Martha K. McClintock - US grants

When female rats five together in groups, their ovarian cycles become synchronized, analogous to the menstrual synchrony observed in groups of women. Ovarian synchrony represents the behavioral control of endocrine function. Among rats, the social signals that regulate the timing of the ovarian cycle are pheromones from different phases of the ovarian cycle. These pheromones can either advance or delay ovulation. In rats, we will continue our research program that integrates studies of the neuroendocrine mechanisms underlying pheromone action with complementary studies of their behavioral function and potential adaptive advantage. In addition, our strong data base in rats has now set the stage for the first definitive test of the existence of human pheromones as mediators of menstrual synchrony among women. 1. We have conceptualized ovarian synchrony as a system of coupled oscillators and developed a powerful and biologically realistic computer model that successfully simulates ovarian synchrony in rats. This computer model has generated specific testable predictions about the neuroendocrine mechanisms of pheromone action in rats. We will use our modified jugular-cannulation technique that enables us to measure hormones repeatedly from the same female rat over several weeks to determine: (a) whether ovulatory pheromones prolong cycles by changing the timing or height of the luteinizing hormone surge (LH, the hormone that triggers ovulation); (b) when rats are sensitive to these pheromones; and (c) the neuroendocrine basis for individual differences in pheromone sensitivity and timing of the LH surge. 2. We will continue to study the function of ovarian pheromones for rats by identifying specific ways that pheromones can confer a selective advantage through their effects on synchrony of birth cycles. For example, rat litters born asynchronously have more female than male pups. We will test the effects of four correlates of birth-cycle synchrony that could produce a female-biased sex ratio, potentially identifying the first known physiological mechanism for a facultative sex ratio bias in mammals. To facilitate the analysis of behavior, we will use a computerized video analysis system. 3. We will provide the first definitive evidence that human pheromones exist that could generate menstrual synchrony among women. We will evaluate the effect of putative pheromones by measuring their effects on the time of ovulation and length of the menstrual cycle. In order to do this, we need improved precision in predicting the day of ovulation and thus have developed a new protocol for predicting ovulation in women that is based on LH levels in a single daily urine sample and, to date, has a 94% accuracy.

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.

Our goal is to identify the neuroanatomical pathways that mediate pheromonal responses in humans. We have determined that women are most senstive to putative pheromones in the late follicular and periovulatory phases of their menstrual cycle. We will use Positron Emission Tomography to study the functional neuroanatomy of the response to olfactory stimuli at that time and determine whether there is evidence for an accessory olfactory system, distinct from the main olfactory system. The role of the CRC will be to collect blood and urine samples and run or provide support for the assays needed to verify menstrual cycle phase.

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.