Gregory F. Ball - US grants

Ball 9514525 Numerous animals integrate various cues from the environment to predict the arrival of improving conditions associated with spring. Arguably the most critical cue is changing daylength, which is responsible for enhancing numerous behaviors including communicative behaviors. Increasing daylength also fosters marked chemical changes in the brain associated with the behavioral changes. In these receptive animals, secondary features may potentiate the positive aspects of increasing daylength. However, increasing daylength after a period of time precipitates the development of refractoriness which terminates behavioral enhancement and brain neurochemical changes. Dr. Gregory Ball is assessing the interplay between daylength and secondary characteristics in fostering seasonal behavioral changes. The studies include an identification of the neuronal circuitry responsible for mediation of the behavioral changes in the animals, as well as a demonstration of the specific secondary cues to which the animals respond. Studies to this point have not identified specific features of the environment other than daylength as enhancors of behavioral activity. These studies will be useful to understanding the survival of species in their nature habitats and the environmental cues to which they are most responsive.

This award is to provide travel fellowships to young American scientists to participate in an international symposium on avian endocrinology to be held in Edinburgh, Scotland on September 14-17th, 1992. State-of-the-art lectures will be held on a broad spectrum of topics from molecular to behavioral endocrinology. The emphasis of the symposium is on the integration of molecular approaches with the organismal level of analysis. In addition, the forum is organized to encourage and promote the interchange of ideas between the young scientists and well-established, senior investigators from all over the world. Indeed a goal is to bring together the researchers that are developing molecular probes with those that can provide insights as to potential experimental applications of these tools. Some very important initial discoveries have been made using avian model systems because it is in these species that molecular, cellular, behavioral, and ecological aspects of hormone action are best integrated. The integration from molecular to organismic levels could lead to a better understanding of basic mechanisms underlying physiology and behavior. The proceedings will be published in a book.

DESCRIPTION (Adapted from applicant's abstract): The goal of this research program is to elucidate the nature of the interaction between a steroid-sensitive neural circuit and the DAergic system. This interaction mediates, in part, the activation of masculine reproductive behavior. DA and testosterone are well-known to play a stimulatory role in the control of male reproductive behavior. It is, however, unclear how the activational effects of DA relate to the regulation of male sex behavior by testosterone. It is hypothesized that DA is part of the biochemical cascade initiated by testosterone that ultimately results in male copulatory behavior and that DA may facilitate male sexual behavior by increasing the behavioral effectiveness of testosterone. The proposed work capitalizes on a number of recent findings concerning the quail preoptic area (POA) which makes this a unique model: The quail POA contains a sexually dimorphic and testosterone-sensitive nucleus, the medial preoptic nucleus (POM), which provides a clearly defined morphological definition of the area critical for the action of testosterone on sexual behavior. The testosterone-metabolizing pathways (in particular its aromatization) mediating the activation of behavior have been described and an immunocytochemical (ICC) procedure has been developed that permits the visualization of aromatase-containing cells in the quail POA. DA turnover is sexually differentiated in the quail POM (higher turnover in males). Finally, in quail there is evidence that the DAergic system regulates aromatase activity in the POA. A series of 11 experiments are proposed that are designed to analyze four specific aspects of the DA action in the activation of male sexual behavior. The first set of experiments will characterize the central mechanisms controlling anticipatory aspects of sexual behavior and thereby provide a comparison with those mechanisms activating the consummatory aspects. A second set of experiments will have the goal of characterizing the DAergic inputs to the POM and nucleus Accumbens of the Stria Terminalis (Ac-nST) complex and their relation to the activation of anticipatory and consummatory aspects of male sexual behavior. The third series of experiments will investigate whether the sexual dimorphism in behavior and the dimorphism in preoptic aromatase activity can be explained, at least in part, by the dimorphism in DAergic activity in the POM. Finally, the fourth series of experiments will ask whether DA stimulates male sexual behavior by modulating the action of testosterone (changes in aromatization) or by acting on other steroid-dependent or -independent mechanisms.

technology /technique development; reproductive system; psychology; communication behavior; biomedical resource; bioengineering /biomedical engineering; Chordata; biomedical equipment development; endocrine gland /system; nervous system; behavioral /social science research tag;

