Walter Wilczynski - US grants

This project will investigate an important question behavioral neuroscience; how sensory and hormonal cues might act to coordinate somatic and visceral expression. The frog forebrain will be employed as a simplified model system for investigating coordination processes, with special attention paid to the distribution of auditory information and the influence of gonadal steroids, two cues directing reproductive behavior, a classic example of coordinated somatomotor-visceromotor expression. The project will use neuroanatomical techniques (HRP and fluorescence tracing) to describe the distribution of sensory input to the basal ganglia (responsible for somatic motor control) and to the hypothalamus/preoptic area (responsible for visceromotor control) to determine if certain sensory systems project in parallel to both; use neurophysiological techniques to investigate one of these inputs, the influence of acoustic communication signals on hypothalamic/preoptic are neurons; and use neurochemical assays to test whether steroid hormones coordinate behavioral control centers by regulating dopamine receptor activity in each. The project will yield insights into the pattern and evoluting of sensory and hormonal control of natural behavior in particular reproductive behavior. Failures of regulation or appropriate coordination of the investigated regions is a hallmark of many pathological processes in humans, from Parkinson's disease to eating disorders, sexual disfunction and abnormal reactions to stress. The proposed project, although basic research, could therefore contribute to the understanding of fundamental neurological processes impaired during many common regulatory disfunctions.

DESCRIPTION (Adapted from Applicant's Abstract): This is a request for support for a one-day symposium entitled "Mechanisms of Mate Choice" to be held at the annual meeting of the American Society of Zoologists in December 1990. The symposium is intended to gather junior and senior researchers who share a common interest in the proximate mechanisms of intraspecific mate choice and who can discuss their findings in the broader context of sexual selection and the evolution of social behavior. The participants approach their research from several different directions, employing techniques that range through molecular biology, neurophysiology, the analysis of animal learning, and field research in animal behavior. Together their research covers these currently growing, major areas of study into this important problem in animal communication and the neural and experiential control of behavior; the genetic determinants of signal production, reception, and mate choice; the role of early and adult learning on the modulation of mate preferences; physiological properties of sensory systems that bias signal detection and mate choice; and the interaction of natural and sexual selection in generating and sustaining preferences. The symposium will provide a unique opportunity for neuroscience researchers to interact and share their results and ideas with the interdisciplinary audience that normally attends the ASZ annual meeting, and will expose neuroscientists to the animal behavior and evolutionary biology researchers that regularly attend that meeting. Proceedings of the symposium will be published in the American Zoologist.

Auditory communication requires a sound call emitted by one animal to be received as a sensory signal and detected reliably by another animal listening. It is important to know how the receiver is matched to the signal in a given species, and how congruence can be maintained over generations despite the individual variability within a species. Nowhere is the match between signal and receiver more crucial than when the communication system is used in mate recognition. Females often use the signal from a calling male to discriminate between members of the same species versus other species, and if the male's signal does not match the female's detection properties he will be ignored as a potential mate. Neurobiology, behavior, morphology and evolutionary biology are combined here to study the "microevolution" of communication in particular populations of cricket frogs. The advertisement calls of males ready to mate will be quantified to see how pitch and timing of their acoustic components differ among the populations. Neurophysiological recording in the brain will be used to see how the auditory pathway processes call features that characterize the population. Behavioral studies will test whether females respond preferentially to calls from their local population. Variation within a population will be analyzed to see how differences affect mate choice, to identify sex differences in the communication system, and to see how the structure of the calling organ, the larynx, may constrain or promote call changes. Finally, genetic relatedness will be assessed biochemically to see if populations that are separated but share similar call structure reflect similar pressures from habitat constraints on acoustic signals, or instead reflect a historical ancestral relation- ship. This work represents a uniquely complete analysis of a particular communication system, likely to uncover fundamental patterns and processes underlying the neural and morphological control and evolution of vertebrate social behavior and communication. Its multidisciplinary scope is likely to produce a wide impact on many areas of biology.

biomedical equipment purchase;

