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Role of Central Serotonin in Anticipation of Rewarding and Punishing Outcomes: Effects of Selective Amygdala or Orbitofrontal 5-HT Depletion.

Rygula R, Clarke HF, Cardinal RN, Cockcroft GJ, Xia J, Dalley JW, Robbins TW, Roberts AC - Cereb. Cortex (2014)

Bottom Line: To address this apparent discrepancy, the present study determined whether both effects could be found in the same animals by performing localized 5-HT depletions in the amygdala or orbitofrontal cortex (OFC) of a New World monkey, the common marmoset. 5-HT depletion in the amygdala impaired response choice on a probabilistic visual discrimination task by increasing the effectiveness of misleading, or false, punishment and reward, and decreased response suppression in a variable interval test of punishment sensitivity that employed the same reward and punisher. 5-HT depletion in the OFC also disrupted probabilistic discrimination learning and decreased response suppression.Computational modeling of behavior on the discrimination task showed that the lesions reduced reinforcement sensitivity.A novel, unitary account of the findings in terms of the causal role of 5-HT in the anticipation of both negative and positive motivational outcomes is proposed and discussed in relation to current theories of 5-HT function and our understanding of mood and anxiety disorders.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychology, University of Cambridge, Cambridge CB2 3EB, UK Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge CB2 3EB, UK Current Address: Affective Cognitive Neuroscience Laboratory, Department of Behavioral Neurobiology and Drug Development, Institute of Pharmacology Polish Academy of Sciences, ul Smetna 12, 31-343 Krakow, Poland.

No MeSH data available.


Related in: MedlinePlus

Reductions in ex vivo tissue levels and in vivo extracellular levels of brain 5-HT following 5,7-DHT infusions into the OFC and amygdala. (A and B) 5-HT levels in the OFC of 5,7-DHT OFC-infused animals (N = 4) and the amygdala of 5,7-DHT amygdala-infused animals (N = 4), respectively, as a percentage of controls (N = 4), at various time points, after surgery. The dotted and dashed lines indicate the mean number of months, after surgery, that 5-HT-depleted monkeys completed the probabilistic discrimination and punishment sensitivity tests, respectively. The filled symbols represent individual 5-HT-depleted animals in the present study, while the crosses represent animals that had received unilateral infusions (previously reported in the case of the amygdala: (Man et al. 2014)). The open squares represent data from bilaterally infused animals from previously reported experimental studies(1–5). (C and D) Mean levels of postmortem tissue levels of 5-HT in the OFC and amygdala of 5,7-DHT OFC-infused and 5,7-DHT amygdala-infused animals, respectively, expressed as a percentage of controls. (E and F) Mean and individual percentage change from control levels of in vivo OFC extracellular 5-HT in 5,7-DHT OFC-infused animals and in vivo amygdala extracellular 5-HT in 5,7-DHT amygdala-infused animals, respectively. Where levels fell below the limit of detection of 7.5 fmol, percentage decreases were calculated using this detection limit (circle in E and circle and triangle in F). 1Four 5,7-DHT OFC-depleted marmosets previously reported in (Clarke et al. 2007), study 1: 2Four 5,7-DHT OFC-depleted marmosets previously reported in (Walker et al. 2006), 3Four 5,7-DHT OFC-depleted marmosets previously reported in (Walker et al. 2009), 4Eight 5,7-DHT OFC-depleted marmosets previously reported in (Clarke et al. 2007), study 2: 5Four 5,7-DHT amygdala-lesioned marmosets previously reported in (Man et al. 2014). See also Supplementary Table 1.
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BHU102F2: Reductions in ex vivo tissue levels and in vivo extracellular levels of brain 5-HT following 5,7-DHT infusions into the OFC and amygdala. (A and B) 5-HT levels in the OFC of 5,7-DHT OFC-infused animals (N = 4) and the amygdala of 5,7-DHT amygdala-infused animals (N = 4), respectively, as a percentage of controls (N = 4), at various time points, after surgery. The dotted and dashed lines indicate the mean number of months, after surgery, that 5-HT-depleted monkeys completed the probabilistic discrimination and punishment sensitivity tests, respectively. The filled symbols represent individual 5-HT-depleted animals in the present study, while the crosses represent animals that had received unilateral infusions (previously reported in the case of the amygdala: (Man et al. 2014)). The open squares represent data from bilaterally infused animals from previously reported experimental studies(1–5). (C and D) Mean levels of postmortem tissue levels of 5-HT in the OFC and amygdala of 5,7-DHT OFC-infused and 5,7-DHT amygdala-infused animals, respectively, expressed as a percentage of controls. (E and F) Mean and individual percentage change from control levels of in vivo OFC extracellular 5-HT in 5,7-DHT OFC-infused animals and in vivo amygdala extracellular 5-HT in 5,7-DHT amygdala-infused animals, respectively. Where levels fell below the limit of detection of 7.5 fmol, percentage decreases were calculated using this detection limit (circle in E and circle and triangle in F). 1Four 5,7-DHT OFC-depleted marmosets previously reported in (Clarke et al. 2007), study 1: 2Four 5,7-DHT OFC-depleted marmosets previously reported in (Walker et al. 2006), 3Four 5,7-DHT OFC-depleted marmosets previously reported in (Walker et al. 2009), 4Eight 5,7-DHT OFC-depleted marmosets previously reported in (Clarke et al. 2007), study 2: 5Four 5,7-DHT amygdala-lesioned marmosets previously reported in (Man et al. 2014). See also Supplementary Table 1.