The understanding of brain plasticity is an important challenge facing the neurosciences today. Brain plasticity refers to the fact that experiences of various sorts can lead to enduring changes in the structure and function of the adult nervous system. Investigating how these changes are regulated is essential if clinical brain interventions are to have a scientific underpinning. There are a variety of animal models of brain plasticity available, often involving responses to brain damage or neurodegenerative diseases. Another class of models investigates brain changes that occur naturally in response to salient environmental stimuli such as those regulating the timing of seasonal breeding (e.g. photoperiod). Seasonal changes in the brain of songbirds, such as canaries (Serinus canaria), are an example of such changes. The volume of brain nuclei involved in vocal control change seasonally and testoterone can promote neuronal growth and even modulate the occurrence of neurogenesis. However, the complete causal link from photoperiodic changes to the modification of morphology has not been established. Furthermore, testosterone is not equally effective in inducing changes in brain morphology at all times of the year and afferent neural input can influence steroid action. This proposal consists of five sections; in section I the goal is to characterize the noradrenergic innervation of the vocal control nuclei [Exps 1-4] as a necessary prelude for subsequent functional studies of the role played by this afferent input in the modulation of seasonal changes in the brain. Section II concerns the investigation of the photoperiodic and endocrine control of plasticity in the canary vocal control circuit [exps 5-6]. Physiological reasons for the variation in effectiveness of testosterone will be investigated in section III [Exps 7-8]. Section IV will investigate whether the noradrenergic inputs to vocal control nuclei change as a function of photoperiodic or hormonal manipulation [Exps 9-11] and section V is devoted to the investigation of whether seasonal/testosterone-induced changes in the orphology of the bovcal control nuclei are dependent on the presence of noradrenergic afferent inputs [Exp 12]. The goal of section VI [Exp 13] is to investigate whether seasonsal/testosterone-induced changes in the responsiveness of the neural substrate mediating steroid action ni the brain are dependent on the presence of noradrenergic inputs. Seasonal changes in the songbird brain provide a unique model system to study how naturally occurring stimuli can modify brain morphology.

DESCRIPTION (Adapted from applicant's abstract): The goal of this research program is to elucidate fundamental neuroendocrine mechanisms mediating the activation of reproductive behavior. It involves an investigation of the interrelationship among hormones, brain, and behavior and includes methods and experimental approaches appropriate to the study of all three of these components of the integrated system that governs hormone-dependent behaviors. The proposed experiments focus on the neuroendocrine mechanisms regulating appetitive and consummatory male sexual behavior in Japanese quail (Coturnix japonica). In particular the related roles played by the catecholamine, dopamine (DA), and the steroid metabolizing enzyme, aromatase, in relation to the activation by testosterone (T) of male reproductive behavior will be investigated. The proposed work capitalizes on previous findings concerning the neuroendocrine control of male sexual behavior in quail that make this species a unique model for these investigations. Especially notable is the ability to localize reliably at the cellular level both the protein and the mRNA of brain aromatase. In this application, 13 experiments are proposed that are designed to analyze three specific aims relating to the interaction of DA and brain aromatase in relation to the effects of T on the neural circuit mediating male sexual behavior. Aim I concerns the differential regulation of appetitive and consummatory aspects of male sexual behavior. Lesion and tract tracing studies, along with histological measures of neural activation, are proposed to characterize the neural circuit mediating these two components of male behavior [Expts 1-6]. Aim II is designed to investigate the dopaminergic regulation of aromatase and will involve both in vivo and in vitro studies of this interaction [Expts 7-11]. Aim III focuses on the identification of sex differences in the connectivity and chemical neuroanatomy of steroid-sensitive brain areas and their relationship to sex differences in the hormonal activation of appetitive and consummatory aspects of male sexual behavior [Expts 12-13]. The elucidation of the mechanisms mediating steroid effects on a neural circuit is relevant to many significant issues facing the field of behavioral neuroscience. Steroid hormones have been found to have wide ranging effects on brain morphology and plasticity both during development and in adulthood. The study of steroid-neurotransmitter interactions also may provide insight into the etiology of sexually differentiated or steroid-dependent diseases.

