Lance Kriegsfeld - Academia.edu (original) (raw)

Papers by Lance Kriegsfeld

F1000 - Post-publication peer review of the biomedical literature, 2016

American Psychological Association eBooks, 2017

Endocrinology, Dec 29, 2010

In spontaneously ovulating rodents, the preovulatory LH surge is initiated on the day of proestru... more In spontaneously ovulating rodents, the preovulatory LH surge is initiated on the day of proestrus by a timed, stimulatory signal originating from the circadian clock in the suprachiasmatic nucleus (SCN). The present studies explored whether kisspeptin is part of the essential neural circuit linking the SCN to the GnRH system to stimulate ovulation in Syrian hamsters (Mesocricetus auratus). Kisspeptin neurons exhibit an estrogen-dependent, daily pattern of cellular activity consistent with a role in the circadian control of the LH surge. The SCN targets kisspeptin neurons via vasopressinergic (AVP), but not vasoactive intestinal polypeptide-ergic, projections. Because AVP administration can only stimulate the LH surge during a restricted time of day, we examined the possibility that the response to AVP is gated at the level of kisspeptin and/or GnRH neurons. Kisspeptin and GnRH activation were assessed after the administration of AVP during the morning (when AVP is incapable of initiating the LH surge) and the afternoon (when AVP injections stimulate the LH surge). Kisspeptin, but not GnRH, cellular activity was up-regulated after morning injections of AVP, suggesting that time-dependent sensitivity to SCN signaling is gated within GnRH but not kisspeptin neurons. In support of this possibility, we found that the GnRH system exhibits pronounced daily changes in sensitivity to kisspeptin stimulation, with maximal sensitivity in the afternoon. Together these studies reveal a novel mechanism of ovulatory control with interactions among the circadian system, kisspeptin signaling, and a GnRH gating mechanism of control.

Frontiers in Endocrinology, 2011

We hypothesized that putative anorectic and orexigenic peptides control the motivation to engage ... more We hypothesized that putative anorectic and orexigenic peptides control the motivation to engage in either ingestive or sex behaviors, and these peptides function to optimize reproductive success in environments where energy fluctuates. Here, the putative orexigenic peptide, gonadotropin-inhibiting hormone (GnIH, also known as RFamide-related peptide-3), and the putative anorectic hormones leptin, insulin, and estradiol were examined during the course of food restriction. Groups of female Syrian hamsters were restricted to 75% of their ad libitum food intake or fed ad libitum for 4, 8, or 12 days. Two other groups were food-restricted for 12 days and then re-fed ad libitum for 4 or 8 days. After testing for sex and ingestive behavior, blood was sampled and assayed for peripheral hormones. Brains were immunohistochemically double-labeled for GnIH and the protein product of the immediate early gene, c-fos, a marker of cellular activation. Food hoarding, the number of double-labeled cells, and the percent of GnIH-Ir cells labeled with Fos-Ir were significantly increased at 8 and 12 days after the start of food restriction. Vaginal scent marking and GnIH-Ir cell number significantly decreased after the same duration of restriction. Food hoarding, but not food intake, was significantly positively correlated with cellular activation in GnIH-Ir cells. Vaginal scent marking was significantly negatively correlated with cellular activation in GnIH-Ir cells. There were no significant effects of food restriction on plasma insulin, leptin, estradiol, or progesterone concentrations. In the dorsomedial hypothalamus (DMH) of energetically challenged females, strong projections from NPY-Ir cells were found in close apposition to GnIH-Ir cells. Together these results are consistent with the idea that metabolic signals influence sexual and ingestive motivation via NPY fibers that project to GnIH cells in the DMH.

eLife, Jan 12, 2015

Whereas it is well established that chronic stress induces female reproductive dysfunction, wheth... more Whereas it is well established that chronic stress induces female reproductive dysfunction, whether stress negatively impacts fertility and fecundity when applied prior to mating and pregnancy has not been explored. In this study, we show that stress that concludes 4 days prior to mating results in persistent and marked reproductive dysfunction, with fewer successful copulation events, fewer pregnancies in those that successfully mated, and increased embryo resorption. Chronic stress exposure led to elevated expression of the hypothalamic inhibitory peptide, RFamide-related peptide-3 (RFRP3), in regularly cycling females. Remarkably, genetic silencing of RFRP3 during stress using an inducible-targeted shRNA completely alleviates stressinduced infertility in female rats, resulting in mating and pregnancy success rates indistinguishable from non-stress controls. We show that chronic stress has long-term effects on pregnancy success, even post-stressor, that are mediated by RFRP3. This points to RFRP3 as a potential clinically relevant single target for stress-induced infertility.

