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Circadian rhythms are endogenous biological cycles that regulate physiology and behavior for optimal adaptive function and survival; they are synchronized to precisely 24 hours by daily light exposure. Disruption of the daily light-dark (LD) cycle by exposure to artificial light at night (ALAN) dysregulates core clock genes and biological function. Exposure to ALAN has been associated with increased health risks in humans, and elderly individuals are at elevated risk for poor outcome from disease and often experience elevated exposure to ALAN due to increased care requirements. The role of disrupted circadian rhythms in healthy, aged animals remains unspecified; thus, we hypothesized that disrupted circadian rhythms via chronic exposure to dim ALAN (dLAN) impair immune response and survival in aged mice. Twenty-month-old C57BL/6 male and female mice were exposed to 24 weeks of LD conditions or dLAN (5 lux); then, cell-mediated immune response was assessed using a delayed-type hypersensitivity test. Aged female mice exposed to dLAN displayed dysregulated hypersensitivity and inflammation as a measure of cell-mediated immune response and decreased lifespan compared to females housed in dark nights. Nighttime lighting did not affect cell-mediated immune response or lifespan in males but dysregulated body mass and increased adrenal mass after immune challenge after chronic exposure to dLAN. Together, these data indicate that chronic exposure to dLAN affects lifespan in aged females and suggest that females are more susceptible to the detrimental consequences of disrupted circadian rhythms.

Male fertility requires the continual production of sperm by the process of spermatogenesis. This process requires the correct timing of regulatory signals to germ cells during each phase of their development. MicroRNAs (miRNAs) in germ cells and supporting Sertoli cells respond to regulatory signals and cause down- or upregulation of mRNAs and proteins required to produce proteins that act in various pathways to support spermatogenesis. The targets and functional consequences of altered miRNA expression in undifferentiated and differentiating spermatogonia, spermatocytes, spermatids and Sertoli cells are discussed. Mechanisms are reviewed by which miRNAs contribute to decisions that promote spermatogonia stem cell self-renewal versus differentiation, entry into and progression through meiosis, differentiation of spermatids, as well as the regulation of Sertoli cell proliferation and differentiation. Also discussed are miRNA actions providing the very first signals for the differentiation of spermatogonia stem cells in a non-human primate model of puberty initiation.

Signaling by androgens through androgen receptor (AR) is essential to complete spermatogenesis in the testis. Similarly, loss of the main estrogen receptor, estrogen receptor 1 (ESR1; also known as ERα), results in male infertility, due in part to indirect deleterious effects on the seminiferous epithelium and spermatogenesis. Effects of steroid hormones are induced primarily through genomic changes induced by hormone-mediated activation of their intracellular receptors and subsequent effects on nuclear gene transcription. However, androgens and estrogens also signal through rapid nonclassical pathways involving actions initiated at the cell membrane. Here we review the data that nonclassical androgen and estrogen signaling pathways support processes essential for male fertility in the testis and reproductive tract. The recent development of transgenic mice lacking nonclassical AR or ESR1 signaling but retaining genomic nuclear signaling has provided a powerful tool to elucidate the function of nonclassical signaling in the overall response to androgens and estrogens. Results from these mice have emphasized that nonclassical signaling is essential for full responses to these hormones, and absence of either nonclassical or classical AR or ESR1 pathways produces abnormalities in spermatogenesis and the male reproductive tract. Although additional work is required to fully understand how classical and nonclassical receptor signaling synergize to produce full steroid hormone responses, here we summarize the known physiological functions of the classical and nonclassical androgen and estrogen signaling pathways in the testis and reproductive tract.