DESCRIPTION (provided by applicant): Understanding brain plasticity is a major challenge facing the neurosciences. One class of animal models useful for these studies involves brain changes that occur naturally in response to salient environmental stimuli that regulate seasonal variation in reproductive physiology. Seasonal changes in the brain of songbirds are one of the most dramatic examples of this natural neuroplasticity. This proposal analyzes the anatomical circuits and cellular events that mediate the effects of steroid hormones on singing behavior and on the morphological plasticity of song control nuclei and investigates the possible effects of singing on brain plasticity. Aim I will determine whether steroids act directly on neurons that are active during singing (Expt 1). Aim II concerns the role of catecholamines in song production by analyzing the relationships among tyrosine hydroxylase-immunoreactive inputs to song control nuclei, immediate early gene expression (IEG) and steroid receptors (Expts 2-4). Aims III and IV will investigate steroid controls of cellular signals that are implicated in the recruitment and survival of new neurons that contribute to seasonal changes in the brain. Aim III will analyze whether steroids act directly on cells that produce Brain Derived Neurotrophic Factor (BDNF) and will investigate the effects of singing on BDNF expression in song nuclei (Expts 5-6). Exp 7 will test with antisense techniques whether singing-induced IEG expression is required for the stimulaton of BDNF production. Reelin, a glycoprotein that plays a key role in neuronal positioning during ontogeny, was recently shown to be present and regulated by testosterone (T) in song nucleus HVc in adult birds. Aim IV will explore the role of reelin in the recruitment of new neurons into HVc by determining whether reelin receptors are present in newborn HVc neurons (Expt 8), characterizing the effects of T on reelin expression (Expts 9-12) and assessing the effects on neuronal incorporation of manipulations of reelin expression (Expt 13). Aim V (expt 14) will investigate whether the seasonal dissociations between the effects of T on song and on the growth of song control nuclei can be explained by the uncoupling of the response to T of some of the cellular responses investigated in the initial phases of the project. These studies will provide an integrated view of cellular mechanisms that mediate song expression and the associated seasonal neuroplasticity and will contribute to an understanding of whether brain changes can be mediated via changes in behavioral expression.

DESCRIPTION (provided by applicant): The goal of this research is to elucidate fundamental relationships among neurotransmitters, hormones, and brain function mediating the activation of appetitive and consummatory male sexual behavior in Japanese quail (Coturnix japonica). In particular the roles played by the catecholamine, dopamine (DA), and the testosterone (T) metabolizing enzyme, aromatase, in relation to the activation by T of male behaviors will be studied. The proposed work includes 12 experiments in 5 aims and capitalizes on findings concerning the neuroendocrine control of sexual behavior in quail that make this species a unique model for these studies. AIM I concerns the neural circuitry that controls the expression of sexual behavior and focuses on the specific projection of preoptic aromatase cells to the mesencephalic central gray (GCt). We will analyze the behavioral effects of estrogens produced in GCt (Exp 1) and a possible sex difference in the organization of this projection (Exp 2). AIM 2 will investigate the role of DA in the control of sexual behavior by analyzing the behavioral effects of central injections of DAergic drugs (Exp 3). AIM 3 will focus on the genomic mechanisms through which T controls the expression of male behavior and of aromatase activity (AA) by investigating sex differences in the expression of estrogen receptors (ERalpha and ERbeta) or of the steroid receptor coactivator-1 (SRC-1) (Exp 4) and analyzing the functional significance of SRC-1 by antisense techniques (Exp 5-6). AIM 4 focuses on rapid changes in AA mediated by phosphorylations and analyzes the reversibility of the aromatae inhibition by phosphorylations (Exp 7) and the contribution of excitatory amino acids to the control of rapid changes in AA (Exp 8). AIM 5 will investigate the effects of rapid variations in estrogen bioavailability due to fast changes in AA by -measuring the levels of 17beta estradiol (E2) present in aromatase cell groups (Exp 9), testing whether E2 rapidly affects the expression of male sexual behavior (Exp 10) as well as investigating rapid changes in the phosphorylation of CREB or tyrosine hydroxylase and tyrosine hydroxylase activity following exposure to E2 (Exp 11-12). These studies will provide new information about the interplay between steroid action and DAergic transmission in the activation of sexual behavior and thereby provide insight into the etiology of male sexual dysfunction and of sexually differentiated or steroid-dependent diseases.

