Geert J. de Vries - US grants

In humans and other animals, gonadal secretions influence sexual differentiation of brain function and behavior. The research proposed in this application aims to elucidate the neural mechanism underlying this differentiation. The focus will be on the vasopressin projections of the sexually dimorphic bed nucleus of the stria terminalis, and the medial amygdaloid nucleus. A prime advantage of studying a particular neurotransmitter system is that one can better estimate whether process involved in sexual differentiation indiscriminately affect developing cells in sexually dimorphic areas, or whether they target specific cells. Furthermore, since one can easier trace connections of cell groups for which the neurotransmitter is known, one can identify brain areas that may be affected by the sexual differentiation of the system under study. Vasopressin projections are a particular case in point. They are very attractive to study, since they are extremely sexually dimorphic: males have many more vasopressin-immunoreactive cells and fibers than females have. Moreover, the effects of hormonal manipulations on these projections are so dramatic, that they can be analyzed reliably. By hormonally manipulating these pathways during development, this research tries to analyze whether and, if so, when gonadal steroids influence the sexual differentiation of the vasopressin pathways. It also tries to reveal which properties of vasopressin projections are sexually differentiated by focusing on the capacity of individual cells to synthesize AVP, on the total number of cells that can synthesize vasopressin, and on the density of the projections. Finally, this research tries to study whether the target tissue influences the differentiation of vasopressin pathways by transplanting neural tissue that contain steroid-sensitive vasopressin neurons into vasopressin-deficient Brattleboro rats. In conclusion, this research will help to identify mechanisms that contribute to sexual differentiation of neurotransmitter systems, and hence to sexual differentiation of brain function and behavior.

DESCRIPTION (adapted from applicant's abstract): This is a request for an Independent Scientist Award. This grant aims to add to our understanding of the neural basis of sexually dimorphic brain function by focusing on a sexually dimorphic system that has been implicated in parental and other sexually dimorphic behaviors and functions. The hypothesis driving this grant is that sex differences in the brain not only serve to generate sex differences in centrally regulated processes and behaviors, but also may enable males and females to show remarkably similar behaviors even though their physiological and hormonal conditions differ dramatically. It does this by studying the role of the sexually dimorphic vasopressin-immunoreactive projections of the bed nucleus of the stria terminalis and the medical amygdaloid nucleus in parental behavior. The strategy is to compare two species of voles: prairie voles (Microtus pennsylvanicus), a monogamous species in which both males and females provide parental care, and meadow voles (Microtus pennsylvanicus), a promiscuous species in which only females provide parental care. This strategy allows comparison of the AvP-ir projections not only between males and females but also between males that show different parental involvement. The research will entail psychopharmacological, hormonal and developmental manipulations, anatomical and cell biological analyses of reproduction-related changes, and behavioral observation. By virtue of its topic this study will contribute to understanding both sex differences in the brain and the neural basis of maternal as well as paternal behavior. The last contribution will be new to the field since virtually nothing is known about neural structures underlying paternal behavior. Research Career Development support is requested to free the PI form teaching and administrative duties. This will allow him to develop new anatomical, cellular, and molecular strategies to assess the contributions of the sexually dimorphic vasopressin projections to parental behavior.

The goal of this program is to provide excellent pre- and postdoctoral trainees with the breadth of knowledge and contemporary research skills essential for developing successful independent research programs in the field of neuroendocrinology. Funds are requested for four predoctoral and two postdoctoral students for training in neuroendocrinology. A hallmark of this program is that it unites trainees and faculty from two graduate programs to provide a perspective far broader than what could be obtained through a single graduate program. The proposed training embraces multiple levels of analysis, from behavioral, to physiological, to cellular, to molecular. Predoctoral trainees will enter this program in their third year, after finishing the specific course requirements of their respective graduate programs. Each student will choose both a primary advisor and a co- advisor. The role of the primary advisor is similar to the traditional role of the thesis advisor. The co-advisor will ensure the multidisciplinary aspect of the training. Trainees will spend part of their time in the co-advisor's laboratory, using techniques and approaches not available in their home laboratory to address questions related to their own thesis research. Postdoctoral trainees will be supported for two years. The primary focus of the postdoctoral training is to build a strong research track record. Postdoctoral trainees will also be actively mentored to develop oral presentation skills, grant writing, and teaching skills necessary to secure and hold an independent academic position. All trainees will actively participate in a series of seminars, journal clubs, and monthly meetings where the participating laboratories present their research. An annual symposium will expose the trainees to neuroendocrinologists from across the U.S.A.

