The contextual brain: implications for fear conditioning, extinction and psychopathology

Maren, Stephen; Phan, K. Luan; Liberzon, Israel

doi:10.1038/nrn3492

Cited by 1,338 publications

(1,366 citation statements)

References 127 publications

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“…Our findings that the pHPC is selectively involved in processing information about environmental cues for which there is a personal history of smoking are consistent with animal studies, in which inactivation of the analogous dorsal HPC has been shown to disrupt expression of psychostimulant CPP (Meyers et al, 2003(Meyers et al, , 2006 and CIR (Fuchs et al, 2005). These animal studies of learned reward are also consistent with human and animal fear conditioning studies, in which the dorsal HPC has been shown to have a central role in context effects (Alvarez et al, 2008;Bast et al, 2003;Maren et al, 2013;Marschner et al, 2008). Interestingly and in contrast with pHPC, aHPC exhibited greater signal in response to smoking, relative to nonsmoking, cues regardless of cue category.…”

Section: Discussionsupporting

confidence: 78%

Hippocampal and Insular Response to Smoking-Related Environments: Neuroimaging Evidence for Drug-Context Effects in Nicotine Dependence

McClernon

Conklin

Kozink

et al. 2015

Neuropsychopharmacol

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Environments associated with prior drug use provoke craving and drug taking, and set the stage for lapse/relapse. Although the neurobehavioral bases of environment-induced drug taking have been investigated with animal models, the influence of drugenvironments on brain function and behavior in clinical populations of substance users is largely unexplored. Adult smokers (n = 40) photographed locations personally associated with smoking (personal smoking environments; PSEs) or personal nonsmoking environment (PNEs). Following 24-h abstinence, participants underwent fMRI scanning while viewing PSEs, PNEs, standard smoking and nonsmoking environments, as well as proximal smoking (eg, lit cigarette) and nonsmoking (eg, pencil) cues. Finally, in two separate sessions following 6-h abstinence they viewed either PSEs or PNEs while cue-induced self-reported craving and smoking behavior were assessed. Viewing PSEs increased blood oxygen level-dependent signal in right posterior hippocampus (pHPC; F 2,685 = 3.74, po0.024) and bilateral insula (left: F 2,685 = 6.87, p = 0.0011; right: F 2,685 = 5.34, p = 0.005). In the laboratory, viewing PSEs, compared with PNEs, was associated with higher craving levels (F 2,180 = 18.32, po0.0001) and greater ad lib smoking (F 1,36 = 5.01, p = 0.032). The effect of PSEs (minus PNEs) on brain activation in right insula was positively correlated with the effect of PSEs (minus PNEs) on number of puffs taken from a cigarette (r = 0.6, p = 0.001). Our data, for the first time in humans, elucidates the neural mechanisms that mediate the effects of real-world drug-associated environments on drug taking behavior under conditions of drug abstinence. These findings establish targets for the development and evaluation of treatments seeking to reduce environment provoked relapse.

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Section: Discussionsupporting

confidence: 78%

Hippocampal and Insular Response to Smoking-Related Environments: Neuroimaging Evidence for Drug-Context Effects in Nicotine Dependence

McClernon

Conklin

Kozink

et al. 2015

Neuropsychopharmacol

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“…Given the observed behavioural effects of CSD, specific brain regions important in the circuitries of fear conditioning (AMYG, vHIPP (Maren et al, 2013)), avoid-escape learning (AMYG, mPFC (Moscarello and LeDoux, 2013)), specific learned helplessness (mPFC (Amat et al, 2005;Pryce et al, 2011)) and fatigue (DeLuca et al, 2009), were investigated in terms of CSD effects on transcriptome-level gene expression, with brains collected at day 17. Importantly, these same regions exhibit altered structure-function-molecular genetic changes in depression e.g.…”

