Robert L. Meisel - US grants

The aim of the proposed experiments is to study sociosexual behaviors (primarily aggression and sexual behavior) in the female hamster, focusing on developing our understanding of the cellular bases of hormone action on behavior. Experiments in the first section of the proposal are designed to determine the specific systemic hormone requirements for the female master's decline in aggressiveness and subsequent rise in sexual responsivity. It is expected that the inhibition of aggression will be estradiol sensitive, whereas sexual receptivity will require both estradiol and progesterone. Section II will examine neural sites of action of estradiol and progesterone in aggression and sexual behavior through the use of localized brain implants of estradiol or the synthetic progestin, R5020. A further dissociation of the hormonal control of aggression and sexual behavior may be related to different brain sites of action of these hormones. Based on the hypothesis that one action of steroid hormones on the brain is via the induction of neuronal protein synthesis, the experiments in Section III will investigate changes in neuronal ultrastructure, indicative of the level of protein synthesis, induced by systemic estradiol and progesterone. Ultrastructural changes in specific brain regions will be correlated with the behavioral state elicited by these hormone treatments. Correlations between sociosexual behaviors and neuronal ultrastructure will also be examined in cycling female hamsters. The role of neuronal protein synthesis in the hormonal activation of behavior will be examined in female hamsters receiving intracranial implants of the protein synthesis inhibitor, anisomycin (Section IV). The hypothesis that the behaviorally-relevant proteins are released by the Golgi complex will also be tested. In the final group of experiments (Section V), autoradiographic analyses of the location of estradiol- and progestin-concentrating cells in the brain and spinal cord of female hamsters will be aimed at 1) interpreting the effects of intracranial hormone treatment on behavior, and 2) assessing regional differences in the estradiol-induction of progestin receptors, a hypothesized regulatory step in progesterone's action on behavior. The value of studying cellular mechanisms of hormone action on an integrated behavioral system is emphasized. The significance of this research in the context of hormone regulation of neuronal plasticity is also considered.

The overall goal of this research program is to study cellular mechanisms of hormone action on sexual and aggressive behaviors in female Syrian hamsters. It is proposed that aggression is an integral component of social behaviors of females in general, and that the results of these studies will be generalizable to females of other species. One focus of these experiments is the identification of a novel functional neural pathway related to the control of aggression in female hamsters. Since factors regulating aggression in females are rarely studied, it is not surprising that nothing is known about the neural pathways underlying female aggression. Related to this goal, the experiments in Section I will focus on afferent and efferent pathways of the ventromedial nucleus of the hypothalamus. This nucleus was chosen for its unique position as the primary site of action of ovarian hormones on aggression and sexual behavior in female hamsters. In Section II, chemical lesions will be made in neural regions that interact monosynaptically with the ventromedial hypothalamus. Lesion sites that produce effects on sexual behavior and aggression will help to define functional pathways for these behaviors, including points of convergence and divergence in the neural control of these behavioral systems. In Section III and IV, studies will examine possible mechanisms through which ovarian hormones can determine the female's behavioral state. In Section III, the possibility that steroids produce dedritic reconfigurations in neurons of the ventromedial hypothalamus will be examined. In Section IV, the effects of steroids on the ultrastructure of neurons in the ventromedial nucleus of the hypothalamus will be assessed. The goals of these sections are 1) to infer biochemical processes in nerve cells stimulated by steroids, and 2) to relate these changes in structure to the behavioral effectiveness of such steroid treatments. In sum, the results of these studies will identify neural systems related to the control of sexual behavior and aggression in females, including ways in which hormones may alter the functional nature of these systems, and therefore, behavior.

Long-term changes in the cellular properties of neurons are known to be part of the mechanisms mediating both continued drug abuse and relapse in individuals who have been abstinent from drug use. However, this leaves open the question of what leads to the initiation and maintenance of drug use prior to the induction of sensitization from repeated drug use? One component of the answer to this question might lie in an individual's life history or prior experiences. Like drugs of abuse, expression of motivated behaviors will activate the mesocorticolimbic dopamine system. It would be of great importance to delineate the cellular processes related to neural plasticity following experience with motivated behaviors (e.g., sexual behavior). We discovered that prior sexual experience sensitizes the dopamine response to sexual interactions and also produces behavioral sensitization to the initial presentation of amphetamine in otherwise drug-naive animals. This latter process, termed 'cross-sensitization', is fundamental to understanding how an animal's life history can contribute to a predisposition to drug abuse. Because so little is known about the cellular mechanisms altered by experience in animals engaging in motivated behaviors, the long-term goal of this project is to compare at the cellular level the degree to which motivated behaviors and drugs of abuse have common (or discrepant) mechanisms of sensitization of dopamine pathways. There are three specific aims to this project. The first aim will identify changes in proteins involved in dendritic remodeling as a function of sexual experience. The second aim will pharmacologically dissect signaling pathways that underlie behavioral and neural morphological responses to sexual experience. The final aim will pharmacologically identify signaling pathways key to the cross-sensitization of sexual experience to amphetamine-induced locomotor behavior. The experiments in this proposal are designed to distinguish those cellular pathways that mediate drug sensitization to the exclusion of sensitization processes important for normal motivated behaviors. The degree to which there are shared anatomical loci and cellular mechanisms between normal motivated behaviors and drug abuse will provide insight into risk factors for the initiation of drug use in humans and for the development of therapies for the treatment of addiction.

