Presynaptic Serotoninergic Regulation of Emotional Processing: A Multimodal Brain Imaging Study
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Background The amygdala is a central node in the brain network that processes aversive emotions and is extensively innervated by dorsal raphe nucleus (DRN) serotonin (5-hydroxytryptamine [5-HT]) neurons. Alterations in DRN 5-HT1A receptor availability cause phenotypes characterized by fearful behavior in preclinical models. However, it is unknown whether 5-HT1A receptor availability is linked specifically to the processing of aversive emotions in humans or whether it modulates connectivity in brain networks involved in emotion processing. To answer this question, we investigated the relationship between DRN 5-HT1A receptor availability and amygdala reactivity to aversive emotion and functional connectivity within the amygdala-cortical network.Methods We studied 15 healthy human participants who underwent positron emission tomography scanning with [(11)C]CUMI-101, a 5-HT1A partial agonist radioligand, and functional magnetic resonance imaging of brain responses during an incidental emotion processing task including happy, fearful, and neutral faces. Regional estimates of 5-HT1A receptor binding potential (nondisplaceable) were obtained by calculating total volumes of distribution for presynaptic DRN and amygdala. Connectivity between the amygdala and corticolimbic areas was assessed using psychophysiologic interaction analysis with the amygdala as the seed region.Results Analysis of the fear versus neutral contrast revealed a significant negative correlation between amygdala response and DRN binding potential (nondisplaceable) (r = -.87, p < .001). Availability of DRN 5-HT1A receptors positively correlated with amygdala connectivity with middle frontal gyrus, anterior cingulate cortex, bilateral precuneus, and left supramarginal gyrus for fearful (relative to neutral) faces.Conclusions Our data show that DRN 5-HT1A receptor availability is linked specifically to the processing of aversive emotions in the amygdala and the modulation of amygdala-cortical connectivity.
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There is a positive correlation between DRN 5-HT1A availability and amygdala connectivity with the prefrontal-precuneus cortical network.
“together with a positive correlation between DRN 5-HT1A availability and amygdala connectivity with the prefrontal-precuneus (ACC, middle frontal gyrus, supramarginal gyrus and precuneus) cortical network.”
From Cognitive neuropsychological theory of antidepressant action: a modern-day approach to depression and its treatment (2021) · cites this paper as Selvaraj et al. 2015
There is a negative correlation between DRN 5HT1A receptor availability and amygdala response to fearful facial expressions.
“A negative correlation between DRN 5HT1A receptors availability and amygdala response to fearful facial expressions was shown (Fisher et al. 2006, Selvaraj et al. 2015)”
From Cognitive neuropsychological theory of antidepressant action: a modern-day approach to depression and its treatment (2021) · cites this paper as Selvaraj et al. 2015
SSRIs seem to act primarily on the negative aspects of emotional processing, while NRIs primarily increase its positive aspects.
“SSRIs seem to act primarily on the ‘negative’ aspects of emotional processing (e.g. decrease fear recognition and normalize exaggerated amygdala response to fearful faces), while NRIs are thought to primarily increase its ‘positive’ aspects (e.g. increase response to rewarding cues).”
From Cognitive neuropsychological theory of antidepressant action: a modern-day approach to depression and its treatment (2021) · cites this paper as Selvaraj et al. 2015
5-HT dysfunction primarily results in production of negative affect (sadness), and NA and DA dysfunction in loss of positive affect and anhedonia.
“This is in line with 5-HT dysfunction suggested to primarily result in the production of negative affect, i.e. sadness, and that of NA and DA, in a loss of positive affect and anhedonia (Pringle and Harmer 2015, Selvaraj et al. 2015).”
From Cognitive neuropsychological theory of antidepressant action: a modern-day approach to depression and its treatment (2021) · cites this paper as Selvaraj et al. 2015
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References 71 · Cited by 29
- Authors
- Selvaraj, S., Mouchlianitis, E., Faulkner, P., Turkheimer, F., Cowen, P. J., Roiser, J. P., & Howes, O.
- Affiliations
- Hammersmith Hospital (GB)
- University College London (GB)
- King's College London (GB)
- University of Oxford (GB)
- Corresponding author
- Selvaraj, Sudhakar
- ORCID
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2015-10
- Volume
- 78
- Issue
- 8
- Pages
- 563-571
- ISSN
- 0006-3223 (ISSN-L)
- PMC
- PMC5322825
- OpenAlex
- W2121684719
- Cited by
- 29
- References
- 71
- Citations by year
- 2025: 3 · 2024: 1 · 2023: 3 · 2022: 6 · 2021: 2 · 2020: 3 · 2019: 1 · 2018: 2 · 2017: 3 · 2016: 2 · 2015: 2 · 2014: 1
- FWCI
- 1.22
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Research Portal (King's College London) (submittedVersion)
- Funders
- Academy of Medical Sciences (AMS-SGCL6-Selvaraj)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural and Behavioral Psychology Studies
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Keywords
- dorsal raphe nucleus, amygdala, fear, facial emotion recognition, anterior cingulate cortex, precuneus, supramarginal gyrus
- MeSH terms
- Adult, Amygdala, Emotions, Female, Frontal Lobe, Gyrus Cinguli, Humans, Image Processing, Computer-Assisted, Magnetic Resonance Imaging, Male, Middle Aged, Parietal Lobe, Psychophysiology, Receptor, Serotonin, 5-HT1A, Positron-Emission Tomography
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