Date

2015

Document Type

Dissertation

Degree

Doctor of Philosophy

Department

Integrative Biology

First Adviser

Benton, Noah A.

Other advisers/committee members

Schneider, Jill; Swann, Jennifer; Burger, Michael; Kriegsfeld, Lance

Abstract

Reproduction and energy metabolism are linked, and the interaction between these two biological systems is important for understanding obesity, infertility, sexual dysfunction, and eating disorders. Little is known about energy-reproduction interactions in natural systems, but understanding the underlying neuroendocrine mechanisms in biologically relevant contexts will be essential for understanding disease. This might be particularly true for diseases that are the result of human-made environments, such as modern, western, industrialized societies in which food is readily available with no energy expenditure required to procure this food. Obesity, diabetes, and metabolic syndrome are rampant in such societies and there are sex differences in the incidence of these diseases that have been linked to reproductive hormones. My work examines the basic biology of the link between energy intake, storage, and expenditure, and reproduction. In the laboratory model system that I study, the Syrian hamster (Mesocricetus auratus), reproductive and ingestive behaviors fluctuate over the ovulatory cycle, and these behavioral fluctuations are amplified by mild deficits in energy availability. For example, in female hamsters, mild food restriction (75% of ad libitum intake) increases food hoarding and decreases the preference for spending time with males vs. spending time with food, but only on days of the estrous cycle when ovarian steroid secretion is relatively low. These particular behaviors (food hoarding and spending time with males) provide a window into motivation, and the data suggest that there is an important interaction between hormones and energy metabolism that controls these two behaviors. It is possible that effects of hormones on behavior are masked by the overabundance of food, an effect that would be expected to occur in women from western, industrialized nations who do not limit their food intake. It is not known, however, how food availability interacts with the hormones of the estrous cycle to set behavioral priorities. I therefore examined the interaction of energy availability with ovarian steroid hormones to rank the motivation to engage in ingestive or reproductive behavior This work is unique in that it examines behavior under semi-natural conditions that mimic important aspects of the natural environment. I used a simulated burrow system, which had been used previously by members of the Schneider laboratory to demonstrate that hormonally-controlled fluctuations in the choice between ingestive and sex behaviors are amplified by food restriction. In Chapter 2, I extended the list of amplifying factors to include not only food restriction, but also exercise and cold ambient temperature, showing that hormonal effects on behavior are responsive to the general availability of metabolic fuels as determined by not only energy intake, but also energy expenditure and storage. I further hypothesized that interactions between energy availability and ovarian steroid hormones would be related to 1) circulating levels of estradiol but not progesterone, 2) circulating levels of the peripheral adipocyte hormone, leptin (a hormone thought to decrease food intake), and 3) cellular activation of gonadotropin inhibiting hormone (GnIH) and/or kisspeptin (Kp) (peptides thought to increase and decrease food intake respectively). Thus, in Chapter 3, adult female Syrian hamsters were mildly food restricted or fed ad libitum, and behavior and cellular activation measured over the estrous cycle. Activation of GnIH and Kp cells was determined by double immunohistochemical staining so that I could co-localize each of these peptides with Fos, the protein product of the immediate-early gene, c-fos. Double-label staining for Fos and GnIH, for example, is a marker for activation of cells that synthesize GnIH. I determined that effects of food restriction on behavior were not associated with changes in the activation of Kp cells; were not associated with circulating levels of estradiol and progesterone; were not associated with the action of ovarian steroids on Kp cells, and were not associated with ovarian steroid effects on circulation concentrations of leptin; although plasma leptin concentrations were significantly decreased by all metabolic challenges, food restriction, cold ambient temperatures, and housing with running wheels. Effects of energy availability on behavior were closely associated with changes in the activation of GnIH cells in the dorsomedial nucleus of the hypothalamus (DMH). In female Syrian hamsters, food restriction significantly elevated activation of GnIH-immunoreactive (ir) cells in the DMH only on infertile days of the estrous cycle. Increases in activation of GnIH-ir were blocked by peripheral treatment with progesterone alone, estradiol plus progesterone, but not estradiol alone (refuting my original hypothesis, and pointing instead to progesterone). These experiments yielded correlational evidence for the effects of GnIH on appetitive ingestive and sex behaviors, as well as for estrous cycle and exogenous steroid modulation of the activation of GnIH cells. I went beyond correlation to manipulate GnIH action to try and determine whether this hormone is necessary and/or sufficient for appetitive ingestive and/or sex behaviors. In Chapter 4, in ad libitum-fed females, intracerebroventricular infusion with GnIH significantly decreased appetitive reproductive behavior (preference for males and courtship scent marking) and increased appetitive ingestive behavior (food hoarding). Thus, elevated levels of GnIH within the brain are sufficient to increase food hoarding or inhibit sexual motivation even when the animal is well nourished. Together, the data are in line with the idea that energetic challenges increase GnIH cellular activation, and perhaps other peptide systems, that occurs during the early follicular phase of the estrous cycle when ovarian steroid concentrations are low. GnIH is one peptide that predisposes females toward vigilant food hoarding and eating food prior to mating, ensuring that if pregnancy occurs there will be ample energy to support the energetically costly process of lactation. Later in the estrous cycle as ovulation nears, the high levels of progesterone that occur in the brain at the time of ovulation switch behavioral priorities-in part by preventing food restriction-induced activation of GnIH cells, and presumably decreasing GnIH secretion. More specifically, food restriction-induced increases in GnIH secretion make food hoarding a priority over reproductive behaviors when fertility is low, and high levels of brain progesterone can overcome the effects of GnIH when fertility is high. I have therefore uncovered some of the neuroendocrine steps involved in the control of behavioral priorities that might optimize reproductive success in environments where energy supply and demand fluctuate.

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