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

Fisher PM, Price JC, Meltzer CC, Moses-Kolko EL, Becker C, Berga SL, Hariri AR - Biol Mood Anxiety Disord (2011)

Bottom Line: The colocalization of 5-HT1A and 5-HT2A receptors on mPFC glutamatergic neurons suggests that their functional interactions may mediate 5-HT effects on this circuit through top-down regulation of amygdala reactivity.Specifically, mPFC 5-HT2A binding was significantly inversely correlated with amygdala reactivity only when mPFC 5-HT1A binding was relatively low.The effect of the interaction between mPFC 5-HT1A and 5-HT2A binding and amygdala reactivity is consistent with the colocalization of these receptors on glutamatergic neurons in the mPFC.

View Article: PubMed Central - HTML - PubMed

Affiliation: Center for Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA. patrick.fisher@gmail.com.

ABSTRACT

Background: The amygdala and medial prefrontal cortex (mPFC) comprise a key corticolimbic circuit that helps shape individual differences in sensitivity to threat and the related risk for psychopathology. Although serotonin (5-HT) is known to be a key modulator of this circuit, the specific receptors mediating this modulation are unclear. The colocalization of 5-HT1A and 5-HT2A receptors on mPFC glutamatergic neurons suggests that their functional interactions may mediate 5-HT effects on this circuit through top-down regulation of amygdala reactivity. Using a multimodal neuroimaging strategy in 39 healthy volunteers, we determined whether threat-related amygdala reactivity, assessed with blood oxygen level-dependent functional magnetic resonance imaging, was significantly predicted by the interaction between mPFC 5-HT1A and 5-HT2A receptor levels, assessed by positron emission tomography.

Results: 5-HT1A binding in the mPFC significantly moderated an inverse correlation between mPFC 5-HT2A binding and threat-related amygdala reactivity. Specifically, mPFC 5-HT2A binding was significantly inversely correlated with amygdala reactivity only when mPFC 5-HT1A binding was relatively low.

Conclusions: Our findings provide evidence that 5-HT1A and 5-HT2A receptors interact to shape serotonergic modulation of a functional circuit between the amygdala and mPFC. The effect of the interaction between mPFC 5-HT1A and 5-HT2A binding and amygdala reactivity is consistent with the colocalization of these receptors on glutamatergic neurons in the mPFC.

No MeSH data available.


Related in: MedlinePlus

Schematic illustrating mPFC projection neurons that act to regulate amygdala response to threat-related stimuli. 5-HT1A and 5-HT2A in mPFC are positioned to modulate this circuitry by biasing excitability of these mPFC neurons, thereby affecting the capacity to regulate amygdala reactivity. 5-HT = serotonin; mPFC = medial prefrontal cortex; CeL = lateral central nucleus of the amygdala; CeM = medial central nucleus of the amygdala; ITC = intercalated cells.
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Figure 4: Schematic illustrating mPFC projection neurons that act to regulate amygdala response to threat-related stimuli. 5-HT1A and 5-HT2A in mPFC are positioned to modulate this circuitry by biasing excitability of these mPFC neurons, thereby affecting the capacity to regulate amygdala reactivity. 5-HT = serotonin; mPFC = medial prefrontal cortex; CeL = lateral central nucleus of the amygdala; CeM = medial central nucleus of the amygdala; ITC = intercalated cells.

Mentions: These findings are remarkably consistent with the predominant anatomical localization of 5-HT1A and 5-HT2A receptors to the axon hillock and apical dendrites of prefrontal glutamatergic pyramidal neurons, respectively. Given its principal localization on apical dendrites proximal to the soma, the excitatory 5-HT2A receptor is situated to mediate 5-HT depolarization of prefrontal glutamatergic neurons. By contrast, the localization of the inhibitory 5-HT1A receptor to the initial portion of the axon hillock positions it to mediate 5-HT hyperpolarization of these same neurons. Considering the high coexpression of 5-HT1A and 5-HT2A receptors on most prefrontal glutamatergic neurons, this arrangement suggests that the 5-HT1A receptor can effectively (and negatively) gate the depolarizing effects of the 5-HT2A receptors on prefrontal output. In turn, such serotonergic modulation of prefrontal neuron output may shape the capacity of this circuitry to exert an inhibitory effect on amygdala reactivity (Figure 4). We interpret our current findings of an inverse correlation of mPFC 5-HT2A binding with amygdala reactivity but only at mean and low levels of 5-HT1A binding as reflecting the coexpression of these receptors and their role in mediating serotonergic modulation of this circuitry. The absence of a main effect of mPFC 5-HT1A binding on amygdala reactivity is further consistent with this gating model, with the capacity for mPFC 5-HT1A receptors to modulate threat-related amygdala reactivity being dependent upon additional signaling mechanisms such as, but not necessarily limited to, mPFC 5-HT2A receptors. Although interpretation of our findings is consistent with the previously described localization of the 5-HT1A and 5-HT2A receptors within prefrontal cortex, our results reflect only statistical correlation, and do not establish causality. Future studies aimed at establishing a causal link between 5-HT1A and 5-HT2A receptor interactions on prefrontal pyramidal neuron excitability and the response of the amygdala in the context of threat are necessary.


