Reduced Serotonin Transporter Availability Decreases Prefrontal Control of the Amygdala

Abstract

After a threatening event, the risk of developing social psychopathologies is increased in short-allele (s) carriers of the serotonin transporter gene. The amygdala becomes overresponsive to emotional stimuli, an effect that could be driven by local hypersensitivity or by reduced prefrontal regulation. This study distinguishes between these two hypotheses by using dynamic causal modeling of fMRI data acquired in a preselected cohort of human s-carriers and homozygous long-allele carriers. Increased amygdala activity in s-carriers originates from reduced prefrontal inhibitory regulation when social emotional behavior needs to be controlled, suggesting a mechanism for increased vulnerability to psychopathologies.

Distinct Effects of Repeated Restraint Stress on Basolateral Amygdala Neuronal Membrane Properties in Resilient Adolescent and Adult Rats

“…Several genetically distinct rodent lines are differentially resistant/vulnerable to the effects of stress (Razzoli et al, 2011;Savignac et al, 2011;Camp et al, 2012;Fuchsl et al, 2014). The amygdala circuits that regulate fear and anxiety are hypothesized to be an important target of some of these genetic differences (Hariri et al, 2002;Smolka et al, 2005;Jovanovic and Ressler, 2010;Mozhui et al, 2010;Alexander et al, 2012;Hermann et al, 2012;White et al, 2012;Rogers et al, 2013;Volman et al, 2013). Many of these transmitter systems listed above directly or indirectly modulate the same signaling cascades that modify SK channel function (Pedarzani and Storm, 1995;Pedarzani et al, 1998;Lee et al, 2003;Bildl et al, 2004;Ren et al, 2006;Maingret et al, 2008), leading to changes in the excitability of amygdala neurons.…”

Monoamine-Sensitive Developmental Periods Impacting Adult Emotional and Cognitive Behaviors

“…Consistent with these behavioral data, brain imaging studies demonstrate an association between the s allele and higher levels of amygdala activation in response to fearful stimuli (Furmark et al, 2004;Hariri et al, 2002;Kobiella et al, 2011;Murphy et al, 2013;Scharinger et al, 2010), reduced grey matter volumes in the dorsolateral PFC, amygdala and the HPC (Atmaca et al, 2011;Frodl et al, 2008;Kobiella et al, 2011;Pezawas et al, 2005), microstructural changes in the uncinate fasciclus, a white matter tract connecting limbic and frontal areas, including the amygdala and anterior cingulate cortex (Pacheco et al, 2009), and decreased coupling of the amygdala-anterior cingulate circuit (Heinz et al, 2005;Lemogne et al, 2011;Pezawas et al, 2005;Roiser et al, 2009;Shah et al, 2009;Volman et al, 2013). Importantly, functional coupling between the anterior cingulate cortex and the amygdala is correlated with trait anxiety (Hahn et al, 2011;Prater et al, 2013).…”

Top-Down Control of Serotonin Systems by the Prefrontal Cortex: A Path toward Restored Socioemotional Function in Depression

“…In humans, depleting 5-HT by reducing the dietary source of its precursor L-tryptophan, or boosting 5-HT via administration of selective serotonin reuptake inhibitors has respectively been shown to induce negative and positive shifts in social perception (Table 2). 68–73 Variants of genes that control 5-HT synaptic availability, such as the serotonin transporter (5-HTT) 74–76 and the 5-HT synthesizing enzyme tryptophan hydroxylase (TPH) 77, 78 have also been associated with alterations in socioemotional behaviors, such as differential sensitivity to the rewarding properties of social cues or reactivity to unfairness. 79 Differential corticolimbic responses to these cues have also been reported in carriers of these polymorphisms.…”

“…79 Differential corticolimbic responses to these cues have also been reported in carriers of these polymorphisms. 76–78 The effect of 5-HT on social behavior is likely to be mediated in part by its effects on neurons from the frontal cortex, as this area is one of the most enriched in serotonergic axons and 5-HT receptors. 5-HT modulates the excitability of cortical neurons and their discharge rate through the activation of several receptor subtypes, of which the 5-HT1 A , 5-HT1 B , 5-HT2 A , and 5-HT3 play major roles.…”