Mentions: Injections of 5,7-DHT into the OFC induced a significant (t3 = −8.10, P = 0.004) reduction of 5-HT in the OFC (compared with sham-operated controls), as measured in postmortem tissue, 10–19 months after surgery (Fig. 2A,C). This reduction was regionally selective with no significant alterations in neighboring prefrontal or cingulate regions (largest t3 = 2.86, ns; Supplementary Table 1A). It was also neurochemically selective with no corresponding reductions of DA or NA within the OFC (ts ≤ 1) or surrounding tissue (largest t3 = −1.6, ns; Supplementary Table 1B). Although the mean level of depletion by the end of the study was only 38.98%, that is, levels that were 61.02 ± 6.36% of controls (Fig. 2C), findings from previously published experimental studies from our laboratory reveal much greater depletions at earlier time points, when the majority of the behavioral studies occurred (Fig. 2A, see dotted and dashed lines for mean time points of behavioral testing). Moreover, in vivo microdialysis in 2 of the 4 animals, immediately after the PVDLR task, and just before the VI test of punishment sensitivity, confirmed that extracellular levels of 5-HT within the OFC showed substantial reductions (Fig. 2E), demonstrating that 5-HT activity in the OFC was still markedly compromised. The samples from the remaining 2 animals could not be analyzed as they were inadvertently thawed when a freezer failed.Figure 2.


Role of Central Serotonin in Anticipation of Rewarding and Punishing Outcomes: Effects of Selective Amygdala or Orbitofrontal 5-HT Depletion.

Rygula R, Clarke HF, Cardinal RN, Cockcroft GJ, Xia J, Dalley JW, Robbins TW, Roberts AC - Cereb. Cortex (2014)