Disruption of circadian rhythms has detrimental host consequences. Indeed, both clinical and foundational science demonstrate a clear relationship between disruption of circadian rhythms and cancer initiation and progression. Because timing of food intake can act as a zeitgeber (i.e., entrainment signal) for the circadian clock, and most individuals in the developed world have access to food at all times of the day in a “24/7” society, we sought to determine the effects of timing of food intake on mammary tumor growth. We hypothesized that restricting access to food to during the inactive phase would accelerate tumor growth. Adult female Balb/C mice received a unilateral orthotopic injection of murine mammary carcinoma 4T1 cells into the ninth inguinal mammary gland. Beginning on the day of tumor injection and continuing until the end of the experiment, mice were food restricted to their active phase (ZT12 (lights off)- ZT0 (lights on), inactive phase (ZT0 - ZT12), or had ad libitum access to food. Mice that were food restricted to their inactive phase displayed a significant increase in body mass on days 7 and 14 of tumor growth relative to active phase or ad libitum fed mice. Additionally, mice fed during their inactive phase demonstrated a 20% reduction in food consumption relative to mice fed during their active phase and a 17% reduction in food consumption relative to ab libitum fed mice. Tumor volume was not significantly different between groups. However, food restricting mice to their inactive phase increased mammary tumor growth efficiency (i.e., mg of tumor mass per gram of food intake) relative to mice fed during the active phase and approached significance (p=0.06) relative to ad libitum fed mice. To determine a potential explanation for the increased tumor growth efficiency, we examined rhythms of activity and body temperature. Mice fed during the inactive phase displayed significantly disrupted daily activity and body temperature rhythms relative to both other feeding regimens. Together, these data demonstrate that improperly timed food intake can have detrimental consequences on mammary tumor growth likely via disrupted circadian rhythms.

Light at night is a pervasive problem in our society; over 80% of the world’s population experiences significant light pollution. Exacerbating this issue is the reality that artificially lit outdoor areas are growing by 2.2% per year and continuously lit areas brighten by 2.2% each year due to the rapid growths in population and urbanization. Furthermore, the increase in the prevalence of night shift work and smart device usage contributes to the inescapable nature of artificial light at night (ALAN). Although previously assumed to be innocuous, ALAN has deleterious effects on the circadian system and circadian-regulated physiology, particularly immune function. Due to the relevance of ALAN to the general population, it is important to understand its roles in disrupting immune function. This review presents a synopsis of the effects of ALAN on circadian clocks and immune function. We delineate the role of ALAN in altering clock gene expression and suppressing melatonin. We review the effects of light at night on inflammation and the innate and adaptive immune systems in various species to demonstrate the wide range of ALAN consequences. Finally, we propose future directions to provide further clarity and expansion of the field.

The goal of this review is to provide a perspective on the nature and importance of the relationship between the circadian and pain systems. We provide: 1) An overview of the circadian and pain systems, 2) a review of direct and correlative evidence that demonstrates diurnal and circadian rhythms within the pain system; 3) a perspective highlighting the need to consider the role of a proposed feedback loop of circadian rhythm disruption and maladaptive pain; 4) a perspective on the nature of the relationship between circadian rhythms and pain. In summary, we propose that there is no single locus responsible for producing the circadian rhythms of the pain system. Instead, circadian rhythms of pain are a complex result of the distributed rhythms present throughout the pain system, especially those of the descending pain modulatory system, and the rhythms of the systems with which it interacts, including the opioid, endocrine, and immune systems.

Time-of-day is a crucial, yet often overlooked, biological variable in biomedical research. We examined the top 25 most cited papers in several domains of behavioral neuroscience to determine whether time-of-day information was reported. The majority of studies report behavioral testing conducted during the day, which does not coincide with the optimal time to perform the testing from an functional perspective of the animals being tested. The majority of animal models used in biomedical research are nocturnal rodents; thus, testing during the light phase (i.e. animals' rest period) may alter the results and introduce variability across studies. Time-of-day is rarely considered in analyses or reported in publications; the majority of publications fail to include temporal details when describing their experimental methods, and those few that report testing during the dark rarely report whether measures are in place to protect from exposure to extraneous light. We propose that failing to account for time-of-day may compromise replication of findings across behavioral studies and reduce their value when extrapolating results to diurnal humans.

