Medial prefrontal cortex determines how stressor controllability affects behavior and dorsal raphe nucleus

Amat, José; Baratta, Michael V.; Paul, Evan D.; Bland, Sondra T.; Watkins, Linda R.; Maier, Steven F.

doi:10.1038/nn1399

Cited by 831 publications

(783 citation statements)

References 37 publications

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“…In keeping with this hypothesis, recent neuroimaging observations suggest that the PFC controls amygdala activity when subjects are presented with negatively valenced stimuli (Ochsner et al, 2002;Phelps and LeDoux, 2005). Based on previous suggestions that 5-HT conveys resilience to adversity (Deakin and Graeff, 1991;Deakin, 1991;Richell et al, 2005), we hypothesize that ATD disrupts PFC-mediated control over subcortical brain regions, such as the amygdala and/or the dorsal raphe nucleus (Amat et al, 2005;Heinz et al, 2005;Pezawas et al, 2005). Such a top-down control failure may interact with reductions in 'background' levels of tonic 5-HT to bias the system toward anticipation of adversity (by increasing prediction errors for future punishment).…”

Section: Discussionsupporting

confidence: 51%

“…The protective bias under baseline, that is the impairment in punishment relative to reward prediction may reflect resilience to aversive signals (Amat et al, 2005;Yehuda et al, 2006; JV Taylor Tavares, L Clark, ML Furey, GB Williams, BJ Sahakian, WC Drevets, unpublished observations). Resilience protects subjects from the detrimental consequences of exposure to adversity and enables them to quickly recover from negative experiences.…”

Section: Discussionmentioning

confidence: 96%

“…In the present task, resilience may have resulted in a paradoxical impairment in the ability to anticipate punishment given specific predictive stimuli. Resilience has been hypothesized to result from cortical, top-down control (from the prefrontal cortex, PFC) over subcortical brain regions that mediate aversive conditioning (eg the amygdala and the dorsal raphe nucleus) (Quirk and Gehlert, 2003;Amat et al, 2005;Pezawas et al, 2005;Urry et al, 2006;Yehuda et al, 2006). In keeping with this hypothesis, recent neuroimaging observations suggest that the PFC controls amygdala activity when subjects are presented with negatively valenced stimuli (Ochsner et al, 2002;Phelps and LeDoux, 2005).…”

Section: Discussionmentioning

confidence: 99%

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Acute Tryptophan Depletion in Healthy Volunteers Enhances Punishment Prediction but Does not Affect Reward Prediction

Cools

Robinson

Sahakian

2007

Neuropsychopharmacol

150

154

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Central serotonin (5-HT) has been implicated in emotional and behavioral control processes for many decades, but its precise contribution is not well understood. We used the acute tryptophan depletion procedure in young healthy volunteers to test the hypothesis that central 5-HT is critical for predicting punishment. An observational reversal-learning task was employed that provided separate measures of punishment and reward prediction. Under baseline, subjects made more prediction errors for punishmentassociated stimuli than for reward-associated stimuli. This bias was abolished after central 5-HT depletion, which enhanced the ability to predict punishment while not affecting reward prediction. The selective potentiation of punishment prediction concurs with recent theorizing, suggesting that central 5-HT carries a prediction error for future punishment, but not for future reward (Daw et al, 2002). Furthermore, the finding highlights the importance of central 5-HT in resilience to adversity and may have implications for a variety of neuropsychiatric disorders including depression and anxiety.

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Section: Discussionsupporting

confidence: 51%

Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Acute Tryptophan Depletion in Healthy Volunteers Enhances Punishment Prediction but Does not Affect Reward Prediction

Cools

Robinson

Sahakian

2007

Neuropsychopharmacol

150

154

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“…Next generation sequencing and canonical pathway analysis were applied to conduct a hypothesis-free, transcriptome-level analysis of effects of CSD on gene expression in specific brain regions. The regions selected for study, ventral hippocampus, medial prefrontal cortex, and central and basolateral nuclei of amygdala, are fundamental to the neurocircuitries underlying the behaviours under study here (Amat et al, 2005;Maren et al, 2013;Moscarello and LeDoux, 2013) as well as the corresponding depression psychopathologies (Capuron et al, 2007;Disner et al, 2011;Mayberg, 2003;Price and Drevets, 2010;Savitz et al, 2013;Sibille et al, 2009;Strigo et al, 2008). 7…”