Journal of Biological Rhythms, May 24, 2023

Beyond visual perception, light has non-image-forming effects mediated by melanopsin-expressing, ... more Beyond visual perception, light has non-image-forming effects mediated by melanopsin-expressing, intrinsically photosensitive retinal ganglion cells (ipRGCs). The present study first used multielectrode array recordings to show that in a diurnal rodent, Nile grass rats ( Arvicanthis niloticus), ipRGCs generate rod/cone-driven and melanopsin-based photoresponses that stably encode irradiance. Subsequently, two ipRGC-mediated non-image-forming effects, namely entrainment of daily rhythms and light-induced arousal, were examined. Animals were first housed under a 12:12 h light/dark cycle (lights-on at 0600 h) with the light phase generated by a low-irradiance fluorescent light (F12), a daylight spectrum (D65) stimulating all photoreceptors, or a narrowband 480 nm spectrum (480) that maximized melanopsin stimulation and minimized S-cone stimulation (λmax 360 nm) compared to D65. Daily rhythms of locomotor activities showed onset and offset closer to lights-on and lights-off, respectively, in D65 and 480 than in F12, and higher day/night activity ratio under D65 versus 480 and F12, suggesting the importance of S-cone stimulation. To assess light-induced arousal, 3-h light exposures using 4 spectra that stimulated melanopsin equally but S-cones differentially were superimposed on F12 background lighting: D65, 480, 480 + 365 (narrowband 365 nm), and D65 − 365. Compared to the F12-only condition, all four pulses increased in-cage activity and promoted wakefulness, with 480 + 365 having the greatest and longest-lasting wakefulness-promoting effects, again indicating the importance of stimulating S-cones as well as melanopsin. These findings provide insights into the temporal dynamics of photoreceptor contributions to non-image-forming photoresponses in a diurnal rodent that may help guide future studies of lighting environments and phototherapy protocols that promote human health and productivity.

Endocrinology, Feb 1, 2010

RFamide-related peptide (RFRP), the mammalian homolog of avian gonadotropin-inhibitory hormone, h... more RFamide-related peptide (RFRP), the mammalian homolog of avian gonadotropin-inhibitory hormone, has a pronounced suppressive action on the reproductive axis across species. In mammals, RFRP acts directly on GnRH neurons, and likely at the level of the pituitary, to inhibit gonadotropin secretion. In the present study, we examined whether RFRP might act outside of mammalian brain on reproductive tissues directly. Using RT-PCR and in situ hybridization, we found that both RFRP and its receptors [G protein-coupled receptor (GPR) 147 and GPR74] are expressed in the testis of Syrian hamster. These results were confirmed and extended using double-and triple-label immunohistochemistry. RFRP expression was observed in spermatocytes and in round to early elongated spermatids. Significant expression of RFRP was not seen in Leydig cells. GPR147 protein was observed in myoid cells in all stages of spermatogenesis, pachytene spermatocytes, maturation division spermatocytes, and in round and late elongated spermatids. GPR74 proteins only appeared in late elongated spermatids. Additionally, we found that RFRP and its receptor mRNA are markedly altered by day length and reproductive condition. These findings highlight a possible novel autocrine and/or paracrine role for RFRP in Syrian hamster testis, potentially contributing to the differentiation of spermatids during spermiogenesis.

HAL (Le Centre pour la Communication Scientifique Directe), Jun 15, 2012

International audienc

HAL (Le Centre pour la Communication Scientifique Directe), May 17, 2011

National audienc

The last 10 years have seen the emergence of wearable personal health tracking devices as a mains... more The last 10 years have seen the emergence of wearable personal health tracking devices as a mainstream industry; however, they remain limited by battery lifetime, specific sensor selection, and a market motivated by a focus on short-term fitness metrics (e.g., steps/day). This hampers the development of a potentially much broader application area based on optimization around biomedical theory for long-term diagnostic discovery. As new biometric sensors come online, the ideal platform enabling the gathering of long-term diagnostic data would have the built-in extensibility to allow testing of different sensor combinations in different research settings to discover what kinds of data can be most useful for specific biomedical applications. Here we present the first generation of a reconfigurable wrist-mounted sensor device measuring 7x4x2cm and weighing 51g with battery (29g without). In its current configuration, it has recorded skin temperature, acceleration, and light exposure; these three variables allow prediction of internal circadian rhythms, as an example of the application of biological theory to enhance pattern detection. This generation is capable of operating long-term with minimal day-today disruption via easily exchangeable batteries, and has enough space for several months of data sampling to gather long-term diagnostic metrics. Future developments will include the addition of energy scavenging and a wireless mesh network for ambient data collection, the combination of which will allow uninterrupted data to be gathered without depending on the user.

