Abstract
Multiple lines of evidence implicate brain serotonin (5-hydroxytryptamine; 5-HT) system dysfunction in the pathophysiology of stressor-related and anxiety disorders. Here we investigate the influence of constitutively deficient 5-HT synthesis on stressor-related anxiety-like behaviors using Tryptophan hydroxylase 2 (Tph2) mutant mice. Functional assessment of c-Fos after associated foot shock, electrophysiological recordings of GABAergic synaptic transmission, differential expression of the Slc6a4 gene in serotonergic neurons were combined with locomotor and anxiety-like measurements in different contextual settings. Our findings indicate that constitutive Tph2 inactivation and consequential lack of 5-HT synthesis in Tph2 null mutant mice (Tph2−/−) results in increased freezing to associated foot shock and a differential c-Fos activity pattern in the basolateral complex of the amygdala. This is accompanied by altered GABAergic transmission as observed by recordings of inhibitory postsynaptic currents on principal neurons in the basolateral nucleus, which may explain increased fear associated with hyperlocomotion and escape-like responses in aversive inescapable contexts. In contrast, lifelong 5-HT deficiency as observed in Tph2 heterozygous mice (Tph+/−) is able to be compensated through reduced GABAergic transmission in the basolateral nucleus of the amygdala based on Slc6a4 mRNA upregulation in subdivisions of dorsal raphe neurons. This results in increased activity of the basolateral nucleus of the amygdala due to associated foot shock. In conclusion, our results reflect characteristic syndromal dimensions of panic disorder and agoraphobia. Thus, constitutive lack of 5-HT synthesis influence the risk for anxiety- and stressor-related disorders including panic disorder and comorbid agoraphobia through the absence of GABAergic-dependent compensatory mechanisms in the basolateral nucleus of the amygdala.
Highlights
Anxiety- and stressor-related disorders represent the most common psychiatric disorders in the European Union with a 12-month prevalence estimate of 14 and 2% of the population.[1]The neural mechanisms underlying the manifestation of anxiety disorders are complex
The motor response evoked by foot shocks (FSs) was higher in FS+ mice compared to the FS − group (F(1,29) = 98.42, P o 0.001; Figure 1c) and positively correlated with post-shock freezing (r2 = 0.521, P o 0.001; Figure 1d)
Split-group analyses detected significantly elevated FS-evoked motor response (F(2,21) = 3.48, P = 0.05; Figure 1c) in FS+ Tryptophan hydroxylase 2 (Tph2)− / − mice compared to FS+ Tph2+/+ littermates of the same group
Summary
Anxiety- and stressor-related disorders represent the most common psychiatric disorders in the European Union with a 12-month prevalence estimate of 14 and 2% of the population.[1]The neural mechanisms underlying the manifestation of anxiety disorders are complex. Fear is an acute reaction to a real or perceived immediate threat[6] and it quickly fades as soon as the threat is removed.[7] In rodents, acute fear involves the preparation of the animal for fight-or-flight responses The activation of this behavioral system manifests in complete motionlessness known as freezing.[8,9] The brain serotonin (5-hydroxytryptamine; 5-HT) system is thought to play an essential role in the control of anxiety-, fear- and panic-like responses in rodents.[10] In humans, several lines of evidence link alterations in 5-HT signaling to panic attacks through a defensive behavioral system activated by acute threats.[11] Panic attacks represent abrupt surges of intense fear or extreme discomfort that reach a peak within minutes. This has been linked recently to alterations in the GABAergic system.[16]
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