Magic and witchcraft, classic topics in the anthropology of religion, involve everyday things such as ashes, ceramics, minerals, shell, and projectile points. In many cultures, people attribute agency to such artifacts, as well as architecture, begging the question what is the archaeological record of such animate beings? To understand past human lifeways more fully, we need to explore the formation processes associated with the interaction between people and other non-human actors. For example, what might we learn from a burned pueblo whose rooms contain ash, projectile points, crystals, and other items? In this paper we argue that deposits in ritually closed pueblos of the North American Southwest, like many other Neolithic villages, likely contain purposely deposited objects in an effort to neutralize the anima left in these places and to prophylactically protect their former inhabitants from future witchcraft. We present Cottonwood Spring Pueblo, New Mexico, as a case study.

Breast cancer survivors receiving chemotherapy often report increased anxiety and depression. However, the mechanism underlying chemotherapy-induced changes in affect remains unknown. We hypothesized that chemotherapy increases cytokine production, in turn altering exploratory and depressive-like behavior. To test this hypothesis, female Balb/C mice received two injections, separated by two weeks, of vehicle (0.9% saline) or a chemotherapeutic cocktail [9 mg/kg doxorubicin (A) and 90 mg/kg cyclophosphamide (C)]. Peripheral and central cytokine concentrations were increased one and seven days, respectively, after AC. Because of the beneficial effects of social enrichment on several diseases with inflammatory components, we examined whether social enrichment could attenuate the increase in peripheral and central cytokine production following chemotherapy administration. Socially isolated mice receiving AC therapy demonstrated increased depressive-like and exploratory behaviors with a concurrent increase in hippocampal IL-6. Whereas, group housing attenuated AC-induced IL-6 and depressive-like behavior. Next, we sought to determine whether central oxytocin may contribute to the protective effects of social housing after AC administration. Intracerebroventricular administration of oxytocin to socially isolated mice recapitulated the protective effects of social enrichment; specifically, oxytocin ameliorated the AC-induced effects on IL-6 and depressive-like behavior. Furthermore, administration of an oxytocin antagonist to group housed mice recapitulated the responses of socially isolated mice; specifically, AC increased depressive-like behavior and central IL-6. These data suggest a possible neuroprotective role for oxytocin following chemotherapy, via modulation of IL-6. This study adds to the growing literature detailing the negative behavioral effects of chemotherapy and provides further evidence that social enrichment may be beneficial to health.

Circadian rhythms are endogenous biological cycles that synchronize physiology and behaviour to promote optimal function. These ~24-hr internal rhythms are set to precisely 24 hr daily by exposure to the sun. However, the prevalence of night-time lighting has the potential to dysregulate these biological functions. Hospital patients may be particularly vulnerable to the consequences of light at night because of their compromised physiological state. A mouse model of stroke (middle cerebral artery occlusion; MCAO) was used to test the hypothesis that exposure to dim light at night impairs responses to a major insult. Stroke lesion size was substantially larger among animals housed in dLAN after reperfusion than animals maintained in dark nights. Mice housed in dLAN for three days after the stroke displayed increased post-stroke anxiety-like behaviour. Overall, dLAN amplified pro-inflammatory pathways in the CNS, which may have exacerbated neuronal damage. Our results suggest that exposure to LAN is detrimental to stroke recovery.

Circadian rhythms are internal manifestations of the solar day that permit adaptations to predictable environmental temporal changes. These ~24-h rhythms are controlled by molecular clockworks within the brain that are reset daily to precisely 24 h by exposure to the light–dark cycle. Information from the master clock in the mammalian hypothalamus conveys temporal information to the entire body via humoral and neural communication. A bidirectional relationship exists between mood disorders and circadian rhythms. Mood disorders are often associated with disrupted circadian clock-controlled responses, such as sleep and cortisol secretion, whereas disruption of circadian rhythms via jet lag, night-shift work, or exposure to artificial light at night, can precipitate or exacerbate affective symptoms in susceptible individuals. Evidence suggests strong associations between circadian rhythms and mental health, but only recently have studies begun to discover the direct interactions between the circadian system and mood regulation. This review provides an overview of disrupted circadian rhythms and the relationship to behavioral health and psychiatry. The focus of this review is delineating the role of disruption of circadian rhythms on mood disorders using human night shift studies, as well as jet lag studies to identify links. We also review animal models of disrupted circadian rhythms on affective responses. Lastly, we propose low-cost behavioral and lifestyle changes to improve circadian rhythms and presumably behavioral health.

