CRF undergoes both radial diffusion and active clearance17. Nonetheless, even at a lower dose of CRF (5 ng/ 200 nl), conditioned place preference was observed (conditioning by drug, F1,14 = 5.415, p < 0.05, two-way repeated measures ANOVA; Fig. 3b and Supplementary Fig. 7b). Taken together, these data indicate that CRF acts in the nucleus accumbens to produce a positive affective state.

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