Effects of the absence of maternal pineal melatonin during pregnancy and lactation offspring neurogenesis, physical growth, neurodevelopment, and behavior.

Author(s)

Lívia Clemente Motta Teixeira

• Document type: Doctoral Thesis
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Instituto de Ciências Biomédicas (ICB/SDI)
• Defense date: 2019-07-24

Examining board members

Jose Cipolla Neto; Rosana Souza Cardoso Alves; Deborah Suchecki; Silvia Honda Takada; Gilberto Fernando Xavier

• Advisor: Jose Cipolla Neto

Abstract

Modern life involves several social situations as artificial light illumination at night and night/shift work that disrupt maternal circadian rhythms and/or reduce maternal melatonin and have been associated with an increased risk of cancer and metabolic disturbances. Maternal melatonin provides photoperiodic information to the fetus and thus influences the regulation and timing of the ospring\'s internal rhythms and preparation for extra-uterine development. To unveil the contribution of maternal melatonin during gestation on lactation on the programming of brain and behavior, we assessed the effects of the absence of maternal melatonin during gestation and lactation (MMD) and its therapeutic replacement on the offspring neurodevelopment and cognition. To study this, we used a model of gestational hypomelatoninemia during pregnancy and lactation resulting from a surgical pinealectomy (PINX) that coincides with in utero and postnatal hippocampal development. We studied if MMD alters the somatic, physical growth and neurobehavioral development of offspring and adult hippocampal-dependent learning, and questioned if these cognitive impairments were associated with changes in the proliferation of new cell and immature neurons. We demonstrated that MMD significantly delayed male ospring\'s onset of fur development, pinna detachment, eyes opening, the eruption of superior incisor teeth, testis descent and the time of maturation of palmar grasp, righting reflex, free-fall righting and walking. Conversely, female ospring neurodevelopment was not affected, later on, male ospring show that MMD was able to disrupt both spatial reference and working memory in the Morris Water Maze paradigm and these deficits correlate with changes in the number of proliferative cells in the hippocampus. We further address the long-term effects of MMD on the offspring metabolism and emotional and cognitive functions, questioning if the behavioral deficits and changes in adult neurogenesis process observed were associated with neuroinflammation and metabolic alterations in males. We have shown that adult offspring born of MMD dams had increased body weight, increased fasting glycemia, and insulin resistance at three months of age. These animals also exhibited object recognition impairments and increased anxiety-like behavior and mitochondrial alterations. Contrary, PINX+MEL-F1 exhibited increased proliferation and survival of hippocampal novel neurons, reduction of increased anxiety-like behavior and improvements in hippocampal-dependent learning. MMD does not induce neuroinflammation in adult hippocampus and hypothalamus and no changes in microglia related proteins. These programming effects from MMD disappear with the appropriate schedule of melatonin replacement therapy during pregnancy and lactation. We provide the first evidence showing that maternal melatonin deprivation during gestation affects fetal brain programming mechanisms responsible for the optimal neurodevelopment with long-term consequences to hippocampus functions and affects energy metabolism programming. (AU)

• FAPESP's process: 14/22313-3 - Influence of the absence of maternal melatonin during pregnancy and lactation on neurogenesis and on somatic and sensorimotor development of the offspring.
• Grantee: Lívia Clemente Motta Teixeira
• Support Opportunities: Scholarships in Brazil - Doctorate