Lisa A. Eckel, PhD - US grants

Anorexia nervosa is a complex eating disorder characterized in part by hypophagia, disorganized eating patterns, body weight loss, hyperactivity, and a dysregulation of the hypothalamic-pituitary-gonadal axis. About 90% of diagnosed cases involve women. Therapeutic treatment of the symptoms of anorexia nervosa is limited due to our lack of understanding of the multiple factors underlying this complex disorder. Animal studies have shown that female rats maintained on a food restriction schedule and given free access to running wheels display hypophagia, rapid body weight loss, increased running wheel activity, and a disruption of ovarian reproductive function. Because these symptoms are similar to the symptoms of anorexia nervosa, this paradigm has been used as an animal model of anorexia nervosa. The aim of this proposal is to use this animal-based model to investigate (a) the spontaneous feeding patterns of female rats with activity-based anorexia, (b) whether estradiol modulates susceptibility to activity-based anorexia, and (c) the patterns of meal-stimulated neuronal activation in female rats with activity-based anorexia: Female rats will be housed in custom-designed cages that permit the continual monitoring of spontaneous feeding and running wheel activity. The effects of estradiol on the development of activity-based anorexia will be investigated in ovariectomized rats with and without estradiol replacement. Finally, c- Fos immunohistochemistry will be used to visualize changes in meal- stimulated neuronal activity. This research will provide novel information regarding the behavioral, hormonal, and neural substrates of activity-based anorexia and will, therefore, provide a foundation for future experiments investigating the mechanism underlying activity- based anorexia. A long-term goal of this research effort is to identify the neurochemical substrate underlying anorexia nervosa in the hope that this may lead to the development of more effective pharmacotherapeutic treatments and intervention programs.

DESCRIPTION (provided by applicant): The ovarian cycle has profound effects on food intake in a variety of species, including humans. This effect is very prominent in female rats which display a 20 - 40 percent decrease in food intake during the estrous (sexually receptive) phase of the cycle. This decline in food intake during estrus appears to be mediated, at least in part, by increased sensitivity to the satiety effects of cholecystokinin (CCK), a gut peptide that is released during meals and functions to decrease food intake by generating a satiety signal that is relayed to the brain via the vagus nerve. The importance of the rat's ovarian cycle in the control of food intake is revealed by ovariectomy, which increases food intake, decreases sensitivity to CCK, promotes body weight gain and, in the absence of estrogen replacement, induces obesity. Although the decline in estrogen activity appears to mediate the hyperphagia and associated body weight gain following ovariectomy, it is not known whether changes in endogenous estrogen activity mediate the decrease in food intake and increase in CCK satiation expressed during estrus in cycling rats. One goal of this proposal is to determine whether antagonism of central estrogen receptor activity will block the estrous-related decrease in food intake and increase in CCK satiation. To investigate this hypothesis, food intake and meal patterns will be monitored in cycling rats treated with an antiestrogen at various phases of the estrous cycle. A second goal is to use c-Fos immunocytochemistry, a marker of neuronal activity, to determine whether increased sensitivity to the satiety effects of CCK during estrus is mediated by increased responsivity of neurons that process satiety signals generated by consumption of a meal and by injection of CCK. A third goal of this proposal is to determine the brain areas where endogenous estrogen acts to decrease food intake and increase CCK satiation during estrus. In this experiment, in situ hybridization and immunocytochemistry techniques will be combined to determine whether those neurons that are activated by CCK express estrogen receptors. Together, these studies have the potential to broaden our understanding of the mechanism by which food intake is controlled across the estrous cycle of female rats. Because eating disorders are more prevalent in women than in men, this proposal targets an important research question with clear clinical relevance .