The 1990s were declared ?The Decade of the Brain? by then President George Bush and Congress. This declaration affirmed what many had known for centuries; the critical importance of the nervous system?s role in coordinating physiological and behavioral processes across a diverse set of taxa. This Presidential/Congressional mandate spurred on a new era of basic science advances in our understanding of neural function. The challenge many years later remains to excite a new generation of scientists committed to accelerating the advances made in this fundamental biological discipline.

A persisting gap in recruiting talented students to careers in science is among historically underrepresented minority groups. The number of underrepresented minorities in neuroscience is woefully small despite the ever growing numbers of these populations in the US. A number of studies suggest that the solution to the problem is to engage and nurture these students through early inclusion in research projects coupled with academic and social support and professional development. Exposure to effective role models, i.e. members of underrepresented minorities who have achieved a measure of success, is warranted as it allows students to see themselves in similar roles.

The overarching goal of the University of Minnesota Minority Undergraduate Summer Research Program is to establish a rigorous program to recruit, nurture, and mentor promising undergraduate science majors from traditionally underrepresented populations to professional careers in research in behavioral neuroendocrinology. The plan for this 10-week course is to 1) recruit these students to a career in science early in their undergraduate career by providing them with a significant research experience, 2) expose these students to the field of biological sciences at large through a capstone poster presentation with students in other research areas, and 3) retain these students in the field, through professional development and ongoing mentored support.

A persisting gap in recruiting talented students to careers in science is targeting students from historically underrepresented minority groups. The number of underrepresented minorities in neuroscience is woefully small despite the ever growing numbers of these populations in the US. The prevailing view, supported by studies of high school and college students, is that the solution to the problem of minority access to research careers is 1) to engage and nurture these students through early inclusion in research projects, coupled with 2) academic and social support and professional development. Exposure to effective role models, i.e. members of underrepresented minorities who have achieved a measure of success, is warranted as it allows students to see themselves in similar roles.

The overarching goal of the University of Minnesota Minority Undergraduate Summer Research Program (May 31-August 11) is to establish a rigorous program to recruit, nurture, and mentor promising undergraduate science majors from traditionally underrepresented populations to professional careers in research in neuroscience. This project will 1) recruit these students to a career in science early in their undergraduate career by providing them with a significant research experience, 2) expose these students to the field of biological sciences at large through a capstone poster presentation with students in other research areas, and 3) retain these students in the field, through professional development and ongoing mentored support.

DESCRIPTION (provided by applicant): In comparison to men, women are at an increased risk to abuse drugs. Across the spectrum of addiction, women show heightened intake of addictive substances, with greater craving, leading to an increased likelihood of addiction and relapse. These responses peak during the follicular phase of the menstrual cycle when estrogen levels are at their highest. These findings have been recapitulated in the female laboratory rat, where estradiol heightens multiple measures of drug responsiveness and abuse. Remarkably, the mechanisms by which estradiol mediates enhanced vulnerability to drug addiction are completely unknown. We propose a novel molecular mechanism mediating the actions of estradiol on nucleus accumbens neurons. Specifically we hypothesize that estradiol stimulation of estrogen receptor ? (ER?) localized to the surface membrane of nucleus accumbens neurons activates metabotropic glutamate receptor 5 (mGluR5) signaling. Activation of ER?/mGluR5 signaling by estradiol, in turn, affects nucleus accumbens spine structure, nucleus accumbens glutamatergic neurotransmission and ultimately responsiveness to drugs of abuse. Collectively, these studies will provide a foundation for developing novel therapeutic approaches targeted to treating drug addiction in women.