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

Fisher PM, Price JC, Meltzer CC, Moses-Kolko EL, Becker C, Berga SL, Hariri AR - Biol Mood Anxiety Disord (2011)

Schematic illustrating mPFC projection neurons that act to regulate amygdala response to threat-related stimuli. 5-HT1A and 5-HT2A in mPFC are positioned to modulate this circuitry by biasing excitability of these mPFC neurons, thereby affecting the capacity to regulate amygdala reactivity. 5-HT = serotonin; mPFC = medial prefrontal cortex; CeL = lateral central nucleus of the amygdala; CeM = medial central nucleus of the amygdala; ITC = intercalated cells.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3377121&req=5

Figure 4: Schematic illustrating mPFC projection neurons that act to regulate amygdala response to threat-related stimuli. 5-HT1A and 5-HT2A in mPFC are positioned to modulate this circuitry by biasing excitability of these mPFC neurons, thereby affecting the capacity to regulate amygdala reactivity. 5-HT = serotonin; mPFC = medial prefrontal cortex; CeL = lateral central nucleus of the amygdala; CeM = medial central nucleus of the amygdala; ITC = intercalated cells.
Mentions: These findings are remarkably consistent with the predominant anatomical localization of 5-HT1A and 5-HT2A receptors to the axon hillock and apical dendrites of prefrontal glutamatergic pyramidal neurons, respectively. Given its principal localization on apical dendrites proximal to the soma, the excitatory 5-HT2A receptor is situated to mediate 5-HT depolarization of prefrontal glutamatergic neurons. By contrast, the localization of the inhibitory 5-HT1A receptor to the initial portion of the axon hillock positions it to mediate 5-HT hyperpolarization of these same neurons. Considering the high coexpression of 5-HT1A and 5-HT2A receptors on most prefrontal glutamatergic neurons, this arrangement suggests that the 5-HT1A receptor can effectively (and negatively) gate the depolarizing effects of the 5-HT2A receptors on prefrontal output. In turn, such serotonergic modulation of prefrontal neuron output may shape the capacity of this circuitry to exert an inhibitory effect on amygdala reactivity (Figure 4). We interpret our current findings of an inverse correlation of mPFC 5-HT2A binding with amygdala reactivity but only at mean and low levels of 5-HT1A binding as reflecting the coexpression of these receptors and their role in mediating serotonergic modulation of this circuitry. The absence of a main effect of mPFC 5-HT1A binding on amygdala reactivity is further consistent with this gating model, with the capacity for mPFC 5-HT1A receptors to modulate threat-related amygdala reactivity being dependent upon additional signaling mechanisms such as, but not necessarily limited to, mPFC 5-HT2A receptors. Although interpretation of our findings is consistent with the previously described localization of the 5-HT1A and 5-HT2A receptors within prefrontal cortex, our results reflect only statistical correlation, and do not establish causality. Future studies aimed at establishing a causal link between 5-HT1A and 5-HT2A receptor interactions on prefrontal pyramidal neuron excitability and the response of the amygdala in the context of threat are necessary.

Bottom Line: The colocalization of 5-HT1A and 5-HT2A receptors on mPFC glutamatergic neurons suggests that their functional interactions may mediate 5-HT effects on this circuit through top-down regulation of amygdala reactivity.Specifically, mPFC 5-HT2A binding was significantly inversely correlated with amygdala reactivity only when mPFC 5-HT1A binding was relatively low.The effect of the interaction between mPFC 5-HT1A and 5-HT2A binding and amygdala reactivity is consistent with the colocalization of these receptors on glutamatergic neurons in the mPFC.

View Article: PubMed Central - HTML - PubMed

Affiliation: Center for Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA. patrick.fisher@gmail.com.

ABSTRACT

Background: The amygdala and medial prefrontal cortex (mPFC) comprise a key corticolimbic circuit that helps shape individual differences in sensitivity to threat and the related risk for psychopathology. Although serotonin (5-HT) is known to be a key modulator of this circuit, the specific receptors mediating this modulation are unclear. The colocalization of 5-HT1A and 5-HT2A receptors on mPFC glutamatergic neurons suggests that their functional interactions may mediate 5-HT effects on this circuit through top-down regulation of amygdala reactivity. Using a multimodal neuroimaging strategy in 39 healthy volunteers, we determined whether threat-related amygdala reactivity, assessed with blood oxygen level-dependent functional magnetic resonance imaging, was significantly predicted by the interaction between mPFC 5-HT1A and 5-HT2A receptor levels, assessed by positron emission tomography.

Results: 5-HT1A binding in the mPFC significantly moderated an inverse correlation between mPFC 5-HT2A binding and threat-related amygdala reactivity. Specifically, mPFC 5-HT2A binding was significantly inversely correlated with amygdala reactivity only when mPFC 5-HT1A binding was relatively low.

Conclusions: Our findings provide evidence that 5-HT1A and 5-HT2A receptors interact to shape serotonergic modulation of a functional circuit between the amygdala and mPFC. The effect of the interaction between mPFC 5-HT1A and 5-HT2A binding and amygdala reactivity is consistent with the colocalization of these receptors on glutamatergic neurons in the mPFC.

No MeSH data available.


Related in: MedlinePlus