Effects of Serotonin Transporter Genotype and (Un)Predictable Maternal Separation on Affective, Cognitive, and Social Behaviors in Female Rats.

Serotonin transporter (SERT) variation is linked to depression risk after stress, conferring an increased risk to SERT-linked polymorphic region (5-HTTLPR) short-allele carriers, who show heightened sensitivity to cumulative stress and childhood maltreatment. To elucidate the neurobiological mechanisms underlying SERT × early-life adversity interactions, animal models capturing this genetic vulnerability are of translational relevance. We evaluated four maternal separation (MS) paradigms to determine how different forms of early-life stress influence adult behavior in female SERT-deficient rats, given the higher prevalence of depression in women and the limited translational value of male-only preclinical findings. We applied several behavioral tests to wildtype (SERT+/+), heterozygous (SERT+/-), and homozygous (SERT-/-) knockout females exposed to MS: predictable 3 h/day (MS180) or 6 h/day (MS360), unpredictable 3 h/day (MSU180), or unpredictable 3 h/day plus unpredictable maternal stress (MSUS180). Controls were 15-min handled. SERT-/- females exhibited higher anxiety-like responses, passive stress coping, and increased social exploration. MS180 and MS360 induced some anxiety-like behaviors, while MS360 increased hedonic responding. Females responded differently to MS depending on their SERT genotype. First, some anxious behaviors of SERT-/- females were attenuated when exposed to unpredictable MS (MSU180 and MSUS180). Second, MSU180 reduced object recognition in SERT-/- females, while enhancing it in SERT+/- females. Third, SERT+/- females exhibited less passive stress coping when exposed to MS360 than all other groups. Neither predictable nor unpredictable MS exposure increased vulnerability to depressive-related behaviors in SERT-deficient females. Variations in SERT expression may confer some beneficial effects in response to MS, depending on the specific genotype and behavioral domain evaluated.