DESCRIPTION (provided by applicant): This grant aims to understand the function of sex differences in developing brains by focusing on the higher level of vasopressin expression in male versus female brains. This is the most consistently found sex difference among vertebrates, and the best understood in terms of function in adult animals. Interestingly, this sex difference is even more dramatic in juveniles (almost absolute), yet no attempts have been made to study its function at this stage. This grant will study whether the sex difference in vasopressin innervation contributes to sex differences in the display and control of social behavior in juvenile rats. The focus will be on social play (or play fighting), a behavior that is much more pronounced in males than in females and probably the first social behavior that is not directed at the mother. The first aim is to paint a comprehensive picture of vasopressin development by monitoring vasopressin mRNA levels, peptide distribution, and receptor binding in the developing brain. This is essential for generating hypotheses as to how vasopressin may contribute to sex differences in social behavior. The second aim is to test whether social play is accompanied by changes in central vasopressin release. The third aim is to test the hypothesis that central vasopressin release contributes to sex differences in the emergence and control of social behavior by testing the effects of vasopressin or vasopressin receptor antagonists on social play and social recognition. Understanding how the brain controls social behavior during development is important as many behavioral disorders show striking sex differences in morbidity that manifest themselves during development. For example, autism spectrum disorders (ASD) are much more common in boys than in girls. Sexual differentiation of the brain likely contributes to these differences. Although recently major advances have been made in understanding the neural basis of social behavior in adulthood, how such behavior is controlled during development is by and large unknown. This grant will address these issues. PUBLIC HEALTH RELEVANCE: Behavioral disorders that manifest themselves during development, such as autism spectrum disorders, are often more common and severe in boys than in girls. Sexual differentiation of the brain likely contributes to these differences. This research explores the behavioral consequences of neural sex differences in juvenile rats.

DESCRIPTION (provided by applicant): The Institute On Neuroscience Summer Research Immersion. Engaging outstanding high school students in authentic and rewarding laboratory research may attract them to research careers. An intensive summer research experience provides an ideal environment for students to experience hands-on, inquiry-based science learning, which will likely enhance their content knowledge, technical skills, and confidence in their ability to conduct scientific research (scientific research self-efficacy). In turn, science elf-efficacy predicts intent to persist in science-related academic and career paths. Likewise for high school teachers, participating in summer research may improve knowledge, skills, and teaching efficacy, ultimately affecting commitment to teaching and retention in teaching careers. Moreover, by translating research experiences into inquiry-based learning opportunities for future students, teachers can exponentially increase the distribution of knowledge and skills acquired in a summer program. Thus, we will facilitate integration of students and teachers into neuroscience research teams through our program called ION/Teach. Our first aim is to engage high school students and teachers in an intensive summer research program, called the Institute on Neuroscience & Teaching (ION/Teach). A diverse group of students and teachers will start the summer with a week-long seminar on basic neuroscience concepts and methods, then engage in seven weeks of mentored lab research with active investigators at metro-Atlanta universities. Weekly professional development workshops will focus on topics such as scientific communication, college prep, and ethical conduct of research. Teacher participants will translate their summer research into standards-based lesson plans. The summer research experience will culminate in a research symposium. Our second aim is to use the ION/Teach program as a basis to test the hypothesis that participation in authentic laboratory research can improve externally demonstrable research skills (e.g. neuroscience content knowledge, competency at the bench or in the clinic, and scientific communication), and/or internal constructs associated with success in science or teaching careers (e.g. research or teaching self-efficacy, low science anxiety, science identity). Beyond individual outcomes for participants, the effectiveness of lesson plan development by the teacher participants will be monitored by assessment instruments that probe student learning outcomes in their classrooms. This research will fill a gap in current knowledge about how best to prepare young people to help address current biomedical, behavioral, and clinical research needs. For teachers, our results will also help identify ways to enhance retention in science classrooms. Ultimately, this project will produce not only students and teachers with research skills and dispositions toward successful careers, but also education research data for dissemination to the international science education community.