Frontiers in Physiology, Nov 5, 2021

Adolescence is a period of continuous development, including the maturation of endogenous rhythms... more Adolescence is a period of continuous development, including the maturation of endogenous rhythms across systems and timescales. Although, these dynamic changes are wellrecognized, their continuous structure and hormonal dependence have not been systematically characterized. Given the well-established link between core body temperature (CBT) and reproductive hormones in adults, we hypothesized that high-resolution CBT can be applied to passively monitor pubertal development and disruption with high fidelity. To examine this possibility, we used signal processing to investigate the trajectory of CBT rhythms at the within-day (ultradian), daily (circadian), and ovulatory timescales, their dependence on estradiol (E2), and the effects of hormonal contraceptives. Puberty onset was marked by a rise in fecal estradiol (fE2), followed by an elevation in CBT and circadian power. This time period marked the commencement of 4-day rhythmicity in fE2, CBT, and ultradian power marking the onset of the estrous cycle. The rise in circadian amplitude was accelerated by E2 treatment, indicating a role for this hormone in rhythmic development. Contraceptive administration in later adolescence reduced CBT and circadian power and resulted in disruption to 4-day cycles that persisted after discontinuation. Our data reveal with precise temporal resolution how biological rhythms change across adolescence and demonstrate a role for E2 in the emergence and preservation of multiscale rhythmicity. These findings also demonstrate how hormones delivered exogenously in a non-rhythmic pattern can disrupt rhythmic development. These data lay the groundwork for a future in which temperature metrics provide an inexpensive, convenient method for monitoring pubertal maturation and support the development of hormone therapies that better mimic and support human chronobiology.

Neuroendocrinology, Aug 12, 2021

Introduction: The mechanisms underlying obesity are not fully understood, necessitating the creat... more Introduction: The mechanisms underlying obesity are not fully understood, necessitating the creation of novel animal models for investigation of metabolic disorders. We have previously found that neurosecretory protein GL (NPGL), a newly-identified hypothalamic neuropeptide, is involved in feeding behavior and fat accumulation in rats. However, the impact of NPGL on obesity remains unclear in any animal model. The present investigation sought to elucidate whether NPGL causes obesity in the obesity-prone mouse strain C57BL/6J. Methods: We overexpressed the NPGL-precursor gene (Npgl) in the hypothalamus using adeno-associated virus in male C57BL/6J mice fed normal chow (NC) or a high-calorie diet (HCD). After 9 weeks of Npgl overexpression, we measured adipose tissues, muscle, and several organ masses in addition to food intake and body mass. To assess the effects of Npgl overexpression on peripheral tissues, we analyzed mRNA expression of lipid metabolism-related genes by quantitative RT-PCR. Whole body energy consumption was assessed using an O2/CO2 metabolism measurement before apparent increasing in body mass. Results: Npgl overexpression increased food intake, body mass, adipose tissues and liver masses, and food efficiency under both NC and HCD, resulting in obesity observable within 8 weeks. Furthermore, we observed fat accumulation in adipose tissues and liver. Additionally, mRNA expression of lipid metabolism-related factors was increased in white adipose tissue and the liver after Npgl overexpression. Npgl overexpression inhibited energy expenditure during dark period. Conclusion: Taken together, the present study suggests that NPGL can act as an obesogenic factor that acts within a short period of time in mice. As a result, this Npgl overexpression-induced obesity can be widely applied to study the etiology of obesity from genes to behavior.

Journal of Neuroendocrinology, Jun 15, 2010

To maximize reproductive success, organisms restrict breeding to optimal times of day or year, wh... more To maximize reproductive success, organisms restrict breeding to optimal times of day or year, when internal physiology and external environmental conditions are suitable for parent and offspring survival. To appropriately coordinate reproductive activity, internal and external standing is communicated to the hypothalamo-pituitary-gonadal (HPG) axis via a coordinated balance of stimulatory and inhibitory neurochemical systems. The cumulative balance of these mediators ultimately drives the pattern of gonadotropin-releasing hormone (GnRH) secretion, a neurohormone that stimulates pituitary gonadotropin secretion. Until 2000, a complementary inhibitor of pituitary gonadotropin secretion had not been identified. At this time, Tsutsui and colleagues uncovered a novel, avian hypothalamic peptide capable of inhibiting gonadotropin secretion in cultured quail pituitary cells. We later examined the presence and functional role for the mammalian ortholog of GnIH, RFamide-related peptide (RFRP-3), in mammals, and confirmed a conserved role for this peptide across several rodent species. To date, a similar distribution and functional role for RFRP-3 have been observed across all mammals investigated, including humans. This overview summarizes the role that RFRP-3 plays in mammals and considers the implications and opportunities for further study by those interested in reproductive physiology and the neural control of sexual behavior and motivation.