DESCRIPTION (provided by applicant): The regulation of social interactions is of fundamental importance to both basic scientists and to clinicians interested in the etiology of mental illness. Such studies can produce general principles that will facilitate insights into the etiology and pathophysiology of mental disorders. This endeavor is a major goal of the NIMH and of this research program. The activation of social behaviors involves not only an individual being in the presence of an appropriate stimulus but also being in the appropriate motivational state. The steroid hormone testosterone is a pro-hormone that can be metabolized via the enzyme aromatase to an estrogen such as estradiol. In the preoptic area, the conversion of testosterone to estradiol is critical for the activation of both sexual motivation and performance. Estradiol ca act in two modes, a slow mode that involves binding to intracellular receptors and the induction of gene expression and a fast mode that involves interactions with the cell membrane and the activation of second messenger systems. Our recent work has shown that the fast actions of estrogens produced by brain aromatase are important for the activation of appetitive sexual behavior (motivational aspects) while the slower genomic actions are important for the activation of copulatory performance. In addition to the preoptic area, aromatase is widely distributed in brain nuclei of the social behavior network. One goal of the current proposal (Aim I) is to investigate in both males and females the function of estrogen production in other nuclei of the social behavior network besides the preoptic area and the effects of estrogens on motivational aspects of other social behaviors besides sexual behavior. Another goal (Aim II) is to study the rapid non-genomic effects of steroid hormones on male sexual motivation and whether these effects are specific to sexual motivation or extend to other motivated responses. We will also assess the neuroanatomical target sites of these effects. Subsequent studies in Aim III will address some the cellular mechanisms of these effects. For example, there is evidence that estrogen receptors embedded in the cell membrane interact with receptors for the excitatory amino acid receptor glutamate. The anatomical pattern of such interactions and the role they play in motivation will be investigated. Finally in the last aim (IV) the rapid regulation of the enzyme, aromatase, that converts androgens to estrogens will be studied. We will assess how behavioral situations that modulate motivation might also modulate aromatase that in turn will affect how much estradiol is available in specific brain areas related to behavioral activation.

DESCRIPTION (provided by applicant): The regulation of social interactions is of fundamental importance to both basic scientists and to clinicians interested in the etiology of mental illness. Such studies can produce general principles that will facilitate insights into the etiology and pathophysiology of mental disorders. This endeavor is a major goal of the NIMH and of this research program. The activation of social behaviors involves not only an individual being in the presence of an appropriate stimulus but also being in the appropriate motivational state. The steroid hormone testosterone is a pro-hormone that can be metabolized via the enzyme aromatase to an estrogen such as estradiol. In the preoptic area, the conversion of testosterone to estradiol is critical for the activation of both sexual motivation and performance. Estradiol ca act in two modes, a slow mode that involves binding to intracellular receptors and the induction of gene expression and a fast mode that involves interactions with the cell membrane and the activation of second messenger systems. Our recent work has shown that the fast actions of estrogens produced by brain aromatase are important for the activation of appetitive sexual behavior (motivational aspects) while the slower genomic actions are important for the activation of copulatory performance. In addition to the preoptic area, aromatase is widely distributed in brain nuclei of the social behavior network. One goal of the current proposal (Aim I) is to investigate in both males and females the function of estrogen production in other nuclei of the social behavior network besides the preoptic area and the effects of estrogens on motivational aspects of other social behaviors besides sexual behavior. Another goal (Aim II) is to study the rapid non-genomic effects of steroid hormones on male sexual motivation and whether these effects are specific to sexual motivation or extend to other motivated responses. We will also assess the neuroanatomical target sites of these effects. Subsequent studies in Aim III will address some the cellular mechanisms of these effects. For example, there is evidence that estrogen receptors embedded in the cell membrane interact with receptors for the excitatory amino acid receptor glutamate. The anatomical pattern of such interactions and the role they play in motivation will be investigated. Finally in the last aim (IV) the rapid regulation of the enzyme, aromatase, that converts androgens to estrogens will be studied. We will assess how behavioral situations that modulate motivation might also modulate aromatase that in turn will affect how much estradiol is available in specific brain areas related to behavioral activation.

