TY  - JOUR
A1  - Waider, J
A1  - Popp, S
A1  - Lange, MD
A1  - Kern, R
A1  - Kolter, JF
A1  - Kobler, J
A1  - Donner, NC
A1  - Lowe, KR
A1  - Malzbender, JH
A1  - Brazell, CJ
A1  - Arnold, MR
A1  - Aboagye, B
A1  - Schmitt-Böhrer, A
A1  - Lowry, CA
A1  - Pape, HC
A1  - Lesch, KP
T1  - Genetically driven brain serotonin deficiency facilitates panic-like escape behavior in mice
JF  - Translational Psychiatry
N2  - 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.
KW  - anxiety
KW  - stress
KW  - serotonin
KW  - genetics
KW  - mice
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-170239
VL  - 7
IS  - e1246
ER  - 
TY  - JOUR
A1  - Gutknecht, Lise
A1  - Popp, Sandy
A1  - Waider, Jonas
A1  - Sommerlandt, Frank M. J.
A1  - Göppner, Corinna
A1  - Post, Antonia
A1  - Reif, Andreas
A1  - van den Hove, Daniel
A1  - Strekalova, Tatyana
A1  - Schmitt, Angelika
A1  - Colaςo, Maria B. N.
A1  - Sommer, Claudia
A1  - Palme, Rupert
A1  - Lesch, Klaus-Peter
T1  - Interaction of brain 5-HT synthesis deficiency, chronic stress and sex differentially impact emotional behavior in Tph2 knockout mice
JF  - Psychopharmacology
N2  - Rationale
While brain serotonin (5-HT) function is implicated in gene-by-environment interaction (GxE) impacting the vulnerability-resilience continuum in neuropsychiatric disorders, it remains elusive how the interplay of altered 5-HT synthesis and environmental stressors is linked to failure in emotion regulation.

Objective
Here, we investigated the effect of constitutively impaired 5-HT synthesis on behavioral and neuroendocrine responses to unpredictable chronic mild stress (CMS) using a mouse model of brain 5-HT deficiency resulting from targeted inactivation of the tryptophan hydroxylase-2 (Tph2) gene.

Results
Locomotor activity and anxiety- and depression-like behavior as well as conditioned fear responses were differentially affected by Tph2 genotype, sex, and CMS. Tph2 null mutants (Tph2\(^{−/−}\)) displayed increased general metabolism, marginally reduced anxiety- and depression-like behavior but strikingly increased conditioned fear responses. Behavioral modifications were associated with sex-specific hypothalamic-pituitary-adrenocortical (HPA) system alterations as indicated by plasma corticosterone and fecal corticosterone metabolite concentrations. Tph2\(^{−/−}\) males displayed increased impulsivity and high aggressiveness. Tph2\(^{−/−}\) females displayed greater emotional reactivity to aversive conditions as reflected by changes in behaviors at baseline including increased freezing and decreased locomotion in novel environments. However, both Tph2\(^{−/−}\) male and female mice were resilient to CMS-induced hyperlocomotion, while CMS intensified conditioned fear responses in a GxE-dependent manner.

Conclusions
Our results indicate that 5-HT mediates behavioral responses to environmental adversity by facilitating the encoding of stress effects leading to increased vulnerability for negative emotionality.
KW  - Serotonin
KW  - Tryptophan hydroxylase-2 (Tph2)
KW  - chronic stress
KW  - gene-by-environment interaction
KW  - anxiety
KW  - fear
KW  - depression
KW  - aggression
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-154586
VL  - 232
SP  - 2429
EP  - 2441
ER  -