Neuroimmunology is the study of the interaction between the immune system and nervous system during development, homeostasis, and disease states. Descriptions of neuroinflammatory diseases dates back centuries. However, in depth scientific investigation in the field began in the late 19th century and continues into the 21st century. Contrary to prior dogma in the field of neuroimmunology, there is immense reciprocal crosstalk between the brain and the immune system throughout development, homeostasis, and disease states. Proper neuroimmune functioning is necessary for optimal health, as the neuroimmune system regulates vital processes including neuronal signaling, synapse pruning, and clearance of debris and pathogens within the central nervous system. Perturbations in optimal neuroimmune functioning can have detrimental consequences for the host and underlie a myriad of physical, cognitive, and behavioral abnormalities. As such, the field of neuroimmunology is still relatively young and dynamic and represents an area of active research and discovery.

Testosterone is essential for spermatogenesis and male fertility. In this review, topics related to testosterone control of spermatogenesis are covered including testosterone production and levels in the testis, classical and nonclassical testosterone signaling pathways, cell- and temporal-specific expression of the androgen receptor in the testis and autocrine and paracrine signaling of testis cells in the testis. Also discussed are the contributions of testosterone to testis descent, the blood-testis barrier, control of gonocyte numbers and spermatogonia expansion, completion of meiosis and attachment and release of elongaed spermatids. Testosterone-regulated genes identified in various mouse models of idsrupted Androgen receptor expression are discussed. Finally, examples of synergism and antagonism between androgen and follicle-stimulating hormone signaling pathways are summarized.

During the evolution of life, the temporal rhythm of our rotating planet was internalized in the form of circadian rhythms. Circadian rhythms are ~24h internal manifestations that drive daily patterns of physiology and behavior. These rhythms are entrained (synchronized) to the external environment, primarily by the light-dark cycle, and precisely controlled via molecular clocks located within the suprachiasmatic nucleus of the hypothalamus. Misalignment and/or disruption of circadian rhythms can have detrimental consequences for human health. Indeed, studies suggest strong associations between mental health and circadian rhythms. However, direct interactions between mood regulation and the circadian system are just beginning to be uncovered and appreciated. This chapter examines the relationship between disruption of circadian rhythms and mental health. The primary focus will be outlining the association between circadian disruption, in the form of night shift work, exposure to light at night, jet lag, and social jet lag, and psychiatric illness (i.e., anxiety, major depressive disorder, bipolar disorder, and schizophrenia). Additionally, we review animal models of disrupted circadian rhythms, which provide further evidence in support of a strong association between circadian disruption and affective responses. Finally, we discuss future directions for the field and suggest areas of study that require further investigation.

Mouse penile development is androgen-dependent. During development of male and female external genitalia, an internal ectodermal epithelial structure forms called the preputial lamina. At puberty the male preputial lamina canalizes to create the preputial space, effectively splitting into two layers: (a) the epithelial lining of the prepuce and (b) the surface epithelium of the penis. The female preputial lamina does not canalize, and instead remodels into the inverted U-shaped clitoral lamina of the adult female mouse. Androgen-dependent penile development was studied in transgenic mice with pathway-selective AR mutant transgenes through which AR signaling was activated either via the classical (AR-C) or the nonclassical pathway (AR-NC). Penile development and canalization of the preputial lamina was observed in AR-C and wild-type male mice naturally having both AR-C and AR-NC pathways. Conversely, clitoral development occurred in AR null (lacking both AR-C and AR-NC pathways) and AR-NC mice. The process of canalization of the preputial lamina seen in wild-type, AR-C and AR-C/AR-NC male mice involved cornification of the preputial lamina which involved up-regulation of keratin 10 and loricrin. Such up-regulation of these epidermal proteins was absent in the developing and adult clitoral lamina seen in wild-type female mice and AR-NC and AR null male (XY) mice. Thus, signaling through AR-C is sufficient to initiate and promote penile development and canalization of the preputial lamina, a process involving epithelial cornification.

