Anthony P. Auger - US grants

An understanding of the cellular processes by which steroid receptors are activated has become increasingly relevant due to rising clinical importance. Steroid receptors located within the central nervous system are involved in altering both the behavior and physiology of an animal. One mechanism by which steroid hormone receptors may be activated is by a cognate ligand binding to the receptor. Recent studies have shown that steroid receptors also may be activated in vitro by modulators of protein phosphorylation in the absence of ligand. This is referred to as ligand-independent activation. More important, recent studies have found that ligand-independent activation of the progestin receptor may occur within the central nervous system using pharmacological manipulations. Indeed, ligand-independent activation of the progestin receptor, via pharmacological manipulations, facilitates reproductive behavior in estradiol-primed female rats. We have evidence that the progestin receptor may be activated in a ligand-independent manner under physiological and behaviorally relevant conditions in female rats. In the present series of experiments, we will attempt to further clarify ligand-independent activation of progestin receptors using a reproductively relevant stimulus. In addition, these experiments are designed to provide training in intracerebroventricular administration of antisense oligonucleotides and in situ hybridization.

DESCRIPTION (applicant's abstract): An understanding of the cellular processes that influence sexual differentiation of the brain during the perinatal period is important as they have enduring consequences on the normal behavior and physiology of an animal. Exposure to gonadal hormones during the perinatal period can either masculinize or feminize the brain. As gonadal hormones affect brain development by binding to intracellular steroid receptors located within the brain, it is important to understand how steroid hormones interact with steroid receptors to influence genomic activity and ultimately brain development. Recent studies have reported that steroid receptors interact with other proteins that are necessary for gene transcription. One such protein, called steroid receptor coactivator-1 (SRC-1), is known to be obligatory for steroid action in in vitro preparations however, it is not known if SRC-1 is required for steroid action within the brain. In the present series of experiments, we will determine if SRC-1 expression is sexually dimorphic within the brain during development and determine if SRC-1 protein is required for steroid action within the brain.

DESCRIPTION (provided by applicant): During brain development, the actions of steroid hormones can have lasting effects on reproductive physiology and behavior in animals. Abnormal steroid hormone action in the brain during development can result in generalized endocrine disorders, such as adrenal hyperplasia, infertility, or early/precocious puberty; therefore, understanding how steroid hormone action is regulated within the brain is critical in understanding how endocrine disorders occur. Nuclear receptor co-activators are a recently identified class of proteins that interact with intracellular steroid receptors and profoundly alter their transcriptional activity. The contribution of nuclear receptor co-activators to steroid hormone action on brain development has not been previously explored. The current proposal uses the rat as an animal model and focuses on how nuclear receptor co-activators influence steroid hormone action in the developing brain. We will use antisense oligodeoxynucleotides to reduce the expression of particular nuclear receptor co-activators during brain development and investigate the consequences on sexually dimorphic behaviors and on sexually dimorphic brain structures. This project will also investigate how nuclear receptor co-activators may be involved in regulating two distinct phenomena of brain differentiation: masculinization, which is defined as increased male typical behaviors, and defeminization, which is defined as reduced female typical behaviors. We have recently found that particular nuclear receptor co-activators are critically involved in steroid-induced defeminization but not masculinization of the brain. We propose to further explore how nuclear receptor co-activators influence steroid-induced "sexual differentiation" of the brain, and how they regulate masculinization vs. defeminization of the brain. My long-term career objective is to become an independent scientist within an academic setting and make important contributions to the field of reproductive physiology. It is his career goal to continue the research presented here in a laboratory of his own, compete for research funding, and to train graduate and postdoctoral students.