The ovarian hormone estradiol has profound effects on most, if not all, of the nervous system. As a result, estradiol influences a variety of physiological functions and,therefore, behavior. Among its varied actions, estradiol exerts a potent inhibitory effect on food intake that is expressed in a variety of species, including humans. In recent years, this action of estradiol has been linked to the development of eating disorders, as well as the increase in appetite and weight gain that is often observed in estradiol-deficient, postmenopausal women. A crucial first step in understanding how estradiol may contribute to either of these conditions is to determine how it affects the controls of food intake in healthy animals. Available evidence suggests that the inhibitory effect of estradiol on food intake is mediated by its ability to increase the strength of other key elements within the satiety-signaling system. Here, we propose to investigate several fundamental questions regarding the possible interaction of estradiol and serotonin (5-HT), one such satiety signal, in the control of food intake in the female rat.A combination of behavioral, pharmacological, antomical, and molecular techniques will be used to investigate our central hypothesis, which is that an increase in 5-HT neurotransmission mediates the anorectic effect of estradiol in the female rat. In Specific Aims 1 and 2, we will establish brain regions that are both necessary and sufficient for the estrogenic inhibition of food intake. In Specific Aim 3, we will determine whether increased activation of postsynaptic 5-HT2C receptors contributes to the estrogenic inhibition of food intake. In Specific Aim 4, we will determine whether estradiol acts with the midbrain raphe system to increase the release and/or turnover of 5-HT within specific brain regions implicated in the control of food intake. Successful completion of these studies will broaden our understanding of the behavioral and neurobiological mechanisms underlying the anorectic effect of estradiol. Because our proposed studies focus on an interactive effect of estradiol and 5-HT in the control of food intake, and abnormalities in serotonergic function have been identified in women with anorexia nervosa, completion of this work has the potential to reveal how estradiol may function as a risk factor for eating- related disorders. Thus, this proposal targets an important research question with clear clinical relevance.

Research in behavioral science is beginning to establish important connections between human behavior, cognition, and biology. The way people think and what they strive for is fundamentally grounded in complex physiological systems -- systems that have been designed through evolution to help people face everyday challenges that are part of social living. Hormonal systems are designed to help people respond adaptively to particular types of social events, including social threats. Emerging research suggests that the release of particular hormones is associated with a variety of motivated responses to social threat, from unselfish helping behavior to aggression and antisocial behavior. The proposed work will advance this general idea.


One major type of social threat that humans regularly face is social exclusion. Exclusion can take forms such as peer rejection, ostracism from a social or work group, or romantic rejection. Regardless of where exclusion originates, research shows that it evokes a range of motivated psychological and behavioral responses. Some of those responses are highly favorable. For instance, sometimes rejected people display increased interest in making friends and behave in kind and generous ways, presumably to regain social acceptance. Other responses to social threat, however, are highly destructive. Rejection can elicit aggression, a sense of meaninglessness, depression, social withdrawal, and even suicide.


Many studies have now investigated psychological and behavioral responses to exclusion. Yet very little work has sought to uncover the basic physiological mechanisms underlying those responses. Understanding those physiological mechanisms is a critical part of identifying the broader processes that lead people to behave constructively or destructively in response to rejection. The proposed work will examine a variety of hormonal responses to social exclusion because such responses provide a window into people's immediate motivational states and tendencies to perform prosocial and antisocial behaviors. Past research suggests that progesterone, cortisol, and testosterone (hormones associated with social bonding, stress, and social dominance, respectively) play a critical role in determining people's responses to exclusion. The proposed experiments will examine the effect of exclusion on hormones such as progesterone, cortisol, and testosterone. Studies will also evaluate the extent to which the release of these hormones following rejection promotes specific prosocial and antisocial behaviors including altruism, affiliation, aggression, and social withdrawal.

Understanding when, why, and for whom positive and negative social behavior occurs is a critical step toward encouraging or modifying such behaviors. Consequently, this research program has implications for improving societal outcomes within a range of personal, social, and organizational contexts, from marriages to school and work settings. The research will also foster deep connections between psychology, cognitive science, and behavioral neuroscience -- research areas that heretofore have had relatively little contact. Finally, the execution of this research will involve the training of several graduate and undergraduate students, many of whom are from groups that are presently underrepresented in science careers.

