Early environments, glucocorticoid receptors, and behavioral epigenetics.

In 1985, a brief report published in Behavioral Neuroscience established the link between neonatal handling and concentrations of hippocampal glucocorticoid receptors (GR) in the adult rat, suggesting a neurobiological basis for the attenuated stress reactivity observed in handled versus nonhandled offspring. To celebrate the 30th anniversary of Behavioral Neuroscience, this article explores the research that preceded and followed from this brief but significant publication. Changes in hippocampal GR induced by handling were determined to be the outcome of a cascade of cellular and molecular events involving thyroid hormones, serotonin turnover, and transcription factor binding to the Nr3c1 gene, leading to increased GR mRNA and protein. Though many hypotheses were proposed for the "handling effect," the role of handling-induced changes in maternal care, particularly pup licking/grooming (LG), generated a productive scientific framework for understanding the handling phenomenon. Indeed, LG has since been demonstrated to alter GR levels through the signaling pathways described for handling. Moreover, epigenetic mechanisms have been discovered to play a critical role in the effects of early life experience and particularly in the regulation of Nr3c1. Overall, the research avenues that have evolved from the initial finding of handling-induced changes in GR have broad applications to our understanding of plasticity, resilience, and the transmission of traits across generations.

Early postnatal handling alters glucocorticoid receptor concentrations in selected brain regions.

Norway rat pups were either handled (H) or undisturbed (nonhandled, NH) in the period between birth and weaning on Day 21. Following weaning, half of the animals in each group were housed socially (Soc), and half were housed in isolation (Isol). At 120-150 days of age, all animals were sacrificed, and the following regions were dissected and frozen at -70 °C until the time of assay: frontal cortex, hippocampus, hypothalamus, amygdala, septum, and pituitary. [3H]Dexamethasone (3H Dex) binding in each region was examined by an in vitro, cytosol, receptor assay. 3H Dex binding was significantly higher in the hippocampus of both H-Soc and H-Isol than in NH groups. In the frontal cortex, 3H Dex binding was higher in the H-Soc animals than in the H-Isol and NH-Isol animals. There were no significant handling or housing effects found in the amygdala, hypothalamus, septum, or pituitary. Thus, early postnatal handling appears to influence the development of the glucocorticoid receptor system in the hippocampus and frontal cortex. These results are discussed as providing a possible mechanism for some of the previously reported effects of early handling on the development of the pituitary-adrenal response to stress.

Nuclear receptors and female reproduction: a tale of 3 scientists, Jensen, Gustafsson, and O'Malley.

Work on the estrogen receptor and glucocorticoid receptor laid the foundation for the discovery of a family of receptors known as the nuclear receptors. Discovery of these receptors has expanded our understanding of many hormonal and nonhormonal substances, which act through the nuclear receptors. These receptors are actually ligand-binding intracellular transcription factors, which induce nuclear expression of specific mRNAs, leading to synthesis of specific proteins with biological activity. This review for the benefit of gynecologists and reproductive physiologists focuses on the work of 3 scientists who were pioneers in the work on the estrogen, glucocorticoid, and progesterone receptors, which has had a major impact on our understanding of reproductive physiology and on the field of nuclear receptors.