? DESCRIPTION (provided by applicant): The proposed Initiative for Maximizing Student Development (IMSD) at Georgia State University (GSU) offers a highly innovative program that will recruit and retain undergraduate students from groups underrepresented in science who will then pursue careers in biomedical sciences. GSU is an ideal institution for an IMSD program as it combines excellence in biomedical and behavioral sciences with a remarkably diverse undergraduate population as well as with GSU's success in training undergraduates from underrepresented minorities. GSU now graduates more African American students than any other non-profit institution of higher learning in the United States. The goal of the proposed IMSD is to combine our existing strengths in biomedical research with the unique success of GSU in educating underrepresented minorities to make it the premier institution in the nation for the education of a highly diverse group of students who will go on to NIH-funded research careers. The objectives of this IMSD program are: (1) to engage high-potential undergraduates from underrepresented groups, recruited from Neuroscience, Biology, Chemistry, and Psychology, in a two-year research immersion and integration program, which includes research during summer as well as academic year activities that will integrate regular coursework with research activities (research semester); (2) to promote survival skills for research careers through an intensive series of professional development workshops and courses in which students will hone their skills in critical thinking, scientific communication, research career planning, and ethics; (3) to create a highly supportive academic and social environment to launch graduate careers in biomedical science by providing instructors with skills to train students from underrepresented groups and help them get entry into PhD programs and by fostering connections with other partner T32 and PREP institutions; and (4) to evaluate progress and identify program, mentor, and trainee dispositions that predict success in biomedical research careers, which we will then use to institutionalize successful program elements beyond the grant period at GSU and, by disseminating and publishing the results of our evaluation, at other institutions.

? DESCRIPTION (provided by applicant): Groundbreaking recent studies indicate that the community of microorganisms living in the digestive tract (the gut microbiota) plays a key role in psychiatric illnesses characterized by disordered emotional and social responses. Accelerated progress has also been made in understanding neural control of anxiety and social behavior, especially with regard to the roles of the `social neuropeptides,' vasopressin and oxytocin. To date nobody has linked these two exciting fields. Two established laboratories with complementary areas of expertise have joined forces to take on this task: one focused on sex differences in the brain and the neural basis of social behavior, the other on molecular pathways underlying the relationship between the microbiome and gut health. Together, these laboratories will develop mouse models to test the overall hypothesis that the gut microbiota acts early in life to permanently program vasopressin and oxytocin systems as well as anxiety- related and social behaviors controlled by these systems. In the first experiment, brain and behavior will be compared during development and in adulthood of germ-free mice after they have been colonized at birth by gut microbiota derived from either of two strains of mice that differ significantly in social and anxiety-related behaviors as well as composition of the microbiome. The second experiment takes advantage of a recent discovery in one of the two participating laboratories that commonly used food additives, i.e., emulsifiers, have surprisingly strong effects on physiology by acting on microbiota composition and its interaction with the host. Preliminary data suggest that these effects extend to the brain and behavior, which will be tested in the current project. Together, this project will address a crucial gap in our understanding of the gut-brain axis and its role in the development of anxiety-related and social behaviors, using physiologically relevant approaches. The findings will make possible subsequent identification of the specific microbiota affecting anxiety-related and social behaviors, and the signaling pathways involved. In addition, the payoff for studying effects of the microbiota on vasopressin and oxytocin expression will go beyond understanding microbiota effects on behavior, to include effects of the microbiota on autonomic functions, metabolic syndrome, and pain, all of which are affected by microbiota and modulated by these peptides.

