Biology subjects

Christianson, J. A.

Publications and source records attributed to Christianson, J. A..

10 recordsLinked to original sources

bioRxiv2026

RE-1 silencing transcription factor is reduced in endometriosis and uterine deletion in mice alters progesterone responsiveness

Endometriosis is a steroid-dependent gynecologic disease characterized by progesterone (P4) resistance, subfertility/infertility, and pelvic pain; however, the molecular mechanisms underlying impaired P4 responsiveness in endometriosis tissue are not fully understood. RE-1 silencing transcription factor (REST), a transcriptional regulator implicated in steroid hormone signaling, has emerged as a potential mediator of P4 responsiveness. Here, we investigated the role of REST in endometriosis using human tissues and a uterine-specific Rest conditional knockout mouse model. Immunohistochemical analysis of eutopic endometrium and ectopic lesions from patients with endometriosis revealed significantly reduced nuclear REST expression compared with control endometrium, suggesting loss of functional REST in disease. To assess the physiological consequences of REST deficiency, uterine-specific Rest knockout (Rest d/d) mice were generated. Rest d/d females exhibited progressive subfertility and hyper-estrogenic uterine tissue characteristics that displayed a blunted responsiveness to P4 treatment. Loss of Rest selectively altered expression of P4-responsive genes associated with endometriosis pathology, despite preserved P4 receptor expression. Following induction of experimental endometriosis, female mice that developed endometriotic-like lesions using Rest-deficient donor tissue developed significantly larger lesions that were less responsive to P4 treatment compared to lesions induced using control tissue. Mechanical sensitivity was modestly increased in mice receiving Rest-deficient tissue, whereas vaginal hyperalgesia was unaffected. These findings identify loss of nuclear REST as a feature of endometriosis and support a role of REST in subfertility, lesion progression, and blunted response to P4. REST may represent a novel molecular contributor to altered P4 responsiveness and a potential therapeutic target in endometriosis. Significance StatementEndometriosis is a common disease in women characterized by altered steroid hormone signaling, infertility, and pelvic pain. RE-1 silencing transcription factor (REST) is a candidate regulator of steroid hormone signaling in gynecologic disease but a role in endometriosis pathophysiology remains unexplored. To fill this knowledge gap, our study utilizes human endometrial and endometriotic tissues coupled with a conditional knockout mouse model for uterine Rest deficiency. We show that REST is significantly reduced in eutopic and ectopic endometrial tissue from women with endometriosis and that deletion from mouse uterine tissue recapitulates clinical characteristics in women with endometriosis including progesterone resistance, sub-fertility and pelvic pain. These findings will further guide future research to understand impaired steroid signaling in the pathophysiology of endometriosis.

physiology↗

bioRxiv2023

Identification of arginine-vasopressin receptor 1a (Avpr1a/AVPR1A) as a novel candidate gene for chronic visceral pain.

Chronic abdominal pain in the absence of ongoing disease is the hallmark of disorders of gut-brain interaction (DGBIs), including irritable bowel syndrome (IBS). While the etiology of DGBIs remains poorly understood, there is evidence that both genetic and environmental factors play a role. In this study, we report the identification and validation of Avpr1a as a novel candidate gene for visceral hypersensitivity (VH), a primary peripheral mechanism underlying abdominal pain in DGBI/IBS. Comparing two C57BL/6 (BL/6) substrains (C57BL/6NTac and C57BL/6J) revealed differential susceptibility to the development of chronic VH following intrarectal zymosan (ZYM) instillation, a validated preclinical model for post-inflammatory IBS. Using whole genome sequencing, we identified a SNP differentiating the two strains in the 5 intergenic region upstream of Avpr1a, encoding the protein arginine-vasopressin receptor 1A (AVPR1A). We used behavioral, histological, and molecular approaches to identify distal colon- specific gene expression differences and neuronal hyperresponsiveness covarying with Avpr1a genotype and VH susceptibility. While the two BL/6 substrains did not differ across other gastrointestinal (GI) phenotypes (e.g., GI motility), VH-susceptible BL/6NTac mice had higher colonic Avpr1a mRNA and protein expression. Moreover, neurons of the enteric nervous system were hyperresponsive to the AVPR1A agonist AVP, suggesting a role for enteric neurons in the pathology underlying VH. These results parallel our findings that patients colonic Avpr1a mRNA expression was higher in patients with higher pain ratings. Taken together, these findings implicate differential regulation of Avpr1a as a novel mechanism of VH-susceptibility as well as a potential therapeutic target specific to VH. SummaryA combination of approaches, from genomic analysis to functional analyses, confirm Avpr1a as a high priority candidate gene for visceral pain.

genetics↗

bioRxiv2023

Exposure to early life stress impairs weight loss maintenance success in mice.