DESCRIPTION (provided by applicant): Disorders of the nervous system are becoming more prevalent in our society, especially considering the growing number of people with neurological disorders as our population ages. To meet the challenge of developing new and effective therapies to treat these disorders, we need to consistently inspire intelligent and talented undergraduate students to enter careers in neuroscience research. This need is particularly acute among populations of students who are currently underrepresented in the field of neuroscience research. Published analyses have made it clear that making students aware of research fields early in their college careers, especially by involving them directly in the research process, is an extremely effective way of developing a student's interest in research as a future profession. For over 25 years, the University of Minnesota has recognized and met this challenge by offering summer residential research programs in biomedical sciences. This proposal is to fund a neuroscience component of these summer programs in which we will train 8 undergraduate students who have completed their freshman or sophomore years in college. We will recruit students nationally, focusing on students from groups that are underrepresented within the neuroscience research profession. We will provide them with a 10 week intensive research experience that will include professional mentoring (academic survival skills and preparation for graduate school) as well as workshops on research ethics. Our goals are to inspire a new generation of neuroscience researchers as well as to create a national mentoring pool who will accept that responsibility for future generations of students. In turn, we expect these individuals to become part of the research infrastructure dedicated to solving medical problems of nervous system dysfunction.

A critical component of successful reproduction in female mammals involves integration with the male's reproductive state. How the female performs this integration is understood at the behavioral level, but is still poorly understood at the neurobiological level. A neural model will be developed to precisely measure chemical signaling of dopamine in a particular brain region (the nucleus accumbens) where dopaminergic activity is temporally synchronized with behavioral interactions with the male for successful reproduction. A technically sophisticated and innovative approach know as fast-scan cyclic voltammetry, combined with electrophysiological recording, will be used to measure dopamine release in the female's nucleus accumbens during reproduction and determine how nerve cells respond to dopamine-mediated signals. The fast scan cyclic voltammetry has the capability of measuring dynamic changes in dopamine signaling by taking measurements every 100 milliseconds, thus temporally coupling dopamine signaling and behavioral responses. This project will not only identify how the nervous system solves a complex problem of reproductive integration of brain and behavioral activities, but will also open up new avenues for detailed analyses of the neural regulation of reproduction and other social behaviors. The transfer of technology from Dr. Paul Garris's lab (Dr. Garris is a world leader in the development of fast-scan cyclic voltammetry) at Illinois State University to the University of Minnesota is a significant impact of the research goals. The project will also provide a platform for making this technology available to a range of investigators throughout the country. The development of this technology and subsequent dissemination will include making the raw data available online as well as creating online simulations that can be used as instructional tools through OmniScience (www.omnisci.org). The project will provide an important research base for the inclusion of undergraduate students, particularly underrepresented minority students, as a component of their science education and literacy.

DESCRIPTION (provided by applicant): This application requests support for the Eighth to Tenth Annual Meetings of the Organization April 24-26, 2014 on the Twin Cities Campus of the University of Minnesota, with the 2015 for the Study of Sex Differences (OSSD). The Eighth Annual Meeting of the OSSD will be held meeting sponsored by Stanford University (and held in San Francisco, CA) and the 2016 meeting sponsored by the University of Pennsylvania. The mission of the OSSD is to enhance knowledge of the biological basis of sex/gender differences in health and disease by facilitating interdisciplinary communication and collaboration among scientists and clinicians from diverse scientific and professional backgrounds. The primary goal of the OSSD annual meeting is to provide a forum for scientists to explore aspects of sex differences research at the genetic, molecular, cellular, organ, and systems levels in humans and model systems. The annual meeting consists of three independent symposia (one focused on New Investigators), ten parallel session symposia, and two poster sessions (highlighting the work of new investigators and trainees). Preliminary symposium topics for the 2014 meeting include: treatment of disorders of sexual development and gender dysphoria; sex differences in epigenetic mechanisms; sex differences in addiction; sex differences in response to neonatal hypoxic insult; report from the NIH SCOR programs; sex differences in drug and device development; sex, hypertension and the immune system; sex differences in the research pipeline; sex specific risk for cardiovascular disease; sex and gender differences in eating disorders. The OSSD Program Committee selects symposia topics from among proposals submitted by the membership. Proposals were selected on the basis of scientific merit, relevance to the goals of the OSSD, a balance of basic and clinical speakers, and rotation of topics of interest across annual meetings. The size and format of this meeting (150-200 participants) provides an excellent opportunity for networking opportunities and interactive discussions. Funds are requested to support registration fees for invited speakers (established, junior and trainee), travel expenses for junior investigators and trainees, and expenses related to the OSSD Annual Meeting Program Book and necessary audio-visual equipment rentals and associated technical support. The annual meeting program, including speaker and poster abstracts will be freely available on the OSSD website. We will partner with the University of Minnesota and the Mayo Clinic in Rochester, MN to organize this event and will request support from the pharmaceutical and biotechnology industries, local businesses, and private donors and foundations to help cover non-NIH costs.