Artificial light at night (LAN) is a pervasive phenomenon in today's society, and the detrimental consequences of LAN exposure are becoming apparent. LAN is associated with the increased incidence of metabolic disorders, cancers, mood alterations, and immune dysfunction in mammals. Consequently, we examined the effects of dim LAN (DLAN) on wound healing. Female C57BL/6 mice were housed for 3 weeks in DLAN or LD conditions prior to wounding. Following wounding, mice were maintained in either their previous light conditions or switched to the opposite lighting conditions for 3 weeks. DLAN prior to wounding impaired healing; specifically, mice in DLAN/DLAN had significantly larger wounds on day 8. Additionally, mice in DLAN/LD had significantly larger wounds on days 5, 7, 8, and 9, and increased average time to closure. These data demonstrate a potential harmful effect of DLAN on wound healing that should be considered and may represent a target for therapeutic intervention.

The advent and wide-spread adoption of electric lighting over the past century has profoundly affected the circadian organization of physiology and behavior for many individuals in industrialized nations; electric lighting in homes, work environments, and public areas have extended daytime activities into the evening, thus, increasing night-time exposure to light. Although initially assumed to be innocuous, chronic exposure to light at night (LAN) is now associated with increased incidence of cancer, metabolic disorders, and affective problems in humans. However, little is known about potential acute effects of LAN. To determine whether acute exposure to low-level LAN alters brain function, adult male, and female mice were housed in either light days and dark nights (LD; 14 h of 150 lux:10 h of 0 lux) or light days and low level light at night (LAN; 14 h of 150 lux:10 h of 5 lux). Mice exposed to LAN on three consecutive nights increased depressive-like responses compared to mice housed in dark nights. In addition, female mice exposed to LAN increased central tendency in the open field. LAN was associated with reduced hippocampal vascular endothelial growth factor-A (VEGF-A) in both male and female mice, as well as increased VEGFR1 and interleukin-1β mRNA expression in females, and reduced brain derived neurotrophic factor mRNA in males. Further, LAN significantly altered circadian rhythms (activity and temperature) and circadian gene expression in female and male mice, respectively. Altogether, this study demonstrates that acute exposure to LAN alters brain physiology and can be detrimental to well-being in otherwise healthy individuals.

During the evolution of life, the temporal rhythm of our rotating planet was internalized in the form of circadian rhythms. Circadian rhythms are ~24h internal manifestations that drive daily patterns of physiology and behavior. These rhythms are entrained (synchronized) to the external environment, primarily by the light-dark cycle, and precisely controlled via molecular clocks located within the suprachiasmatic nucleus of the hypothalamus. Misalignment and/or disruption of circadian rhythms can have detrimental consequences for human health. Indeed, studies suggest strong associations between mental health and circadian rhythms. However, direct interactions between mood regulation and the circadian system are just beginning to be uncovered and appreciated. This chapter examines the relationship between disruption of circadian rhythms and mental health. The primary focus will be outlining the association between circadian disruption, in the form of night shift work, exposure to light at night, jet lag, and social jet lag, and psychiatric illness (i.e., anxiety, major depressive disorder, bipolar disorder, and schizophrenia). Additionally, we review animal models of disrupted circadian rhythms, which provide further evidence in support of a strong association between circadian disruption and affective responses. Finally, we discuss future directions for the field and suggest areas of study that require further investigation.