DESCRIPTION (provided by applicant): This project investigates the ways in which participation in social interactions change brain systems associated with reproductive function, and the hormones and behavior they control. Following previous work the project will focus on three forebrain systems, the gonadotropin releasing hormone cells that directly control the pituitary and its regulation of gonadal steroids, tyrosine hydroxylase (dopaminergic) containing cells in several locations that participate in several processes related to reward, motor control, and several aspects of male sexual behavior and endocrine control, and arginine vasotocin ceils which comprise an important neuromodulator system influencing social behavior and communication. The project uses a combination of behavioral tests, endocrinological manipulations, and neuroanatomical methods (particularly immunocytochemistry), tied together with statistical model testing using Structural Equation Modeling, to test several hypotheses about the way in which exposure to communication signals associated with sociosexual behavior sculpt brain systems. It will test the specific hypothesis that sex steroid changes triggered by social stimulation is the critical, mediating factor in inducing the neural changes resulting from such stimulation and examine alternative mechanistic routes by which androgens might act. It will also test two hypotheses concerning the mechanisms underlying the neural changes: that the resultant neural changes involve activation of the pCREB signaling pathway that has been demonstrated to be important in other brain areas for mediating neural plasticity associated with cognitive memory, and/or that the neural changes reflect an increase in neurogenesis. Furthermore, it will compare changes induced by social stimulation to those induced by changes in hormonal state independent of social cues. Supporting the hypothesis driven portions of the project will be more descriptive studies identifying the location of androgen receptors and aromatase enzymes so as to provide neuroanatomical data with which to interpret the hormonal effects on the three target populations and more generally on any observed patterns of pCREB formation and neurogenesis up-regulation. Lastly, the data obtained in different portions of the project will be employed to test alternative hypotheses about the causal relationships among the brain changes, the hormonal changes, and the behavioral changes induced by social stimulation. The project will enhance the understanding of the ways in which social interactions change the levels of circulating sex and stress hormones in an individual, and how these changes may in turn affect the brain systems important for controlling sexual behavior, aggression, and endocrine regulation. These are all natural behaviors with clinical significance, as dysfunctions of sexual response and reproductive function, affiliation and aggression, and stress are important human clinical problems.

This project investigates how social experiences involving aggressive interactions interact with stress to change how aggressively an individual responds in future social interactions. The project will first document how aggressive tendencies and stress responses change over repeated bouts of social aggression over several days. Changes in hormonal state during this period will also be documented. Experiments will then follow to test whether two hormones are important in regulating the changes in aggressive behavior that follow this experience. These hormones are the androgen sex steroid hormones (testosterone and dihydrotestosterone), and the stress steroid hormone corticosterone. The project will also use a neuroanatomical functional imaging technique, cytochrome oxidase histochemistry, to identify brain areas that change their metabolic, or functional, properties as a result of aggressive interactions and as a result of chronic changes in hormone levels. These neuroanatomical data will be correlated with the behavioral data to identify key brain changes that underlie the shift from less to more aggression and that differentiate dominant from subordinate status. The results from all parts of the project will ultimately be used to model the interrelationships of behavioral experience, hormone level, and brain metabolic profiles using a statistical technique called "structural equation modeling" in order to test hypotheses about causal interactions among all three classes of variables. The results of the project will provide new information about the factors leading to individual differences in aggression and other responses to social challenges.

Participating in social interactions causes great changes in an individual's behavior and physiology. Some of these changes are very persistent and affect the way an individual behaves or responds physically in subsequent social encounters. These effects are most dramatic in cases where an individual acts aggressively or is the target of aggression from a social rival. In many animal species, such interactions lead to persistent changes in status within a social hierarchy, such as being dominant or subordinate. This project examines the brain changes that result from such aggressive social interactions and the subsequent change into a dominant or subordinate individual. The project focuses on a set of neurochemical agents called "neurotrophins" that are produced and released by neurons and that are known to be important in neural development and modification of brain areas important for learning. The project tests the hypothesis that social interactions cause these neurotrophins to be increased in key brain areas responsible for processing sensory signals, memory formation, and the regulation of emotional and physiological state, and that this increase triggers persistent changes in key brain areas and the social, emotional, and physiological processes they control. Furthermore, it tests the hypothesis that individuals that win aggressive interactions and become social dominants and individuals that lose such interactions and become social dominants show similar neurotrophin changes in sensory and general memory areas, but very different changes in the limbic system brain regions responsible for aggression, reproduction, emotional processing, and hormone regulation leading to very different brain organizations in individuals that experience different outcomes of their social interaction. The results of this project will provide new information about the factors leading to individual differences in aggression and other responses to social challenges and to a better understanding of brain's regulation of social behavior. The project will offer unique opportunities for student training and will expect that these student present their findings at national meetings and as co-authors on peer-reviewed publications.