Cambridge University Press eBooks, Mar 25, 2002

As the seasons change, animals face alterations in environmental stressors. In particular, the pr... more As the seasons change, animals face alterations in environmental stressors. In particular, the prevalence and intensity of pathogenic infection are often seasonal. This book presents evidence that infection is cyclical with the seasons and that this phenomenon is mirrored in cycles of immune function. The goal of this book is to identify the mechanisms by which the immune system is bolstered to counteract seasonally recurrent stressors, such as extreme temperature reductions and food shortages. The authors consider how such environmental changes create energetically demanding conditions that can compromise host immunity and lead to illness and death. Specifically, stress, infectious diseases, autoimmune diseases, and human cancers are examined, and the role of hormones such as melatonin and glucocorticoids is considered. The book begins with an overview of seasonality, biological rhythms and photoperiodism, and basic immunology, and continues with the characterization of seasonal fluctuations in disease prevalence, energetics, and endocrinology as they relate to immune function. Finally, the clinical significance of seasonal patterns in immune function is addressed to emphasize the role that seasonal changes in host immunity and hormones may play in the development and treatment of infections. This is the first monograph to examine seasonal immune function from an interdisciplinary perspective. Practitioners as well as advanced undergraduates and graduate students in biology, immunology, human and veterinary medicine, neuroscience, endocrinology, and zoology will find its approach both insightful and relevant.

Journal of Biological Rhythms, May 3, 2022

Biological rhythms in core body temperature (CBT) provide informative markers of adolescent devel... more Biological rhythms in core body temperature (CBT) provide informative markers of adolescent development under controlled laboratory conditions. However, it is unknown if these markers are preserved under more variable, semi-naturalistic conditions, and if CBT may therefore prove useful in a real-world setting. To evaluate this possibility, we examined fecal steroid concentrations and CBT rhythms from pre-adolescence (p26) through early adulthood (p76) in intact male and female Wistar rats under natural light and climate at The Stephen Glickman Field Station for the Study of Behavior, Ecology and Reproduction. Despite greater environmental variability, CBT markers of pubertal onset and its rhythmic progression were comparable to those previously reported in laboratory conditions in female rats and extend actigraphy-based findings in males. Specifically, sex differences emerged in CBT circadian rhythm (CR) power and amplitude prior to pubertal onset and persisted into early adulthood, with females exhibiting elevated CBT and decreased CR power compared to males. Within-day (ultradian rhythm; UR) patterns also exhibited a pronounced sex difference associated with estrous cyclicity. Pubertal onset, defined by vaginal opening, preputial separation, and sex steroid concentrations, occurred later than previously reported under lab conditions for both sexes. Vaginal opening and increased fecal estradiol concentrations were closely tied to the commencement of 4-day oscillations in CBT and UR power. By contrast, preputial separation and the first rise in testosterone concentration were not associated with adolescent changes to CBT rhythms in male rats. Together, males and females exhibited unique temporal patterning of CBT and sex steroids across pubertal development, with tractable associations between hormonal concentrations, external development, and temporal structure in females. The preservation of these features outside the laboratory supports CBT as a strong candidate for translational pubertal monitoring under semi-naturalistic conditions in females.

• Ultradian (2-5 h) rhythm power of distal body temperature and heart rate variability (RMSSD) ex... more • Ultradian (2-5 h) rhythm power of distal body temperature and heart rate variability (RMSSD) exhibits a stereotyped inflection point and peak in the days leading up to the LH surge in premenopausal women. • Circadian rhythms of distal body temperature and single time-point/day metrics do not permit anticipation of the LH surge. • Measurement of continuous metabolic and autonomic outputs, enabling assessment of ultradian rhythms, may be of value to the fertility awareness method. .