DESCRIPTION (provided by applicant): Translational research represents a major initiative for advancing knowledge of all forms of psychopathology. This work includes translating the neural mechanisms that underlie normal and abnormal behavior in animals into clinical studies of the causes and treatment of mental disorders. However, segregation of doctoral training in Neuroscience and Clinical Psychology, with separate course requirements, lab experiences, and exposure to outside speakers, impedes new scientists' preparation to undertake translational approaches in their own research. The broad, long-term objectives of the proposed Integrated Clinical Neuroscience (ICN) Training Program are to train the next generation of researchers to become leaders in translational research who will make key contributions across several areas of psychopathology characterized by dysregulated (disinhibited) behaviors including eating disorders, suicidality, psychopathy, and externalizing spectrum disorders. These problems are associated with significant psychological and medical morbidity, elevated mortality, and high economic burden, underscoring the need for translational approaches. The ICN Training Program will provide integrated instruction and supervision to 4 predoctoral trainees earning Ph.D.s in Clinical Psychology and Neuroscience at Florida State University through several components: 1) cross-area courses, 2) cross-area lab rotations to conduct collaborative, cross-area dissertation research, 3) a Special Speaker Series in which national scholars conducting translational work will present their research to trainees, and trainees will present their ongoing research to invited speakers, ICN training faculty, the Department, and community, 4) presentation of research at conferences and in published papers, as well as 5) instruction in grant writing and additional (cross-area) instruction in the responsible conduct of research. Predoctoral trainees will apply for the ICN Training Program by describing research they plan to conduct in collaboration with their primary advisor and cross-area mentor, classes they will complete, and how the ICN Training Program will contribute to their career development as translational scientists. ICN training faculty come from the Clinical and Neuroscience programs based on cross-area connections in research addressing dysregulated behaviors. Trainees will be appointed at the beginning of their third or fourth year to ensure selection of the most promising trainees who have completed basic program requirements and have established research in their primary advisor's lab that they can extend through work in a cross-area lab rotation. The duration of support will be 2 years. This timing and duration optimize benefit of training grant support for completion of dissertation research. Training facult have strong track records of NIH funding and in training students for productive research careers. The proposed training grant will build upon this success by ensuring that new Ph.D. students are ideally positioned to initiate cutting-edge translational research as they develop independent programs of research to address mental disorders characterized by dysregulated behaviors.

Humans, like many other vertebrate species, developed a physiological immune system designed to detect and destroy harmful organisms that have entered the body. Recent research suggests that, in addition to this physiological immune system, there evolved a behavioral immune system comprised of psychological and behavioral mechanisms designed to detect and defend against pathogen threats even before they enter the body. For example, people are quick to notice and avoid others who display cues of infection (e.g., coughing, lesions). The studies in this proposal will examine the behavioral immune system in depth, and link its action to multiple aspects of physiological and psychological functioning.

Past research has treated the physiological and behavioral immune systems independently. Yet, an evolutionary perspective suggests that there should be an adaptive relationship between physiological and psychological functioning. Thus, the studies in this proposal test the prediction that concerns about disease increase behaviors designed to prevent initial contagion (e.g., avoiding others who appear sick), as well as increase physiological processes designed to destroy pathogens that have entered the body (e.g., secretion of cytokines). Activation of both behavioral and physiological immune systems would provide the best possibility of overcoming a disease threat.

This research also examines the specific processes underlying behavioral immune system activation. To be effective, the behavioral immune system must be sensitive to the possibility of contagion. Some physical characteristics are more associated with disease than other physical characteristics (e.g., the presence of a rash more than hair color). In addition, sometimes people feel more susceptible to disease than at other times (e.g., after touching a bloody cut versus after washing their hands). We propose that both of these factors - implicit disease associations and perceptions of disease susceptibility - influence the degree to which the behavioral immune system is activated.

Last, this research examines ways of down-regulating behavioral immune system activation. Prior research suggests that disease concerns can lead people to avoid and have negative attitudes toward individuals who, although are not actually contagious, display physical characteristics that are stereotypically associated with disease (e.g., obesity). Thus, understanding ways of down-regulating such disease-based anti-social behavior is key for reducing prejudice and discrimination. Our studies examine how minimizing disease-associations (e.g., decreasing the link between disease and obesity) as well as reducing perceptions of disease susceptibility (e.g., making people feel immunized against disease) can reduce behavioral immune system activation and therefore decrease prejudice toward groups stereotypically associated with disease.

In sum, the studies in this proposal integrate research from social cognition, immunology, and evolutionary psychology to test three broad hypotheses: (1) Behavioral immune responses to disease threat are complemented by anticipatory physiological immune responses (2) Behavioral immune system activation is mediated by those physiological responses and by specific implicit cognitions, and (3) The behavioral immune system can be down-regulated by manipulating those implicit cognitions. The results of these studies will have an important impact on theoretical and empirical work in social psychology, cognitive science, and other related domains of study. The proposed research is therefore interdisciplinary in nature, and will foster synergistic connections between research in domains that historically have had relatively little contact but are increasingly being integrated (e.g., psychophysiology and prejudice). Additionally, the execution of the proposed research will involve training for both graduate and undergraduate students
from groups underrepresented in science careers.