Lactational Serotonergic Perturbation Imprints Stress-Related Transcriptional Profiles in the Adolescent Female Rat Prefrontal Cortex

ACS Chem Neurosci. 2026 May 22. doi: 10.1021/acschemneuro.6c00082. Online ahead of print.

ABSTRACT

Early life perturbations of serotonin (5-hydroxytryptamine, 5-HT) signaling induce long-term neurobehavioral consequences. We previously demonstrated that perinatal manipulation of the 5-HTergic system in rats leads to distinct adult biobehavioral outcomes depending on sex and time of intervention, with postnatal manipulations leading to cognitive deficits in females. Moreover, we showed that prenatal disruption of 5-HT signaling alters the response to acute stress in male adolescents. Here, we investigated whether postnatal exposure to the selective serotonin reuptake inhibitor fluoxetine (FLX) affects adolescent behavior and molecular stress responsivity. Rats were exposed to FLX during the lactation period and behaviorally characterized during adolescence to assess distinct psychiatric-like phenotypes. Transcriptional responses to acute restraint stress (ARS) were evaluated in the prefrontal cortex (PFC) and the dorsal and ventral hippocampus. Although no behavioral alterations were detected, postnatal FLX exposure modified the ARS-induced molecular response. In particular, females exposed to FLX during lactation showed a blunted induction of immediate early genes, early response genes, and brain-derived neurotrophic factor isoforms in the PFC. These findings indicate an altered stress-responsive transcriptional profile that may represent an early molecular alteration preceding the cognitive deficits previously observed selectively in adult females.

PMID:42170745 | DOI:10.1021/acschemneuro.6c00082