Early life stress increases obesity risk, but its impact on weight loss maintenance is unknown. Mice underwent neonatal maternal separation (NMS) from 0-3 weeks and were weaned onto high fat sucrose diet (HFSD) from 3-20 weeks. Calorie-restricted weight loss on a low fat sucrose diet (LFSD) occurred over 2 weeks to induce a 20% loss in body weight, which was maintained for 6 weeks. After weight loss, half the mice received running wheels (EX) the other half remained sedentary (SED). Mice were then fed ad libitum on HFSD or LFSD for 10 weeks and allowed to regain body weight. NMS mice had greater weight regain, total body weight and adiposity compared to naive mice. During the first week of refeeding, NMS mice had increased food intake and were in a greater positive energy balance than naive mice, but total energy expenditure was not affected by NMS. Female mice were more susceptible to NMS-induced effects, including increases in adiposity. NMS and naive females were more susceptible to HFSD-induce weight regain. Exercise was beneficial in the first week of regain in male mice, but long-term only those on LFSD benefited from EX. As expected, HFSD led to greater weight regain than LFSD.

physiology↗

bioRxiv2022

Early life stress exposure increases susceptibility to high fat/high sucrose diet in female mice

Exposure to stress early in life has been associated with adult-onset co-morbidities such as chronic pain, metabolic dysregulation, obesity, and inactivity. We have established an early life stress model using neonatal maternal separation (NMS) in mice, which displays evidence of increased body weight and adiposity, widespread mechanical allodynia, and hypothalamic-pituitary-adrenal axis dysregulation in male mice. Early life stress and consumption of a western style diet contribute to the development of obesity, however, relatively few pre-clinical studies have been performed in female rodents, which are known to be protected against diet induced obesity and metabolic dysfunction. In this study we gave naive and NMS female mice access to a high-fat/high-sucrose (HFS) diet beginning at 4 weeks of age. Robust increases in body weight and fat were observed in HFS-fed NMS mice during the first 10 weeks on the diet, driven partly by increased food intake. Female NMS mice on a HFS diet showed widespread mechanical hypersensitivity compared to either naive mice on a HFS diet or NMS mice on a control diet. HFS diet-fed NMS mice also had impaired glucose tolerance and fasting hyperinsulinemia. Strikingly, female NMS mice on a HFS diet showed evidence of hepatic steatosis with increased triglyceride levels and altered glucocorticoid receptor levels and phosphorylation state. They also exhibited increased energy expenditure as observed via indirect calorimetry and expression of pro-inflammatory markers in perigonadal adipose. Altogether, our data suggest that early life stress exposure increased the susceptibility of female mice to develop diet-induced metabolic dysfunction and pain-like behaviors.

physiology↗

bioRxiv2020

Reduced Liver-Specific PGC1a Increases Susceptibility for Short-Term Diet-induced Weight Gain in Male Mice

Central integration of peripheral neural signals is one mechanism by which systemic energy homeostasis is regulated. Previous work described increased acute food intake following chemical reduction of hepatic fatty acid oxidation and ATP levels, which was prevented by common hepatic branch vagotomy (HBV). However, possible offsite actions of the chemical compounds confound the precise role of liver energy metabolism. Herein, we used a liver-specific PGC1a heterozygous (LPGC1a) mouse model, with associated reductions in mitochondrial fatty acid oxidation and respiratory capacity, to assess the role of liver energy metabolism in systemic energy homeostasis. LPGC1a male mice have 70% greater high-fat/high-sucrose (HFHS) diet-induced weight gain and 35% greater positive energy balance compared to wildtype (WT) (p<0.05). The greater energy balance was associated with altered feeding behavior and lower activity energy expenditure during HFHS in LPGC1a males. Importantly, no differences in HFHS-induced weight gain or energy metabolism was observed between female WT and LPGC1a mice. WT and LPGC1a mice underwent sham or HBV to assess whether vagal signaling was involved in HFHS-induced weight gain of male LPGC1a mice. HBV increased HFHS-induced weight gain (85%, p<0.05) in male WT, but not LPGC1a mice. As above, sham LPGC1a males gain 70% more weight during short-term HFHS feeding than sham WT (p<0.05). These data demonstrate a sexspecific role of reduced liver energy metabolism in acute diet-induced weight gain, and the need of more nuanced assessment of the role of vagal signaling in short-term diet-induced weight gain. Key Points SummaryO_LIReduced liver PGC1a expression results in reduced mitochondrial fatty acid oxidation and respiratory capacity in male mice. C_LIO_LIMale mice with reduced liver PGC1a expression (LPGC1a) demonstrate greater short-term high-fat/high-sucrose diet-induced weight gain compared to wildtype. C_LIO_LIGreater positive energy balance during HFHS feeding in male LPGC1a mice is associated with altered food intake patterns and reduced activity energy expenditure. C_LIO_LIFemale LPGC1a mice do not have differences in short-term HFHS-induced body weight gain or energy metabolism compared to wildtype. C_LIO_LIDisruption of vagal signaling through common hepatic branch vagotomy increases short-term HFHS-induced weight gain in male wildtype mice, but does not alter male LPGC1a weight gain. C_LI