Section: Discussionmentioning

confidence: 99%

“…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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“…Now the current study provides some of the first evidence for the reversal of behavioural effects of stress-induced IDO1-KYN pathway activation. Given the importance of amygdala and hippocampus in fear conditioning (Duvarci and Pare, 2014;LeDoux, 2000;Maren et al, 2013;Wolff et al, 2014) and stress-related psychiatric disorders (Harmer, 2013;Phelps and LeDoux, 2005;Price and Drevets, 2010; 31 Sheline et al, 2001), it is noteworthy that amygdala and vHIPP, together with other brain regions, exhibited increased levels of kynurenines. In healthy humans, LPS induced increased amygdala reactivity to fearful faces (Inagaki et al, 2012).…”

Section: Integrating Current Findings With Existing Evidence For Kyn-mentioning

confidence: 99%

Mouse chronic social stress increases blood and brain kynurenine pathway activity and fear behaviour: Both effects are reversed by inhibition of indoleamine 2,3-dioxygenase

Fuertig

Azzinnari

Bergamini

et al. 2016

Brain, Behavior, and Immunity

118

125

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Psychosocial stress is a major risk factor for mood and anxiety disorders, in which excessive reactivity to aversive events/stimuli is a major psychopathology. In terms of pathophysiology, immuneinflammation is an important candidate, including high blood and brain levels of metabolites belonging to the kynurenine pathway. Animal models are needed to study causality between psychosocial stress, immune-inflammation and hyper-reactivity to aversive stimuli. The present mouse study investigated effects of psychosocial stress as chronic social defeat (CSD) versus control-handling (CON) on: Pavlovian tone-shock fear conditioning, activation of the kynurenine pathway, and efficacy of a specific inhibitor (IDOInh) of the tryptophan-kynurenine catabolizing enzyme indoleamine 2,3-dioxygenase (IDO1), in reversing CSD effects on the kynurenine pathway and fear. CSD led to excessive fear learning and memory, whilst repeated oral escitalopram (antidepressant and anxiolytic) reversed excessive fear memory, indicating predictive validity of the model. CSD led to higher blood levels of TNF-, IFN-, kynurenine (KYN), 3-hydroxykynurenine (3-HK) and kynurenic acid, higher KYN and 3-HK in amygdala and hippocampus. However, CSD was without effect on IDO1 gene or protein expression in spleen, ileum and liver, whilst increasing liver TDO2 gene expression. Nonetheless, oral IDOInh reduced blood and brain levels of KYN and 3-HK in CSD mice to CON levels, and we therefore infer that CSD increases IDO1 activity by increasing its post-translational activation. Furthermore, repeated oral IDOInh reversed excessive fear memory in CSD mice to CON levels. IDOInh reversal of CSD-induced hyper-activity in the kynurenine pathway and fear system contributes significantly to the evidence for a causal pathway between psychosocial stress, immune-inflammation and the excessive fearfulness that is a major psychopathology in stress-related neuropsychiatric disorders. ABSTRACTPsychosocial stress is a major risk factor for mood and anxiety disorders, in which excessive reactivity to aversive events/stimuli is a major psychopathology. In terms of pathophysiology, immune-inflammation is an important candidate, including high blood and brain levels of metabolites belonging to the kynurenine pathway. Animal models are needed to study causality between psychosocial stress, immune-inflammation and hyper-reactivity 3-HK in CSD mice to CON levels, and we therefore infer that CSD increases IDO1 activity by increasing its post-translational activation. Furthermore, repeated oral IDOInh reversed excessive fear memory in CSD mice to CON levels. IDOInh reversal of CSD-induced hyperactivity in the kynurenine pathway and fear system contributes significantly to the evidence for a causal pathway between psychosocial stress, immune-inflammation and the excessive fearfulness that is a major psychopathology in stress-related neuropsychiatric disorders.3

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The contextual brain: implications for fear conditioning, extinction and psychopathology

Cited by 1,338 publications

References 127 publications

Hippocampal and Insular Response to Smoking-Related Environments: Neuroimaging Evidence for Drug-Context Effects in Nicotine Dependence

Hippocampal and Insular Response to Smoking-Related Environments: Neuroimaging Evidence for Drug-Context Effects in Nicotine Dependence

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

Mouse chronic social stress increases blood and brain kynurenine pathway activity and fear behaviour: Both effects are reversed by inhibition of indoleamine 2,3-dioxygenase

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