Link to the University of Pittsburgh Homepage
Link to the University Library System Homepage Link to the Contact Us Form

In vivo assessment of serotonergic signaling pathways underlying the corticolimbic response to threat in humans

Fisher, Patrick MacDonald (2010) In vivo assessment of serotonergic signaling pathways underlying the corticolimbic response to threat in humans. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

Primary Text

Download (1MB) | Preview


A corticolimbic circuit including the amygdala and medial prefrontal cortex (mPFC) affects sensitivity to threat, related aspects of personality and risk for psychopathology. Serotonin (5‐HT) is a potent neuromodulator of this circuit, however, 5‐HT receptors mediating these effects and genetic sources of variability in 5‐HT receptor availability are not understood. We determined the association between 5‐HT1A and 5‐HT2A binding and the response to threat within this corticolimbic circuit using a multimodal neuroimaging strategy in humans in vivo. Corticolimbic circuit function was assessed with a threat‐related faces matching paradigm using functional magnetic resonance imaging (fMRI). Regional 5‐HT1A and 5‐HT2A binding was assessed with [11C]WAY100635 and [18F]altanserin PET, respectively. We evaluated the association between receptor binding and common polymorphisms (rs6295, rs6311 and 5‐HTTLPR) in 5‐HT related genes.In Study 1 we found that 5‐HT1A binding within the dorsal raphe nucleus was inversely associated with threat‐related amygdala reactivity. This is consistent with 5‐HT1A autoreceptors negatively regulating 5‐HT release, which within the amygdalapotentiates its response to threat. In Study 2 we found that mPFC 5‐HT2A binding was inversely associated with threat‐related amygdala reactivity and positively associated with amygdala habituation and amygdala‐mPFC functional connectivity. In Study 3 we found that mPFC 5‐HT1A binding significantly moderated the inverse association between mPFC 5‐HT2A binding and amygdala reactivity.These findings are consistent with the co‐localization of 5‐HT1A and 5‐HT2A on glutamatergic neurons within mPFC indicating the 5‐HT2A receptor is localized to facilitate regulation of the amygdala and the 5‐HT1A receptor is localized to moderate its effects within mPFC. In Study 4 we found that 5‐HTTLPR genotype predicted 5‐HT1A and 5‐HT2A binding in brain regions within this circuit such that the S and LG alleles were associated with reduced 5‐HT1A and 5‐HT2A binding.These findings provide novel insight into mechanisms that mediate the effects of 5‐HT signaling on the response to threat of a key corticolimbic circuit in humans. Our findings indicate that 5‐HT1A and 5‐HT2A receptors contribute significantly to threat‐related corticolimbic circuit function in humans. Furthermore, the 5‐HTTLPR may contribute to individual variability in neural and behavioral sensitivity to threat by biasing 5‐HT1A and 5‐HT2A availability.


Social Networking:
Share |


Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Fisher, Patrick MacDonaldpmf6@pitt.eduPMF6
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairBradberry, Charles Wbradberr@pitt.eduBRADBERR
Committee MemberHariri, Ahmad
Committee MemberHolmes,
Committee MemberSibille, Etienne
Committee MemberPrice, Julie
Committee MemberGianaros, Peter
Date: 14 December 2010
Date Type: Completion
Defense Date: 19 November 2010
Approval Date: 14 December 2010
Submission Date: 8 December 2010
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Neurobiology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: amygdala; BOLD fMRI; multi-modal; PET; serotonin; corticolimbic; threat
Other ID:, etd-12082010-161224
Date Deposited: 10 Nov 2011 20:09
Last Modified: 15 Nov 2016 13:53


Monthly Views for the past 3 years

Plum Analytics

Actions (login required)

View Item View Item