The molecular mechanisms by which androgens act via the androgen receptor (AR) to maintain male fertility are poorly understood. Transgenic mice were produced expressing mutant ARs that can only (1) alter gene transcription through the classical response pathway (AR-C) or 2) activate kinase signaling cascades via the nonclassical pathway (AR-NC). AR-NC allowed completion of meiosis and the production of haploid germ cells. Expression of AR-C was sufficient to produce sperm and fertility. However, added AR-NC activity contributed to maintaining the blood-testis barrier, plus correct migration and orientation of maturing spermatids needed for fully efficient sperm production. AR-C activity is required for expression of cohesion and synaptonemal complex proteins that are essential for chromosome synapsis. AR-C supported partial development of prostate and coagulating glands, but full development required both pathways. Our results indicate that AR-C activity alone partially restores male fertility, but AR-NC is obligatory to maximize fertility.

Testosterone is essential for spermatogenesis and male fertility. In this review, topics related to testosterone control of spermatogenesis are covered including testosterone production and levels in the testis, classical and nonclassical testosterone signaling pathways, cell- and temporal-specific expression of the androgen receptor in the testis and autocrine and paracrine signaling of testis cells in the testis. Also discussed are the contributions of testosterone to testis descent, the blood-testis barrier, control of gonocyte numbers and spermatogonia expansion, completion of meiosis and attachment and release of elongaed spermatids. Testosterone-regulated genes identified in various mouse models of idsrupted Androgen receptor expression are discussed. Finally, examples of synergism and antagonism between androgen and follicle-stimulating hormone signaling pathways are summarized.

Although much has been learned about circadian clocks and rhythms over the past few decades, translation of this foundational science underlying the temporal regulation of physiology and behavior to clinical applications has been slow. Indeed, acceptance of the modern study of circadian rhythms has been blunted because the phenomenology of cyclic changes had to counteract the 20th century dogma of homeostasis in the biological sciences and medicine. We are providing this review of clinical data to highlight the emerging awareness of circadian variation in efficacy of medications for physicians, clinicians, and pharmacists. We are suggesting that gold-standard double-blind clinical studies should be conducted to determine the best time of day for optimal effectiveness of medications; also, we suggest that time of day should be tracked and reported as an important biological variable in ongoing clinical studies hereafter. Furthermore, we emphasize that time of day is, and should be considered, a key biological variable in research design similar to sex. In common with biomedical research data that have been historically strongly skewed toward the male sex, most pharmaceutical data have been skewed toward morning dosing without strong evidence that this is the optimal time of efficacy.

Background Cytokines are key signaling molecules within the immune system that regulate a host’s response to pathogens and neuronal damage. Aberrant cytokine signaling has been implicated in many neurological diseases. Therefore, accurately measuring cytokine concentrations within the brain is crucial. New method This study demonstrates that removing blood within brain vasculature via saline perfusion does not alter brain parenchymal cytokine protein concentrations or mRNA expression. Results Hippocampal protein and mRNA data demonstrate that brain parenchymal cytokine concentrations do not significantly differ based on the method of euthanasia (i.e., perfusion or no perfusion). These results are consistent within naive and immune challenged mice. Comparison with existing method Due to the potential of cytokine contamination from circulating blood, it is believed that transcardial perfusion is required for accurate measurement of cytokine concentrations and gene expression within the brain. However, our data indicate that cytokine concentrations are unaffected by not perfusing mice with saline prior to tissue collection. Conclusions Brain cytokine concentrations are unaffected by perfusing with saline prior to tissue collection; this holds true regardless of immune status (homeostatic or immune challenged), suggesting that this time-consuming step may be unnecessary.