Intellectual merit. How brain areas involved in thinking and memory influence eating is a question that has been largely ignored in neuroscience. This research will investigate how the hippocampus, a brain area involved in memory, affects eating behavior. The hypothesis that guides this project is that the memory of a recently eaten meal influences the timing of the next meal. The overall goal of this research will be to test whether the hippocampus forms a memory of a meal and inhibits eating during the period immediately after a meal. Experiments in Specific Aim 1 will answer the question, "Does the hippocampus inhibit meal initiation?" by testing whether temporarily disrupting neural activity in the hippocampus after rats have eaten a meal will decrease the time it takes them to start their next meal. Experiments in Specific Aim 2 will answer the question, "Do brain cells in the hippocampus form a memory of a meal?" by testing whether eating a meal increases hippocampal levels of activity-regulated cyotskeletal protein (Arc), which is a gene that is activated when memories are formed in the brain. These experiments will also begin to identify the meal-related stimuli that are necessary for the hippocampus to form a memory of a meal and inhibit meal onset.

Broader impacts. This research will significantly increase our understanding of the factors that influence the timing between two meals. Given that the interval between two meals determines the number of meals and is thus a major determinant of food intake, learning the role of the hippocampus in its control will make an important contribution to what is known about both energy regulation and hippocampal-dependent memory. The investigators devote significant effort to mentoring undergraduate and graduate students and will continue to mentor women and underrepresented minorities in scientific research. A portion of the funding will be used to provide a stipend for one graduate student researcher, summer funding for one promising undergraduate student researcher, and travel funds for both students to attend a national conference yearly. As part of this project, one of the investigators will serve as a faculty camp counselor and teacher at a summer Brain Camp and will teach about memory and eating. Finally, the investigators and their students will continue to actively disseminate their research findings through school visits, conference presentations, university seminars, and publication of manuscripts.

The Sociogenomics Initiative RCN aims to identify the fundamental mechanisms of social behavior common across all organisms by bringing together faculty researchers, students, and science educators to advance understanding of the genomic mechanisms of social behavior. It integrates molecular genetic knowledge with biological higher levels to understand how gene expression modulates brain areas, how those areas regulate behavior within and between individuals, and how social systems evolve to yield the diversity of behavioral, brain, and gene expression patterns seen in the biological world. It facilitates interaction among researchers and enhances student training through a program including an annual Sociogenomics International Meeting (SGIM) to review and solidify ongoing research and develop new multidisciplinary projects, combined with technical workshops and other scientific activities to advance the skills and training of researchers and students in genomic approaches to social behavior. These activities are supplemented by exchanges between Network laboratories to foster new research collaborations, with a special goal of placing organism-oriented students or postdocs into systems biology, informatics, or molecular labs to facilitate integration across multiple levels of analysis. An SGI web site will facilitate on-going interactions among the Network members and the scientific community at large.

Broader Impacts: The Initiative will have a transformational impact by stimulating new genomic approaches to the study of social behavior and integrating them across levels from molecular to organismal to evolutionary. It will also contribute to training the next generation of scientists with programs for students from undergraduate to postdoctoral.

Data Management: Collection of new data will not be supported by this grant. However, summaries of symposium talks and technical presentations will be posted on the open-access SGI website, and network members will be encouraged to post relevant, published research articles on the SGI website (as consistent with applicable copyright and intellectual property considerations).

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.