Martha K. McClintock - US grants

The timing of female fertility can be altered by social signals from females in a social group. In rats, ovulation can be accelerated by odors from pregnant or preovulatory females and delayed by odors from lactating or ovulatory females. These odors are pheromones and may result in the synchronization or suppression of estrus within the social group, two different strategies for achieving successful reproduction under different conditions and examples of the behavioral regulation of fertility. We propose to: (1) Identify the hormonal response to odors produced during the birth cycle (pregnancy, birth, and lactation) and the estrous cycle, using a modified jugular cannulation technique. Our technique is novel, because it permits repeated sampling of several steroids and gonadotropins from intact female rats. Because this type of data has not been available previously, even our baseline data will be unique and useful. Once we have established the normal relationship of these hormones, we will be able to assess the effect of birth and estrous cycle pheromones on that relationship and distinguish among several hypothesized mechanisms for controlling the time of ovulation. (2) Determine the endocrine basis for individual differences in fertility that may affect differential reproductive success, including individual differences in vulnerability to birth cycle pheromones, reproductive behavior, and length of the reproductive lifespan. (3) Finally, we will determine whether birth cycle pheromones mediate the social suppression of postpartum fertility, a phenomenon that may have particular significance for the evolution of pheromonal regulation of female fertility.

The Committee on biopsychology at the University of Chicago spans the Division of Social and biological Sciences and has provided national leadership for the discipline since its inception. The Committee studies behavior and its bi- directional interaction with neural and endocrine mechanisms and its ecological and evolutionary context. The strength of the committee derives from bringing all three levels of analysis together as an integrated system, including mental processes and integrative physiological systems other than the brain. This degree granting Committee is unique in the nation because it combines the biopsychology of humans with the biopsychology of animals. The University of Chicago is the only university to provide both graduate and undergraduate training in behavioral neuroscience and endocrinology and this award enables them to renovate their research and research training space in this important research area.

vomeronasal systems; olfactory stimulus; menstrual cycle; glucose metabolism; pheromone; olfactions; hormone regulation /control mechanism; behavioral /social science research tag; clinical research; positron emission tomography; human subject;

DESCRIPTION (provided by applicant): Understanding human cancer in the context of the social environment is essential for optimizing cancer prevention and care. By identifying stress mechanisms that impact on a patient's neuroendocrine physiology and subsequent tumor biology, we will increase our understanding of tumor biology. The neuroendocrine system links behavior and experience with hormone secretion (e.g. estrogen and cortisol) resulting in hormone-induced gene expression changes within both tumor cells and their microenvironment. However, the cellular and molecular mechanisms underlying the role of chronic stress in breast tumor biology remain poorly understood. Because of the complex genetic and environmental variation found in human populations, identifying the cellular and molecular mechanisms through which stress responses affect cancer biology will require transdisciplinary approaches to traditional models already used for studying cancer. The Conzen and McClintock laboratories have developed such an approach to studying the role of social stress in two complementary rodent models of human breast cancer. We discovered that chronic social isolation leads to a heightened glucocorticoid response to a superimposed stressor; in turn, mammary gland gene expression and morphology suggest an alteration in adipose tissue architecture during gland development. Moreover, social isolation and the ensuing increased stress (glucocorticoid-mediated) reactivity are associated with a significant increase in mammary gland fat metabolism, even prior to invasive cancer development. Based on these data, we propose to study mammary gland fat tissue and its paracrine effects on tumor growth by identifying the gene expression changes as well as the secreted proteins and factors that can contribute to increased tumor growth rates. We predict that completion of these studies will uncover novel stress-induced microenvironment mechanisms affecting mammary tumor growth.