Hormones and Behavior, Dec 1, 2003

Historically, the brain has been viewed as protected from the infiltration of peripheral hematopo... more Historically, the brain has been viewed as protected from the infiltration of peripheral hematopoietic cells by the blood-brain barrier. However, numerous immune cell types have been found in the central nervous system (CNS). Mast cells, granulocytic immune cells, are found in the CNS of birds and mammals and their numbers and location are influenced by both extrinsic and intrinsic factors, including reproductive behavior and endocrine status. The present study used female prairie voles (Microtus ochrogaster) to investigate the interactions between brain mast cells and stimuli associated with estrus induction. Unlike spontaneous ovulators such as rats and mice, female prairie voles are induced into estrus by chemosensory stimuli present in conspecific male urine. Prior to estrus induction, female voles have undetectable concentrations of estrogen that rise rapidly following exposure to a male or male urine. In the first experiment, we examined whether mast cells may be influenced by estrus induction. Female voles exposed to conspecific male urine had increased numbers of mast cells in the main olfactory bulbs and epithalamus (medial habenula), but not the thalamus or median eminence, relative to control groups. Next, to determine if this mast cell increase was the result of elevated estrogen concentrations, female voles were injected with estradiol or vehicle and brain mast cell numbers analyzed. No differences in brain mast cell numbers were observed between estradiolinjected and control females in any brain area investigated. Together, these results lend further support to the contention that mast cell numbers and/or distribution can be influenced by reproductively relevant stimuli and underscore the utility of this vole model for delineating the function of brain mast cells.

Scientific Reports, Nov 23, 2020

The menstrual cycle is characterized by predictable patterns of physiological change across times... more The menstrual cycle is characterized by predictable patterns of physiological change across timescales. Although patterns of reproductive hormones across the menstrual cycle, particularly ultradian rhythms, are well described, monitoring these measures repeatedly to predict the preovulatory luteinizing hormone (LH) surge is not practical. In the present study, we explored whether non-invasive measures coupled to the reproductive system: high frequency distal body temperature (DBT), sleeping heart rate (HR), sleeping heart rate variability (HRV), and sleep timing, could be used to anticipate the preovulatory LH surge in women. To test this possibility, we used signal processing to examine these measures in 45 premenopausal and 10 perimenopausal cycles alongside dates of supra-surge threshold LH and menstruation. Additionally, urinary estradiol and progesterone metabolites were measured daily surrounding the LH surge in 20 cycles. Wavelet analysis revealed a consistent pattern of DBT and HRV ultradian rhythm (2-5 h) power that uniquely enabled anticipation of the LH surge at least 2 days prior to its onset in 100% of individuals. Together, the present findings reveal fluctuations in distal body temperature and heart rate variability that consistently anticipate the LH surge, suggesting that automated ultradian rhythm monitoring may provide a novel and convenient method for non-invasive fertility assessment. The fertility-awareness-method (FAM), a set of practices used to estimate the fertile and infertile days of the menstrual cycle, is challenging to implement and to study, and existing studies of its effectiveness are inconclusive 1. However, an observation-based method of family planning or contraception has several potential benefits, including a lack of hormonal disruption, personalization, and relatively low cost. One challenge inherent to current FAM practices is the reliance on historical basal body temperature and symptom trends (e.g., breast tenderness, libido, cervical fluid) that can vary substantially by individual, within-individual from cycle-to-cycle 2 , and that provide predominantly retrospective information. The challenges of FAM have led the majority of those seeking to avoid pregnancy to adopt another form of contraception. Unfortunately, the most widely used method, female hormonal contraception, has short and long term risks for many users, including increased breast cancer rate 3,4 , luteal phase deficiency 5 , dysmenorrhea 5,6 , altered cognition 7,8 , and depressed mood 9,10. These risks, combined with increasing recognition that many physiological systems vary in a structured manner across the menstrual cycle 11-14 , provide the impetus to develop FAM approaches that employ high-temporal-resolution, non-invasive measures of physiology. The menstrual cycle is a continuous, rhythmic succession of endocrine, ovarian, and uterine events. Briefly, the cycle begins with onset of menstruation, followed by rising levels of estradiol, follicular maturation, and proliferation of the uterine lining 15,16. Ovulation, which is triggered by numerous factors including estradiol, a surge of luteinizing hormone (LH), the presence of a mature Graafian follicle, and likely time of day 17 , frequently occurs between 1/2 and 3/4 of the way through the cycle in humans 18. Other physiological systems, including metabolism 19, 20 and autonomic balance 21 , fluctuate with the menstrual cycle. An individual is mostly likely to become pregnant during the time leading up to, and shortly past, the ovulation event, making identification of this peri-ovulatory period central for the successful use of the FAM.