Medial prefrontal cortex serotonin 1A and 2A receptor binding interacts to predict threat-related amygdala reactivity

Fisher, Patrick M.; Price, Julie C.; Meltzer, Carolyn C.; Moses‐Kolko, Eydie L.; Becker, Carl; Berga, Sarah L.; Hariri, Ahmad R.

doi:10.1186/2045-5380-1-2

Cited by 47 publications

(43 citation statements)

References 78 publications

(96 reference statements)

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“…Based on this co-localization, the inhibitory 5-HT 1A receptor appears to be localized to moderate or 'gate' the capacity of the excitatory 5-HT 2A receptor to facilitate regulation of threat-related amygdala reactivity, as was observed in the previously described study. [77]. Consistent with the co-localization of these receptors, we found that 5-HT 1A binding significantly moderated the negative association between 5-HT 2A binding and threat-related amygdala reactivity, such that mPFC 5-HT 2A binding was significantly inversely correlated with amygdala reactivity, but only when mPFC 5-HT 1A binding was relatively low.…”

Section: (C) Prefrontal 5-ht 2a Receptorsupporting

confidence: 83%

Identifying serotonergic mechanisms underlying the corticolimbic response to threat in humans

Fisher

Hariri

2013

Phil. Trans. R. Soc. B

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A corticolimbic circuit including the amygdala and medial prefrontal cortex (mPFC) plays an important role in regulating sensitivity to threat, which is heightened in mood and anxiety disorders. Serotonin is a potent neuromodulator of this circuit; however, specific serotonergic mechanisms mediating these effects are not fully understood. Recent studies have evaluated molecular mechanisms mediating the effects of serotonin signalling on corticolimbic circuit function using a multi-modal neuroimaging strategy incorporating positron emission tomography and blood oxygen level-dependent functional magnetic resonance imaging. This multi-modal neuroimaging strategy can be integrated with additional techniques including imaging genetics and pharmacological challenge paradigms to more clearly understand how serotonin signalling modulates neural pathways underlying sensitivity to threat. Integrating these methodological approaches offers novel opportunities to identify mechanisms through which serotonin signalling contributes to differences in brain function and behaviour, which in turn can illuminate factors that confer risk for illness and inform the development of more effective treatment strategies.

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Section: (C) Prefrontal 5-ht 2a Receptorsupporting

confidence: 83%

Identifying serotonergic mechanisms underlying the corticolimbic response to threat in humans

Fisher

Hariri

2013

Phil. Trans. R. Soc. B

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“…Some children are born with a higher biological sensitivity to their social context, which is a function both of the greater translational efficiency of the 2A receptor in the AA genotype, and of greater density of the receptors in the prefrontal cortex in the AA genotype (Yildirim andDerksen, 2013: 1274). Higher serotonergic activity in the prefrontal cortex is in turn associated with greater reactivity in the amygdala in response to threatening emotional stimuli (Fisher et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Culture as a mediator of gene-environment interaction: Cultural consonance, childhood adversity, a 2A serotonin receptor polymorphism, and depression in urban Brazil

Dressler¹,

Balieiro²,

Araújo³

et al. 2016

Social Science & Medicine

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Research on gene-environment interaction was facilitated by breakthroughs in molecular biology in the late 20th century, especially in the study of mental health. There is a reliable interaction between candidate genes for depression and childhood adversity in relation to mental health outcomes. The aim of this paper is to explore the role of culture in this process in an urban community in Brazil. The specific cultural factor examined is cultural consonance, or the degree to which individuals are able to successfully incorporate salient cultural models into their own beliefs and behaviors. It was hypothesized that cultural consonance in family life would mediate the interaction of genotype and childhood adversity. In a study of 402 adult Brazilians from diverse socioeconomic backgrounds, conducted from 2011 to 2014, the interaction of reported childhood adversity and a polymorphism in the 2A serotonin receptor was associated with higher depressive symptoms. Further analysis showed that the gene-environment interaction was mediated by cultural consonance in family life, and that these effects were more pronounced in lower social class neighborhoods. The findings reinforce the role of the serotonergic system in the regulation of stress response and learning and memory, and how these processes in turn interact with environmental events and circumstances. Furthermore, these results suggest that gene-environment interaction models should incorporate a wider range of environmental experience and more complex pathways to better understand how genes and the environment combine to influence mental health outcomes.

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“…The serotonergic neurons and 5-HT receptors, specifically the 5-HT 1A and 5-HT 2A receptors, are a key modulator of the PFC-amygdala corticolimbic circuit involved in threat and emotional responses [39]. PTSD-related aberrancies in this serotonergic system may cause inappropriate or incomplete extinction of conditioned fear.…”

Section: Discussionmentioning

confidence: 99%

Predator Exposure/Psychosocial Stress Animal Model of Post-Traumatic Stress Disorder Modulates Neurotransmitters in the Rat Hippocampus and Prefrontal Cortex

et al. 2014

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Post-Traumatic Stress Disorder (PTSD) can develop in response to a traumatic event involving a threat to life. To date, no diagnostic biomarkers have been identified for PTSD. Recent research points toward physiological abnormalities in the hypothalamic-pituitary-adrenal (HPA) axis, sympathoadrenal medullary and immune system that may be implicated in the disorder. The modulation of neurotransmitters is another possible mechanism, but their role in the progression of PTSD is poorly understood. Low serotonin (5-HT) may be a factor, but it may not be the only neurotransmitter affected as modulation affects levels of other neurotransmitters. In this study, we hypothesized the predator exposure/psychosocial stress rodent model of PTSD may alter levels of 5-HT and other neurotransmitters in the rat hippocampus and prefrontal cortex (PFC). Male Sprague-Dawley rats were used in this experiment. We induced PTSD via a predator exposure/psychosocial stress model, whereby rats were placed in a cage with a cat for 1 hour on days 1 and 11 of the 31-day experiment. Rats also received psychosocial stress via daily cage cohort changes. On day 32, the rats were sacrificed and the brains dissected to remove the hippocampus and PFC. Norepinephrine (NE), 5-Hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), dopamine (DA), and 3,4-Dihydroxyphenylacetic acid (DOPAC), and 5-HT levels in the hippocampus and PFC were measured with high-performance liquid chromatography (HPLC). In the hippocampus, 5-HT and HVA were lower, while NE and DOPAC were higher, in the PTSD group vs. controls. In the PFC, only 5-HT was lower, while NE, DA, and DOPAC were higher, in the PTSD group vs. controls. The rate limiting enzymes tyrosine hydroxylase and tryptophan hydroxylase were also examined and confirmed our findings. These results demonstrate that the predator exposure/psychosocial stress model of PTSD produces neurotransmitter changes similar to those seen in human patients and may cause a heightened noradrenergic response.

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Medial prefrontal cortex serotonin 1A and 2A receptor binding interacts to predict threat-related amygdala reactivity

Cited by 47 publications

References 78 publications

Identifying serotonergic mechanisms underlying the corticolimbic response to threat in humans

Identifying serotonergic mechanisms underlying the corticolimbic response to threat in humans

Culture as a mediator of gene-environment interaction: Cultural consonance, childhood adversity, a 2A serotonin receptor polymorphism, and depression in urban Brazil

Predator Exposure/Psychosocial Stress Animal Model of Post-Traumatic Stress Disorder Modulates Neurotransmitters in the Rat Hippocampus and Prefrontal Cortex

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