Acute carbamoylated erythropoietin reduces social stress-induced anxiety and depression-related behaviors

The hormone and trophic factor Erythropoietin (EPo) promotes red blood cell production and has neurotrophic effects, modulating behavior and promoting neural plasticity, like neurogenesis. Modifying EPo by attaching a carbamoyl group (cEPo) results in similar neuronal effects without erythropoietic actions. We hypothesize that neuroplastic and learning effects of cEPo may be dependent on its action in dorsal dentate gyrus of the hippocampus, where neurogenesis occurs. The Stress Alternatives Model (SAM) is a 4-day social stress and decision-making paradigm with a large novel aggressor that provides opportunities to avoid interaction via escape routes. Early, male test mice display stable Escape (avoiding aggression) or Stay (acquiescence to aggressor) behavioral phenotypes. In these studies, mice were given a single intracerebroventricular (icv; 100 ng), or single intra-dentate gyrus (iDG; 10 ng) injection of cEPo or vehicle. By Day 4, 30% of icv cEPo treated mice and 37.5% of iDG cEPo treated mice reversed their phenotype (Stay to Escape). Mice receiving vehicle injections did not change. Normalization of social preference, and reduction in fear freezing behavior, after cEPo treatment, coincide with transcriptional changes of orexin receptors (Hcrtr₁ & Hcrtr₂) in the hippocampus, including phenotype- and treatment-dependent alterations in learning-associated molecular signaling molecules. Hippocampal Hcrtr₁ moderately colocalize with EPo receptors (Epor) in the dentate gyrus, while Hcrtr₂ is expressed with Epor in CA₁. Anxiolytic actions of cEPo during social interaction indicate mechanisms that influence learning in stressful situations, suggesting that cEPo may be a novel agent for treatment of comorbid conditions related to anxiety, depression, and PTSD.