physiology↗

bioRxiv2020

A high fat anti-inflammatory diet improves widespread allodynia despite worsening metabolic outcomes in adult mice exposed to neonatal maternal separation

Inflammation plays a key role in the progression and maintenance of chronic pain, which impacts the lives of millions of Americans. Despite growing evidence that chronic pain can be improved by treating underlying inflammation, successful treatments are lacking and pharmaceutical interventions are limited due to drug side effects. Here we are testing whether an anti-inflammatory diet (AID) containing a combination of key anti-inflammatory compounds, at clinically relevant doses, improves pain-like behaviors in a preclinical model of chronic widespread hypersensitivity induced by neonatal maternal separation (NMS). Our results demonstrate a benefit of the AID on pain-like behaviors, despite the diet being high in fat, which led to increased caloric intake, adiposity, and weight gain. The AID specifically increased measures of metabolic syndrome and inflammation in female mice, compared to an isocaloric, macronutrient-matched diet lacking the anti-inflammatory compounds. Male mice, especially those exposed to NMS, were equally susceptible to both diets worsening metabolic measures. This work highlights important sexual dimorphic outcomes related to early life stress exposure and dietary interventions, as well as a potential disconnect between improvements in pain-like behaviors and metabolic measures.

physiology↗

bioRxiv2020

Voluntary wheel running improves outcomes in an early life stress-induced model of urologic chronic pelvic pain syndrome in male mice

Patients with a history of early life stress (ELS) exposure have an increased risk of developing chronic pain and mood disorders later in life. The severity of ELS in patients with urologic chronic pelvic pain syndrome (UCPPS) is directly correlated with symptom severity and increased comorbidity, and is inversely related to likelihood of improvement. Voluntary exercise improves chronic pain symptoms and our group and others have shown that voluntary wheel running can improve outcomes in stress-induced UCPPS models, suggesting that exercise may negate some of the outcomes associated with ELS. Here we provide further evidence that voluntary wheel running can attenuate increased perigenital mechanical sensitivity, bladder output, and mast cell degranulation in the bladder and prostate in male mice that underwent neonatal maternal separation (NMS). Sedentary male NMS mice had reduced serum corticosterone, which was not impacted by voluntary wheel running, although stress-related regulatory gene expression in the hypothalamus and hippocampus was significantly increased following exercise. Neurogenesis in the dentate gyrus of the hippocampus was diminished in sedentary NMS mice and significantly increased in both exercised naive and NMS mice. Sucrose consumption increased in exercised naive but not NMS mice, and anxiety behaviors measured on an elevated plus maze were increased following exercise. Together these data suggest that voluntary wheel running is sufficient to normalize many of the UCPPS-related outcomes resulting from NMS. Exercise also increased hippocampal neurogenesis and stress-related gene expression within the hypothalamic-pituitary-adrenal axis, further supporting exercise as a non-pharmacological intervention for attenuating outcomes related to ELS exposure.

neuroscience↗

bioRxiv2020

Early life stress reduces voluntary exercise and its prevention of diet-induced obesity and metabolic dysfunction in mice

The development of obesity-related metabolic syndrome (MetS) involves a complex interaction of genetic and environmental factors. One environmental factor found to be significantly associated with MetS is early life stress (ELS). We have previously reported on our mouse model of ELS, induced by neonatal maternal separation (NMS), that displays altered regulation of the hypothalamic-pituitary-adrenal (HPA) axis and increased sensitivity in the urogenital organs, which was attenuated by voluntary wheel running. Here, we are using our NMS model to determine if ELS-induced changes in the HPA axis also influence weight gain and MetS. Naive (non-stressed) and NMS male mice were given free access to a running wheel and a low-fat control diet at 4-weeks of age. At 16-weeks of age, half of the mice were transitioned to a high fat/sucrose (HFS) diet to investigate if NMS influences the effectiveness of voluntary exercise to prevent diet-induced obesity and MetS. Overall, we observed a greater impact of voluntary exercise on prevention of HFS diet-induced outcomes in naive mice, compared to NMS mice. Although body weight and fat mass were still significantly higher, exercise attenuated fasting insulin levels and mRNA levels of inflammatory markers in epididymal adipose tissue in HFS diet-fed naive mice. Only moderate changes were observed in exercised NMS mice on a HFS diet, although this could partially be explained by reduced running distance within this group. Interestingly, sedentary NMS mice on a control diet displayed impaired glucose homeostasis and moderately increased pro-inflammatory mRNA levels in epididymal adipose, suggesting that early life stress alone impairs metabolic function and negatively impacts the therapeutic effect of voluntary exercise.