Reductions in ex vivo tissue levels and in vivo extracellular levels of brain 5-HT following 5,7-DHT infusions into the OFC and amygdala. (A and B) 5-HT levels in the OFC of 5,7-DHT OFC-infused animals (N = 4) and the amygdala of 5,7-DHT amygdala-infused animals (N = 4), respectively, as a percentage of controls (N = 4), at various time points, after surgery. The dotted and dashed lines indicate the mean number of months, after surgery, that 5-HT-depleted monkeys completed the probabilistic discrimination and punishment sensitivity tests, respectively. The filled symbols represent individual 5-HT-depleted animals in the present study, while the crosses represent animals that had received unilateral infusions (previously reported in the case of the amygdala: (Man et al. 2014)). The open squares represent data from bilaterally infused animals from previously reported experimental studies(1–5). (C and D) Mean levels of postmortem tissue levels of 5-HT in the OFC and amygdala of 5,7-DHT OFC-infused and 5,7-DHT amygdala-infused animals, respectively, expressed as a percentage of controls. (E and F) Mean and individual percentage change from control levels of in vivo OFC extracellular 5-HT in 5,7-DHT OFC-infused animals and in vivo amygdala extracellular 5-HT in 5,7-DHT amygdala-infused animals, respectively. Where levels fell below the limit of detection of 7.5 fmol, percentage decreases were calculated using this detection limit (circle in E and circle and triangle in F). 1Four 5,7-DHT OFC-depleted marmosets previously reported in (Clarke et al. 2007), study 1: 2Four 5,7-DHT OFC-depleted marmosets previously reported in (Walker et al. 2006), 3Four 5,7-DHT OFC-depleted marmosets previously reported in (Walker et al. 2009), 4Eight 5,7-DHT OFC-depleted marmosets previously reported in (Clarke et al. 2007), study 2: 5Four 5,7-DHT amygdala-lesioned marmosets previously reported in (Man et al. 2014). See also Supplementary Table 1.
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BHU102F2: Reductions in ex vivo tissue levels and in vivo extracellular levels of brain 5-HT following 5,7-DHT infusions into the OFC and amygdala. (A and B) 5-HT levels in the OFC of 5,7-DHT OFC-infused animals (N = 4) and the amygdala of 5,7-DHT amygdala-infused animals (N = 4), respectively, as a percentage of controls (N = 4), at various time points, after surgery. The dotted and dashed lines indicate the mean number of months, after surgery, that 5-HT-depleted monkeys completed the probabilistic discrimination and punishment sensitivity tests, respectively. The filled symbols represent individual 5-HT-depleted animals in the present study, while the crosses represent animals that had received unilateral infusions (previously reported in the case of the amygdala: (Man et al. 2014)). The open squares represent data from bilaterally infused animals from previously reported experimental studies(1–5). (C and D) Mean levels of postmortem tissue levels of 5-HT in the OFC and amygdala of 5,7-DHT OFC-infused and 5,7-DHT amygdala-infused animals, respectively, expressed as a percentage of controls. (E and F) Mean and individual percentage change from control levels of in vivo OFC extracellular 5-HT in 5,7-DHT OFC-infused animals and in vivo amygdala extracellular 5-HT in 5,7-DHT amygdala-infused animals, respectively. Where levels fell below the limit of detection of 7.5 fmol, percentage decreases were calculated using this detection limit (circle in E and circle and triangle in F). 1Four 5,7-DHT OFC-depleted marmosets previously reported in (Clarke et al. 2007), study 1: 2Four 5,7-DHT OFC-depleted marmosets previously reported in (Walker et al. 2006), 3Four 5,7-DHT OFC-depleted marmosets previously reported in (Walker et al. 2009), 4Eight 5,7-DHT OFC-depleted marmosets previously reported in (Clarke et al. 2007), study 2: 5Four 5,7-DHT amygdala-lesioned marmosets previously reported in (Man et al. 2014). See also Supplementary Table 1.
Mentions: Injections of 5,7-DHT into the OFC induced a significant (t3 = −8.10, P = 0.004) reduction of 5-HT in the OFC (compared with sham-operated controls), as measured in postmortem tissue, 10–19 months after surgery (Fig. 2A,C). This reduction was regionally selective with no significant alterations in neighboring prefrontal or cingulate regions (largest t3 = 2.86, ns; Supplementary Table 1A). It was also neurochemically selective with no corresponding reductions of DA or NA within the OFC (ts ≤ 1) or surrounding tissue (largest t3 = −1.6, ns; Supplementary Table 1B). Although the mean level of depletion by the end of the study was only 38.98%, that is, levels that were 61.02 ± 6.36% of controls (Fig. 2C), findings from previously published experimental studies from our laboratory reveal much greater depletions at earlier time points, when the majority of the behavioral studies occurred (Fig. 2A, see dotted and dashed lines for mean time points of behavioral testing). Moreover, in vivo microdialysis in 2 of the 4 animals, immediately after the PVDLR task, and just before the VI test of punishment sensitivity, confirmed that extracellular levels of 5-HT within the OFC showed substantial reductions (Fig. 2E), demonstrating that 5-HT activity in the OFC was still markedly compromised. The samples from the remaining 2 animals could not be analyzed as they were inadvertently thawed when a freezer failed.Figure 2.

Bottom Line: To address this apparent discrepancy, the present study determined whether both effects could be found in the same animals by performing localized 5-HT depletions in the amygdala or orbitofrontal cortex (OFC) of a New World monkey, the common marmoset. 5-HT depletion in the amygdala impaired response choice on a probabilistic visual discrimination task by increasing the effectiveness of misleading, or false, punishment and reward, and decreased response suppression in a variable interval test of punishment sensitivity that employed the same reward and punisher. 5-HT depletion in the OFC also disrupted probabilistic discrimination learning and decreased response suppression.Computational modeling of behavior on the discrimination task showed that the lesions reduced reinforcement sensitivity.A novel, unitary account of the findings in terms of the causal role of 5-HT in the anticipation of both negative and positive motivational outcomes is proposed and discussed in relation to current theories of 5-HT function and our understanding of mood and anxiety disorders.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychology, University of Cambridge, Cambridge CB2 3EB, UK Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge CB2 3EB, UK Current Address: Affective Cognitive Neuroscience Laboratory, Department of Behavioral Neurobiology and Drug Development, Institute of Pharmacology Polish Academy of Sciences, ul Smetna 12, 31-343 Krakow, Poland.

No MeSH data available.


Related in: MedlinePlus