Abstract Disorders of social behavior and communication are increasingly prevalent and pose a substantial burden to society. These disorders often show sex differences in prevalence, expression and severity. One explanation for these differences reflects dysfunction in the sexually different social brain. A particularly relevant neuropeptide system in this respect is the vasopressin (AVP) innervation of the brain, which shows marked sex differences across many species, including humans, and which has been implicated in both aggressive and affiliation behavior. AVP fibers are prominent in most areas of the social brain and many of these originate from cells within the posterior bed nucleus of the stria terminalis (BNST). However, so far no studies have directly targeted these cells to test their role in social behavior. Here we do so using viral vector technology to test the overarching hypothesis that these BNST AVP cells promote male-typical affiliation and that they do so by receiving direct social sensory and arousal/reward-related modulatory input. We will test this hypothesis across two specific aims using a multi-disciplinary approach: (i) does removal of BNST AVP cells eliminate prosocial communication in male, but not female, mice? (ii) does viral-vector tracing of monosynaptic connections to BNST-AVP cells reveal sensory and modulatory inputs? The answer to these novel research questions will uncover a fundamental mechanism by which the brain regulates sexually-differentiated social communication, and will contribute to identifying causes of, and treatments for, disorders of social communication.

Abstract Disorders of social behavior and communication are increasingly prevalent and pose a substantial burden to society. These disorders often show sex differences in prevalence, expression, and severity. One explanation for these differences reflects dysfunction in the sexually different social brain. A particularly relevant neuropeptide system in this respect is the vasopressin (VP) innervation of the brain, which shows marked sex differences across many species, including humans, and has been implicated in aggressive as well as affiliation behavior. Indeed, the main receptor for VP in the brain, V1aR, is now a major target for drug development for treating core symptoms of autism. Despite the significance of this system, few studies have directly assessed how, when, and where V1aR signaling influences communication behavior in adults. This lack of data is particularly acute in mice, a key biomedically-relevant species. We propose to remedy this by generating a new mouse line that expresses cre-recombinase (Cre) under the control of the Avpr1a promoter (Avpr1a-Cre), rigorously characterizing its behavioral phenotype in both sexes, then performing a targeted experiment manipulating V1aR in the lateral septum as a test of this new resource. As a comparison, we will also test the role of the oxytocin receptor in LS on social communication using identical experimental approaches. The availability of a validated Avpr1a-Cre line will enable rapid progress in mapping the connectional architecture and determining the behavioral/physiological functions of different V1aR cell populations using modern techniques. This, in turn, will uncover a fundamental mechanism by which the brain regulates social communication, and will contribute to identifying causes of, and treatments for, disorders of social communication in both males and females.

This project aims to understand the function of sex differences in neural control of social behavior by focusing on the higher level of vasopressin expression in male versus female brains. This is the most consistently found sex difference among vertebrates, and the best understood in terms of function in adult animals. This grant will study whether the sex difference in vasopressin innervation contributes to sex differences in the display and control of social behavior. We will take advantage of new powerful genetic approaches that allows us to target vasopressin cells specifically. The first aim is to test whether removal of the sexually dimorphic vasopressin cells in the bed nucleus of the stria terminalis and medial amygdaloid nucleus affects social behavior differently in males and females. The second aim is to test whether inhibition or excitation of these cells alters social behavior differently in males and females. The third aim is to identify the in- and outputs of these cells, to begin to understand the neural circuitry via which vasopressin affects social behavior differently in males and females. Understanding how the brain controls social behavior differently in males and females is important as many behavioral disorders show striking sex differences in morbidity. Sexual differentiation of the brain likely contributes to these differences. Although recently major advances have been made in understanding the neural basis of social behavior in adulthood, how such behavior is controlled differently in males and females is, by and large, unknown. This grant will address these issues.