Maternal piromelatine treatment is associated with attenuated behavioral alterations and sex-specific changes in hippocampal pCREB/BDNF signaling in adult offspring following prenatal constant-light exposure.

Abstract

Maternal exposure to constant light during pregnancy (CLE) is associated with disrupted circadian organization and persistent behavioral alterations in adult offspring. This study examined behavioural performance and 24-hour locomotor activity patterns, as well as hippocampal pCREB and BDNF levels, in adult male and female offspring following prenatal CLE and maternal treatment with piromelatine (pir), which acts as an agonist at melatonin MT1/MT2 and serotonin 5-HT1A/5-HT1D receptors. Pregnant Wistar rats under light-dark regime received vehicle (veh), whereas dams exposed to CLE received vehicle (LL-veh), pir (10 mg/kg), or melatonin. Compared to the LL-veh groups, offspring from pir-treated dams exhibited reduced anxiety- and depression-like responses and improved working memory in both sexes. Individual-subject cosinor analysis revealed heterogeneous 24-hour locomotor rhythmicity within and between groups. No significant treatment-group effect was detected for MESOR or amplitude, and the descriptive acrophase patterns did not provide evidence of treatment-induced restoration or normalization of circadian organization. Maternal pir treatment was associated with higher hippocampal pCREB and BDNF levels in male, but not female offspring relative to the LL-veh group. While the behavioral and molecular differences occurred concurrently in males, these findings do not prove that pCREB/BDNF signaling mediated the behavioral outcomes. Furthermore, the study cannot distinguish the direct developmental effects of maternal pir exposure from those mediated through maternal or offspring circadian rhythm. Therefore, the findings should be interpreted as long-term behavioral and sex-specific molecular differences associated with maternal pir treatment rather than as evidence of circadian-independent antidepressant, anxiolytic, cognitive-enhancing, or BDNF-enhancing actions.