Project Summary The epidemic increase in the prevalence of diabetes and obesity is a public health crisis. Addressing this epidemic requires understanding the variation within the population in how people transition among non- diabetic, pre-diabetic, and diabetic states, as well as their morbidity and mortality. A comprehensive study of all transitions and outcomes in a nationally-representative sample of US older adults is critical to accurately forecast future prevalence and demand for health care. Equally important is identifying novel approaches to reduce diabetes risk, its complications and mortality. While behavioral interventions are beneficial, we have early evidence that people?s social interactions may also independently reduce diabetes risk and progression. Our central hypothesis is that a significant portion of individual variation in diabetic trajectories is associated with different social environments. We will test our hypotheses by (1) combining two high- quality, national datasets, each with unique strengths, creating a synthesized data set more comprehensive than either alone and (2) assaying a broad panel of biomeasures (including A1C). The National Social Life, Health, and Aging Project (NSHAP) has collected longitudinal data at three waves (2005, 2010 and 2015 (2015 biomeasure to be assayed here), health data, medication usage, as well as the most comprehensive assessment of social relationships and intimate partners of any national survey of older adults. The Health and Retirement Study (HRS) has also collected longitudinal A1C and social data from a larger sample of older adults bi-yearly since 2006. The proposed analyses combine these datasets to increase the precision of our estimates, while leveraging NSHAP?s unique social and biological data. The tools we develop for combining and analyzing these datasets are applicable to other chronic diseases and conditions of aging and will be made freely available to the research community, along with complete biomeasure data, providing an invaluable public resource for studying a wide range of health issues. For Aim 1, we will estimate the transition rates among non-diabetic, pre-diabetic, and diabetic states in the U.S. population of older adults by obesity, health status, and demographic subgroups. For Aim 2, we will test the hypothesis that social factors such as large social networks, positive social and intimate relationships, social support, social participation, social stress-buffering and low levels of isolation and loneliness are associated with a lower likelihood of diabetes progression and even reversals. For Aim 3, we will test whether differences in the rate of diabetic transitions are mediated through specific physiological (inflammation, stress biology, sex steroids) and health behavior mechanisms (activity and sleep). Understanding the mechanisms by which social factors affect diabetes risk may help 1) better target specific types of social interventions to the social context of individuals, 2) demonstrate how social interventions need to vary by diabetic transition, and 3) identify key members of a social network that would be most effectively targeted as part of a social intervention.

PROJECT ABSTRACT The developing mammary gland (MG) is vulnerable to environmental and lifestyle risk factors that increase breast cancer (BC) burden in later adulthood. Therefore, optimizing BC prevention and care requires a lifespan approach to identify specific early life risk factors, to understand these risk factors? underlying molecular mechanisms in promoting cancer risk, and to design appropriate interventions that reduce BC in adulthood. Using a Sprague-Dawley rat model of human BC, we have established a dynamic and successful transdisciplinary collaboration among a breast cancer biologist, an endocrinologist, and a biopsychologist to understand how adverse early life exposures lead to increased mammary cancer risk in adulthood. We find that glucocorticoid (GC) reactivity to everyday stressors is heighted by social isolation in puberty and young adulthood and is associated with increased adult mammary cancer burden. Moreover, heightened GC reactivity during puberty impairs ductal development and increases mammary stem cell populations, two characteristics that have been linked to increased mammary cancer. We now propose to determine how heightened GC reactivity disrupts MG development and increases cancer burden by examining the underlying molecular mechanisms connecting glucocorticoid receptor (GR) activation with MG developmental defects (Aim 1). In Aim 2 we will introduce both pharmacological- and social environmental-interventions in early adulthood to reverse heightened stress reactivity. We predict these interventions will restore normal MG ductal differentiation and thereby decrease later cancer risk. In Aim 3, we will examine how heightened GC reactivity during puberty inappropriately preserves mammary stem cell (MaSC) populations that are known to increase later cancer risk. We will also investigate the association between circulating steroid hormone levels, in conjunction with their localized production within the MG microenvironment, and ductal maturation and MaSC biology. Completion of these studies will uncover novel stress-mediated molecular and cellular mechanisms of disrupted MG development linked to subsequent mammary cancer and determine whether these stress- mediated events are reversible with early adulthood interventions.