Section: Introductionmentioning

confidence: 99%

Mouse social stress induces increased fear conditioning, helplessness and fatigue to physical challenge together with markers of altered immune and dopamine function

et al. 2014

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In neuropsychiatry, animal studies demonstrating causal effects of environmental manipulations relevant to human aetiology on behaviours relevant to human psychopathologies are valuable. Such valid models can improve understanding of aetio-pathophysiology and preclinical discovery and development of new treatments. In depression, specific uncontrollable stressful life events are major aetiological factors, and subsequent generalized increases in fearfulness, helplessness and fatigue are core symptoms or features. Here we exposed adult male C57BL/6 mice to 15-day psychosocial stress with loss of social control but minimal physical wounding. One cohort was assessed in a 3-day test paradigm of motor activity, fear conditioning and 2-way avoid-escape behaviour on days 16-18, and a second cohort was assessed in a treadmill fatigue paradigm on days 19 and 29, followed by the 3-day paradigm on days 30-32. All tests used a physical aversive stimulus, namely mild, brief electroshocks. Socially stressed mice displayed decreased motor activity, increased fear acquisition, decreased 2-way avoid-escape responding (increased helplessness) and increased fatigue. They also displayed increased plasma TNF and spleen hypertrophy, and adrenal hypertrophy without hyper-corticoidism. In a third cohort, psychosocial stress effects on brain gene expression were assessed using next generation sequencing. Gene expression was altered in pathways of inflammation and G-protein coupled receptors in prefrontal cortex and amygdala; in the latter, expression of genes important in dopamine function were de-regulated including down-regulated Drd2, Adora2a and Darpp-32. This model can be applied to identify targets for treating psychopathologies such as helplessness or fatigue, and to screen compounds/biologics developed to act at these targets. AbstractIn neuropsychiatric research, animal studies that demonstrate causal effects of environmental manipulations relevant to human aetiological factors on emotional and cognitive behaviours relevant to human psychopathologies are valuable. Such valid animal models can be useful for improved understanding of aetio-pathophysiology and preclinical discovery and development of new treatments. In depression, specific uncontrollable stressful life events are major aetiological factors, and subsequent generalized increases in fearfulness, helplessness and fatigue are core psychopathology symptoms or features. In the present study we exposed adult male C57BL/6 mice to an environmental manipulation of 15-day psychosocial stress with loss of social control but with minimal physical wounding. One cohort of stressed and control mice was assessed in a novel 3-day test paradigm of motor activity, fear conditioning and 2-way avoid-escape behaviour on days 16-18, and a second cohort was assessed in a treadmill fatigue paradigm on days 19 and 29, followed by the 3-day paradigm on days 30-32. All tests used a physical aversive stimulus, namely mild, brief electroshocks. The socially stressed mice displayed dec...

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“…However, depending on the nature of the stress, e.g., psychogenic or metabolic, different neural pathways and neurotransmitter systems may be invoked (e.g., see Herman et al 2005;Sawchenko et al 2000). For instance, recent reports have emphasized a potential role for changes serotonin (5-HT) activity in the prefrontal cortex specifically after uncontrollable versus controllable stress (Amat et al 2005).…”

Section: Introductionmentioning

confidence: 99%

Chronic intermittent cold stress and serotonin depletion induce deficits of reversal learning in an attentional set-shifting test in rats

et al. 2008

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Rationale-Chronic stress perturbs modulatory brain neurotransmitter systems, including serotonin (5-HT), and is a risk factor for psychiatric disorders such as depression. Deficits in cognitive flexibility, reflecting prefrontal cortical dysfunction, are prominent in such disorders. Orbitofrontal cortex (OFC) has been implicated specifically in reversal learning, a form of cognitive flexibility modulated by 5-HT.Objectives-Assess the effects of chronic intermittent cold (CIC) stress, a potent metabolic stressor, on performance of rats in an attentional set shifting test (AST). Assess a possible role for serotonin in CIC-induced deficits, and test the effects of acute serotonin reuptake blockade. Methods-MaleSprague-Dawley rats were exposed to CIC stress (14 days × 6 hr/day at 4 °C) before testing on the AST. In subsequent experiments, brain 5-HT was depleted in naïve rats with para-chlorophenylalanine, or 5-HT release was increased acutely in CIC-stressed rats with citalopram (5 mg/kg, s.c.) given 30 min prior to the first reversal task. Microdialysis was used to assess CICinduced changes in 5-HT release in OFC during testing.Results-CIC-stressed rats exhibited a selective impairment on the first reversal task in the AST. 5-HT depletion induced a similarly selective deficit in reversal learning. The CIC-induced impairment in reversal learning was attenuated by acute 5-HT reuptake blockade. 5-HT release was reduced in OFC of CIC-stressed rats during behavioral testing.Conclusions-The CIC stress-induced impairment of cognitive flexibility may involve dysregulation of 5-HT modulatory function in OFC. Such deficits may thus model relevant symptoms of neuropsychiatric disorders that respond positively to SSRI treatment.

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Medial prefrontal cortex determines how stressor controllability affects behavior and dorsal raphe nucleus

Cited by 831 publications

References 37 publications

Acute Tryptophan Depletion in Healthy Volunteers Enhances Punishment Prediction but Does not Affect Reward Prediction

Acute Tryptophan Depletion in Healthy Volunteers Enhances Punishment Prediction but Does not Affect Reward Prediction

Mouse social stress induces increased fear conditioning, helplessness and fatigue to physical challenge together with markers of altered immune and dopamine function

Chronic intermittent cold stress and serotonin depletion induce deficits of reversal learning in an attentional set-shifting test in rats

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