[unreadable] DESCRIPTION (provided by applicant): During early brain development, steroid hormone exposure differentiates male from female brain. Although there are numerous physiological and behavioral differences between men and women, perhaps the most profound sex differences are in neurological and psychiatric disorders. For example, women are more likely to exhibit signs of depression, multiple sclerosis, and Alzheimer's disease. Men are more likely to exhibit signs of attention-deficit hyperactivity, autism, and dyslexia. As most sex differences in the brain are a result of early steroid hormone exposure, it is possible that sex differences in some disorders are partly influenced by abnormal steroid receptor action in developing brain. Therefore it is important to understand how steroid receptor activity is regulated in developing brain. Previously, it was assumed that steroid receptors were only activated by steroid hormones; however, recent data indicate that steroid receptors are also activated in the absence of steroid, referred to as ligand-independent activation. Although numerous investigators are currently studying ligand-independent activation of steroid receptors in cell culture assays and in adult female brain, few studies investigate the role of ligand-independent activation of steroid receptors in brain development. We plan to investigate the functional role ligand-independent activation of estrogen receptors (ER) in developing brain. Our recent data indicate that acute changes in dopamine transmission during the first few days of life can dramatically alter the developmental organization of social play behavior by activating ER in a ligand-independent manner. We believe that these data are not only exciting in that they suggest a potential steroid hormone independent mechanism for sexual differentiation of the brain, but they also investigate the developmental organization of social play behavior. As social play behavior is dramatically disrupted in children with Autism and Asperger's syndrome, and social play behavior in rodents has been used as a rodent model for the study of autism, it is possible that these data will further our understanding of how sexually dimorphic social disorders occur during brain development. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): The current proposal is a renewal application (previously R13 MH074334-01) for funds to enhance and extend the training potential of the annual meeting of the Society for Behavioral Neuroendocrinology (SBN). Founded in 1996 in response to the need for an umbrella organization to unite the diverse disciplines involved in behavioral neuroendocrine research, the SBN holds an annual meeting with an average attendance of over 400 members, which has grown an approximate 50% since its last submission of the proposal. This growth likely results from the effectiveness of the previous support of this proposal in enhancing the trainee's experience, breadth of speakers, and timely scientific workshops. Current membership in the society is 567, with 141 trainees and 426 faculty members. The SBN is an interdisciplinary scientific organization dedicated to the study of hormonal processes and neuroendocrine systems that regulate behavior. This focus is unique among professional societies, thus SBN's annual meetings and its journal Hormones and Behavior provide vital forums for the integration of ideas across the field of behavioral neuroendocrinology. This integration occurs on multiple fronts and spans all levels of biological organization, from molecular to organismal. SBN members conduct research on myriad organisms across a diversity of contexts, including field- based investigations of animals in their natural habitats, laboratory research on important model systems, and clinical research on a variety of topics directly related to human health. The SBN meeting holds career and trainee workshops, and symposia of which include topics related to steroid hormone action, genes, and brain-behavioral relationships with regard to mental health. A critical component of its mission and this proposal is the enhancement of trainee and career development. PUBLIC HEALTH RELEVANCE: Hormones exert profound influences on the brain throughout life and have major consequences for the risk of developing and potential outcomes of neurological disorders. The Society for Behavioral Neuroendocrinology is an interdisciplinary scientific organization dedicated to the study of hormonal processes and neuroendocrine systems that regulate behavior.

A functional role for progesterone and its receptor in female behavior and physiology is fairly well established; however, the data on progesterone and progestin receptor (PR) function in males are relatively sparse. Although there are only a few studies examining the action of progesterone in males, the results confirm an exciting yet understudied role for progesterone and/or the progestin receptor in adult male behavior and physiology. The goal of this project is to test the hypothesis that progesterone impairs social behavior, specifically social memory/recognition and recently collected preliminary data strongly support this hypothesis in a male rodent model. This research is valuable as it will develop a framework for understanding the role that progesterone plays in influencing social behavior (i.e., social recognition) in males, and provide new molecular targets, such as the underlying steroid /neuropeptide interactions and epigenetic mechanisms, for understanding how social recognition is regulated. These studies will also aid in the understanding of which neural pathways in the brain become compromised in some disease states in which one?s ability to socially recognize other individuals is impaired. The current project will also provide a valuable opportunity for education and dissemination of knowledge. The training provided is designed to give back to the community by engaging students from elementary to graduate school, as well as increase participation of women and students from underrepresented backgrounds in all aspects of experimental science. The data and techniques used to gain these data will be shared with the scientific community, as well as disseminated to the public.