TY  - JOUR
A1  - Strekalova, Tatyana
A1  - Pavlov, Dmitrii
A1  - Trofimov, Alexander
A1  - Anthony, Daniel C.
A1  - Svistunov, Andrei
A1  - Proshin, Andrey
A1  - Umriukhin, Aleksei
A1  - Lyundup, Alexei
A1  - Lesch, Klaus-Peter
A1  - Cespuglio, Raymond
T1  - Hippocampal over-expression of cyclooxygenase-2 (COX-2) is associated with susceptibility to stress-induced anhedonia in mice
JF  - International Journal of Molecular Sciences
N2  - The phenomenon of individual variability in susceptibility/resilience to stress and depression, in which the hippocampus plays a pivotal role, is attracting increasing attention. We investigated the potential role of hippocampal cyclooxygenase-2 (COX-2), which regulates plasticity, neuroimmune function, and stress responses that are all linked to this risk dichotomy. We used a four-week-long chronic mild stress (CMS) paradigm, in which mice could be stratified according to their susceptibility/resilience to anhedonia, a key feature of depression, to investigate hippocampal expression of COX-2, a marker of microglial activation Iba-1, and the proliferation marker Ki67. Rat exposure, social defeat, restraints, and tail suspension were used as stressors. We compared the effects of treatment with either the selective COX-2 inhibitor celecoxib (30 mg/kg/day) or citalopram (15 mg/kg/day). For the celecoxib and vehicle-treated mice, the Porsolt test was used. Anhedonic (susceptible) but not non-anhedonic (resilient) animals exhibited elevated COX-2 mRNA levels, increased numbers of COX-2 and Iba-1-positive cells in the dentate gyrus and the CA1 area, and decreased numbers of Ki67-positive cells in the subgranular zone of the hippocampus. Drug treatment decreased the percentage of anhedonic mice, normalized swimming activity, reduced behavioral despair, and improved conditioned fear memory. Hippocampal over-expression of COX-2 is associated with susceptibility to stress-induced anhedonia, and its pharmacological inhibition with celecoxib has antidepressant effects that are similar in size to those of citalopram.
KW  - major depression
KW  - inducible cyclooxygenase-2 (COX-2)
KW  - hippocampus
KW  - anhedonia
KW  - chronic stress
KW  - stress resilience
KW  - fear conditioning
KW  - celecoxib
KW  - citalopram
KW  - mouse
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-284056
SN  - 1422-0067
VL  - 23
IS  - 4
ER  - 
TY  - JOUR
A1  - Svirin, Evgeniy
A1  - Veniaminova, Ekaterina
A1  - Costa-Nunes, João Pedro
A1  - Gorlova, Anna
A1  - Umriukhin, Aleksei
A1  - Kalueff, Allan V.
A1  - Proshin, Andrey
A1  - Anthony, Daniel C.
A1  - Nedorubov, Andrey
A1  - Tse, Anna Chung Kwan
A1  - Walitza, Susanne
A1  - Lim, Lee Wei
A1  - Lesch, Klaus-Peter
A1  - Strekalova, Tatyana
T1  - Predation stress causes excessive aggression in female mice with partial genetic inactivation of tryptophan hydroxylase-2: evidence for altered myelination-related processes
JF  - Cells
N2  - The interaction between brain serotonin (5-HT) deficiency and environmental adversity may predispose females to excessive aggression. Specifically, complete inactivation of the gene encoding tryptophan hydroxylase-2 (Tph2) results in the absence of neuronal 5-HT synthesis and excessive aggressiveness in both male and female null mutant (Tph2\(^{−/−}\)) mice. In heterozygous male mice (Tph2\(^{+/−}\)), there is a moderate reduction in brain 5-HT levels, and when they are exposed to stress, they exhibit increased aggression. Here, we exposed female Tph2\(^{+/−}\) mice to a five-day rat predation stress paradigm and assessed their emotionality and social interaction/aggression-like behaviors. Tph2\(^{+/−}\) females exhibited excessive aggression and increased dominant behavior. Stressed mutants displayed altered gene expression of the 5-HT receptors Htr1a and Htr2a, glycogen synthase kinase-3 β (GSK-3β), and c-fos as well as myelination-related transcripts in the prefrontal cortex: myelin basic protein (Mbp), proteolipid protein 1 (Plp1), myelin-associated glycoprotein (Mag), and myelin oligodendrocyte glycoprotein (Mog). The expression of the plasticity markers synaptophysin (Syp) and cAMP response element binding protein (Creb), but not AMPA receptor subunit A2 (GluA2), were affected by genotype. Moreover, in a separate experiment, naïve female Tph2\(^{+/−}\) mice showed signs of enhanced stress resilience in the modified swim test with repeated swimming sessions. Taken together, the combination of a moderate reduction in brain 5-HT with environmental challenges results in behavioral changes in female mice that resemble the aggression-related behavior and resilience seen in stressed male mutants; additionally, the combination is comparable to the phenotype of null mutants lacking neuronal 5-HT. Changes in myelination-associated processes are suspected to underpin the molecular mechanisms leading to aggressive behavior.
KW  - tryptophan hydroxylase-2 (Tph2)
KW  - female aggression
KW  - 5-HT receptors
KW  - glycogen synthase kinase-3 β (GSK-3β)
KW  - myelination
KW  - predation stress
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-267250
SN  - 2073-4409
VL  - 11
IS  - 6
ER  -