Project Summary Basic and clinical research that was initiated in the late 20th century and continues to this day has transformed our thinking about brain resilience. The term brain plasticity is often invoked to describe adaptive changes in the adult brain. This proposed research program concerns the study of neuroplasticity in a seasonal context. This phenomenon involves naturally occurring brain changes that allow an animal to cope with seasonal variation in the physical and social environment to facilitate survival and reproductive success. We study how the steroid hormone testosterone regulates brain changes and the associated changes in behavior in seasonally breeding male and female canaries. These birds possess a well-defined neural circuit, called the song system, which regulates an important learned social behavior, song. Song varies seasonally in that it is more common and more complex in spring when it is produced primarily by males to attract females. Females also produce song but at a lower rate with simpler structure. Key forebrain song nuclei are much larger in volume in the spring in males than in the fall when song is produced less frequently; these song nuclei volumes also are larger in males than in females. Such seasonal changes in brain and behavior may recapitulate behavioral and brain plasticity that occurs during the vocal learning process. Our recent work in canaries has shown that testosterone acts in a pleiotropic manner to regulate multiple aspects of song behavior by having anatomically specific effects in the forebrain song nuclei and in the medial preoptic area, that testosterone can induce male-like changes in neurogenesis and in song behavior in adult female canaries but apparently cannot induce a complete sex reversal, and finally that species variation in perineuronal nets (specialized structures of the extracellular matrix) correlates with species variation in adult vocal plasticity. In this proposal, we capitalize on these findings by investigating the regulation by steroid hormones of brain plasticity and the related song learning and behavior as well as sex differences in their action. The proposal is organized into four aims. In Aim I we ask whether steroid hormone-induced plasticity in the song control nucleus is similar in males and females. Aim II investigates indirect effects of testosterone on song behavior and brain activity related to song by assessing how steroid action in the medial preoptic nucleus indirectly facilitates song-related immediate early gene expression and singing behavior in the song control circuit. Aim III addresses the critical question of the function of adult neurogenesis in songbirds as we will ablate neuroblasts in a site-specific manner with the use of the focused X- ray irradiation method in the ventricular zone in testosterone-treated male and female canaries and assess the morphological and behavioral consequences of these ablations. In Aim IV we will test the hypothesis that perineuronal nets play an important role in limiting brain and behavioral plasticity as it applies to song learning. This research will contribute to the development of more mechanistic insights into brain plasticity as well as help us identify how steroid hormones might serve in a neuroprotective and/or cognitive enhancer-like manner.

This collaborative research brings together five public universities with the goal of developing, implementing, studying, evaluating and disseminating a state level AGEP Alliance model to increase the number of historically underrepresented minority (URM) tenure-track faculty in the biomedical sciences. This AGEP Alliance model represents a state system approach to recruiting and training URM postdoctoral fellows and transitioning them into tenure-track faculty positions. In addition to providing professional development and mentoring for a group of 16 URM postdoctoral fellows and early career faculty, this AGEP Alliance also addresses institutional URM faculty hiring and advancement policies and practices. This AGEP Alliance model work is through partnerships between the University of Maryland Baltimore County, Salisbury University, Towson University, the University of Maryland College Park (UMCP), and the University of Maryland at Baltimore.

This alliance was created in response to the NSF's Alliances for Graduate Education and the Professoriate (AGEP) program solicitation (NSF 16-552). The AGEP program seeks to advance knowledge about models to improve pathways to the professoriate and success of URM graduate students, postdoctoral fellows and faculty in specific STEM disciplines and/or STEM education research fields. AGEP Transformation Alliances develop, replicate or reproduce; implement and study, via integrated educational and social science research, models to transform the dissertator phase of doctoral education, postdoctoral training and/or faculty advancement, and the transitions within and across the pathway levels, of URMs in STEM and/or STEM education research careers. While this Alliance is primarily funded by the AGEP program, additional support has been provided by the NSF INCLUDES program, which focuses on catalyzing the STEM enterprise to collaboratively work for inclusive change. The ADVANCE program also provided support for this AGEP Alliance model work, and the ADVANCE program embraces three goals that are relevant to this Alliance model's development, implementation and testing: To develop systemic approaches to increase the participation and advancement of women in academic STEM careers; to develop innovative and sustainable ways to promote gender equity that involve both men and women in the STEM academic workforce; and to contribute to the research knowledge base on gender equity and the intersection of gender and other social identities in STEM academic careers.

As the nation addresses a STEM achievement gap between URM and non-URM undergraduate and graduate students, our universities and colleges struggle to recruit, retain and promote URM STEM faculty who serve as role models and academic leaders for URM students to learn from, work with and emulate. Recent NSF reports indicate that URM STEM associate and full professors occupy 8% of these senior faculty positions at all 4-year colleges and universities, and about 6% of these positions at the nation's most research-intensive institutions. This AGEP Alliance's state system approach is advancing a model to improve the success of URM early career biomedical sciences faculty, which ultimately leads to improved academic mentorship for URM undergraduate students in STEM and innovative biological science research to benefit our nation's security, economic progress and prosperity.

The integrated research component, led by UMCP's KerryAnn O'Meara examines how the intersectionality of race, ethnicity and gender shape the experiences of candidates for assistant professorships, and the evaluation of those candidates by reviewers. Institutional faculty hiring practices, processes and procedures are also being studied to better understand how they advantage or disadvantage some candidates over others.

This AGEP Alliance state system model is engaging institutional leadership and external advisory boards, which will provide feedback to the team and suggest adjustments to model development, implementation and testing, as well as efforts for institutional transformation and sustainability. Staff at Westat will provide formative and summative evaluations. The dissemination plan includes article submissions to peer-reviewed social science, academic career diversity, and disciplinary education and research journals.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.