The growing presence of artificial lighting across the globe presents a number of challenges to human and ecological health despite its societal benefits. Exposure to artificial light at night, a seemingly innocuous aspect of modern life, disrupts behavior and physiological functions. Specifically, light at night induces neuroinflammation, which is implicated in neuropathic and nociceptive pain states, including hyperalgesia and allodynia. Because of its influence on neuroinflammation, we investigated the effects of dim light at night exposure on pain responsiveness in male mice. In this study, mice exposed to four days of dim (5 lux) light at night exhibited cold hyperalgesia. Further, after 28 days of exposure, mice exhibited both cold hyperalgesia and mechanical allodynia. No heat/hot hyperalgesia was observed in this experiment. Altered nociception in mice exposed to dim light at night was concurrent with upregulated interleukin-6 and nerve growth factor mRNA expression in the medulla and elevated μ-opioid receptor mRNA expression in the periaqueductal gray region of the brain. The current results support the relationship between disrupted circadian rhythms and altered pain sensitivity. In summary, we observed that dim light at night induces cold hyperalgesia and mechanical allodynia, potentially through elevated neuroinflammation and dysregulation of the endogenous opioid system.

Light has substantial influences on the physiology and behavior of most laboratory animals. As such, lighting conditions within animal rooms are potentially significant and often underappreciated variables within experiments. Disruption of the light/dark cycle, primarily by exposing animals to light at night (LAN), disturbs biological rhythms and has widespread physiological consequences because of mechanisms such as melatonin suppression, sympathetic stimulation, and altered circadian clock gene expression. Thus, attention to the lighting environment of laboratory animals and maintaining consistency of a light/dark cycle is imperative for study reproducibility. Light intensity, as well as wavelength, photoperiod, and timing, are all important variables. Although modern rodent facilities are designed to facilitate appropriate light cycling, there are simple ways to modify rooms to prevent extraneous light exposure during the dark period. Attention to lighting conditions of laboratory animals by both researchers and research care staff ensures best practices for maintaining animal welfare, as well as reproducibility of research results. (PsycINFO Database Record

Artificial light at night (ALAN) is a pervasive phenomenon. Although initially assumed to be innocuous, recent research has demonstrated its deleterious effects on physiology and behavior. Exposure to ALAN is associated with disruptions to sleep/wake cycles, development of mood disorders, metabolic disorders, and cancer. However, the influence of ALAN on affective behavior in tumor-bearing mice has not been investigated. We hypothesize that exposure to ALAN accelerates mammary tumor growth and predict that ALAN exacerbates negative affective behaviors in tumor-bearing mice. Adult (&gt, 8 weeks) female C3H mice received a unilateral orthotropic injection of FM3A mouse mammary carcinoma cells (1.0 × 105 in 100 μL) into the fourth inguinal mammary gland. Nineteen days after tumor inoculation, mice were tested for sucrose preference (anhedonia-like behavior). The following day, mice were subjected to an open field test (anxiety-like behavior), followed by forced swim testing (depressive-like behavior). Regardless of tumor status, mice housed in ALAN increased body mass through the first ten days. Tumor-bearing ALAN-housed mice demonstrated reduced latency to tumor onset (day 5) and increased terminal tumor volume (day 21). Exposure to ALAN reduced sucrose preference independent of tumor status. Additionally, tumor-bearing mice housed in dark nights demonstrated significantly increased anxiety-like behavior that was normalized via housing in ALAN. Together, these data reaffirm the negative effects of ALAN on tumorigenesis and demonstrate the potential anxiolytic effect of ALAN in the presence of mammary tumors.

Molecular mechanisms by which androgens signal through the androgen receptor (AR) to maintain male fertility are poorly understood. Transgenic mice were produced expressing mutant ARs that can only (1) alter gene transcription through the classical response pathway (AR-C) or (2) activate kinase signaling cascades via the nonclassical pathway (AR-NC). AR-C is sufficient to produce sperm and fertility. Haploid germ cell production, the blood-testis barrier, and spermatid migration are supported by AR-NC. Gene expression essential for chromosome synapsis during meiosis requires AR-C. We identify targets of androgen signaling required for male fertility and provide a mechanistic explanation for meiotic germ cell arrest in the absence of androgen signaling. Prostate differentiation occurs with AR-C alone, but full development requires synergistic nonclassical signaling. Both AR signaling pathways are necessary for normal male reproductive tract development and function, validating our mouse models for studies of AR functions in other target tissues.