Anti-angiogenic mechanisms and serotonergic dysfunction in the Rgs2 knockout model for the study of psycho-obstetric risk.

Psychiatric and obstetric diseases are growing threats to public health and share high rates of co-morbidity. G protein-coupled receptor signaling (e.g., vasopressin, serotonin) may be a convergent psycho-obstetric risk mechanism. Regulator of G Protein Signaling 2 (RGS2) mutations increase risk for both the gestational disease preeclampsia and for depression. We previously found preeclampsia-like, anti-angiogenic obstetric phenotypes with reduced placental Rgs2 expression in mice. Here, we extend this to test whether conserved cerebrovascular and serotonergic mechanisms are also associated with risk for neurobiological phenotypes in the Rgs2 KO mouse. Rgs2 KO exhibited anxiety-, depression-, and hedonic-like behaviors. Cortical vascular density and vessel length decreased in Rgs2 KO; cortical and white matter thickness and cell densities were unchanged. In Rgs2 KO, serotonergic gene expression was sex-specifically changed (e.g., cortical Htr2a, Maoa increased in females but all serotonin targets unchanged or decreased in males); redox-related expression increased in paraventricular nucleus and aorta; and angiogenic gene expression was changed in male but not female cortex. Whole-cell recordings from dorsal raphe serotonin neurons revealed altered 5-HT1A receptor-dependent inhibitory postsynaptic currents (5-HT1A-IPSCs) in female but not male KO neurons. Additionally, serotonin transporter blockade by the SSRI sertraline increased the amplitude and time-to-peak of 5-HT1A-IPSCs in KO neurons to a greater extent than in WT neurons in females only. These results demonstrate behavioral, cerebrovascular, and sertraline hypersensitivity phenotypes in Rgs2 KOs, some of which are sex-specific. Disruptions may be driven by vascular and cell stress mechanisms linking the shared pathogenesis of psychiatric and obstetric disease to reveal future targets.

Chrysippus's pigeon: Exclusion-based responding in an avian model.

Inference by exclusion can be exhibited by deductively responding to new stimuli that are presented in the context of familiar stimuli. We investigated exclusion-based responding in pigeons using a 2-alternative forced-choice discrimination task. In Phase 1, pigeons learned to associate 2 stimuli (A and B) with Response 1 and 2 stimuli (C and D) with Response 2. Following successful acquisition of these stimulus-response pairings, pigeons advanced to Phase 2, in which stimuli A and B were now reassigned to Response 2. Based on their Phase 1 training, pigeons should initially choose Response 1 when presented with A and B in Phase 2 (this response is now incorrect, but the birds would not yet have had the opportunity to learn the new stimulus-response associations). Also, in Phase 2, stimuli E and F-new stimuli replacing stimuli C and D-were concurrently presented and assigned to Response 1. Without prior training, pigeons' initial responding to E and F in Phase 2 should be at chance. However, if the pigeons were to apply an exclusion rule (stimuli E and F stand in opposition to stimuli A and B), then they might initially choose Response 2 for new stimuli E and F because they are concurrently choosing Response 1 for stimuli A and B. If that is the case, then choice accuracy for stimuli E and F should also be below chance. Indeed, our pigeons responded at reliably below chance levels to stimuli E and F, consistent with their exhibiting an exclusion rule-based strategy, which could actually arise from a more mechanical underlying process such as acquired equivalence formation. (PsycINFO Database Record