DESCRIPTION Sexual dysfunction in women is primarily characterized by low levels of sexual arousal and desire. Because no effective treatments exist for disorders of sexual desire in women, the FDA was pressured to fast-track approval for the drug Addyi despite the absence of clinical evidence that the drug provided any therapeutic benefit. Underlying the inability to construct a rational approach to developing therapeutics for disorders of sexual desire in women is the lack of research on the mechanistic basis for female sexual desire in pre-clinical models. We have developed a Syrian hamster model of sexual desire that captures several essential elements needed to translate the findings to women. We developed a procedure to evaluate the rewarding properties of female sexual behavior, an element reported to be lacking in women with low sexual desire. Women with low sexual desire also do not initiate sexual contacts with their spouse or partner. In this regard we discovered an experimental approach to test the female hamster's willingness to initiate sexual contacts with a male. Based on these hamster studies we demonstrated that the rewarding consequences of sexual interactions with a male feed forward to increase the female's sexual contacts. We further identified the mesolimbic dopamine system, and prefrontal glutamatergic afferents, centered on the nucleus accumbens, as a critical neural node mediating the rewarding effects of sexual behavior in females. The research in this proposal takes three specific approaches to establish a programmatic understanding of the neurobiology of female sexual desire. In the first aim we will use inhibitory DREADDs to determine the relative contribution of dopamine and glutamate afferents to the nucleus accumbens to the development of sexual reward and initiation of sexual interactions with the male in our hamster model. We will also examine the contributions of these afferents to changes in dendritic spine morphology consequent to female sexual experience. The second aim takes a discovery approach to examining three possible intracellular signaling pathways mediating the effects of sexual experience on behavioral and morphological plasticity. The last aim will pharmacologically manipulate the individual signaling pathways to identify which of these pathways are potential molecular targets for therapeutic development to treat problems of sexual desire in women. Collectively this research will take a systematic approach to developing a neurobiology of female sexual desire with an eye to the rational development of effective therapies.

Despite the many initiatives designed to increase diversity among neuroscience researchers, the sad fact is that there has been a decline in the proportion and absolute numbers of minority researchers in the field of neuroscience. This failure is disturbing at a number of levels, but perhaps most notably highlights the inability of more senior investigators to effectively mentor junior investigators in their discipline. The loss of diversity among career scientists means a loss of diversity of thought, which in turn limits the generation of new ideas and scientific progress in the neurosciences. The inability of the multiple training programs to increase diversity is not an indictment of those programs, but rather it illustrates limitations in program approach. As a result, we propose to take a different route to addressing this problem. Our program is based on published findings that underrepresented individuals are lost in the system at transition points in their training, i.e., graduate school to postdoctoral training, postdoctoral training to faculty members, and tenure for young faculty. From self-report data, a principal contributing factor regarding attrition is that individuals feel isolated by not having meaningful ethnic and/or racial peer groups. In this R25 program we propose to take a longitudinal approach to mentoring in which we establish peer groups across each stage of professional development and utilize these peer groups to provide interactive mentoring within a community. We will recruit from across the nation a cohort of trainees from underrepresented backgrounds, consisting of graduate students, postdoctoral fellows, and early stage investigators. For each of these cohorts we will provide longitudinal training in professional skills and mentoring. Through both mentor/mentee and peer-to-peer/peer-to-near peer mentorship structures, we will tailor professional development consistent with the progression of the trainee, while simultaneously creating a network of support amongst its participants. A key element of the program will be to teach the participants in the program how to be effective mentors themselves as a means to maintain the longitudinal development of program participants. Finally, we will provide access to high-level research cores and laboratories to enhance the scientific impact of the participants? research. Participants will meet in Minnesota for one week each summer for professional training and guidance. For topics that span across career stage, the cohort will work together. There will also be specialized training sessions specific to academic rank. In addition to the on-site summer training, there will be two additional formal training events. In the fall, our trainees and mentors will meet at the annual Society for Neuroscience meeting to participate in both professional development and a social event. In the winter, there will be an on-line video teleconference discussion following the group?s completion of an on-line professional development session. Overall, our goal is to fundamentally alter mentored training, and significantly enhance workforce diversity in the academic pursuit of research on neurological disorders.