physiology↗

bioRxiv2019

Divergent Energy Expenditure Impacts Mouse Metabolic Adaptation to Acute High-Fat/High-Sucrose Diet Producing Sexually Dimorphic Weight Gain Patterns

ObjectiveLong-term weight gain can result from cumulative small weight increases due to short-term excess caloric intake during weekends and holidays. Increased physical activity may mediate weight gain through increases in energy expenditure (EE) and reductions in energy balance. Current methods for modulating mouse EE (e.g. - exercise, chemical uncouplers, etc.) have confounding effects. However, it is known that mouse EE linearly increases as housing temperature decreases below the thermoneutral zone. MethodsTo determine how robust differences in baseline EE impact 7-day changes in weight and body composition on low-fat and high-fat, high-sucrose (HFHS) diets, we performed indirect calorimetry measurements in male and female mice housed at divergent temperatures (20{degrees}C vs. 30{degrees}C). ResultsAs expected, mice housed at 30{degrees}C have [~]40% lower total EE and energy intake compared to 20{degrees}C mice regardless of diet or sex. Energy balance was increased with HFHS in all groups, with [~]30% greater increases observed in 30{degrees}C versus 20{degrees}C mice. HFHS increased weight gain regardless of temperature or sex. Interestingly, no HFHS-induced weight gain differences were observed between females at different temperatures. In contrast, 30{degrees}C male mice on HFHS gained [~]50% more weight than 20{degrees}C males, and [~]80% more weight compared to 30{degrees}C females. HFHS increased fat mass across all groups but 2-fold higher gains occurred in 30{degrees}C mice compared to 20{degrees}C mice. Females gained [~]35% less fat mass than males at both temperatures. ConclusionsTogether, these data reveal an interaction between divergent ambient temperature-induced EE and sex that impacted diet-induced patterns of short-term weight gain and body composition. HighlightsO_LIUtilized ambient temperature differences as an experimental tool to study the impact of divergent baseline energy expenditure on metabolic adaptation to high-fat, high-sucrose diet. C_LIO_LIBaseline energy expenditure and sex interact to impact diet-induced changes in body composition and weight gain. C_LIO_LIThe energy expenditure and sex interaction is a result of an inverse relationship between fat mass gain and weight-adjusted total energy expenditure, as well as, diet-induced non-shivering thermogenesis. C_LIO_LIThese data support that the hypothesis that higher energy expenditure amplifies the coupling of energy intake to energy expenditure during energy dense feeding, resulting in reduced positive energy balance and reduced gains in weight and adiposity. C_LIO_LIFirst evidence that energy expenditure level plays a role in the composition of weight gained by female mice during acute HFHS feeding. C_LIO_LIThis study further highlights issues with obesity/energy metabolism research performed in mice at sub-thermoneutral housing temperatures, particularly with sex comparisons. C_LI GRAPHIC ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=100 SRC="FIGDIR/small/840702v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@39eb69org.highwire.dtl.DTLVardef@8e564forg.highwire.dtl.DTLVardef@c46714org.highwire.dtl.DTLVardef@4b5898_HPS_FORMAT_FIGEXP M_FIG Legend: Male and female mice housed at 30{degrees}C had lower energy expenditure (EE) & energy intake (EI), while having greater energy balance (EB), during 7-day high-fat/high-sucrose (HFHS) feeding compared to male and female mice, respectively, housed at 20{degrees}C. However, female mice had lower EB compared to males at both housing temperature. Female mice housed at 30{degrees}C gained less weight than 30{degrees}C males but gained the same relative amount of fat mass during acute HFHS feeding. Interestingly, 20{degrees}C females gained the same amount of weight as 20{degrees}C males but gained primarily fat-free mass, while the males gained the same proportion of fat as 30{degrees}C males and females. C_FIG

physiology↗

bioRxiv2019

Foot shock stress generates persistent widespread hypersensitivity and anhedonic behavior in an anxiety-prone strain of mice

A significant subset of patients with urologic chronic pelvic pain syndrome (UCPPS) suffer from widespread, as well as pelvic, pain and experience mood-related disorders, including anxiety, depression, and panic disorder. Stress is a commonly-reported trigger for symptom onset and exacerbation within these patients. The link between stress and pain is thought to arise, in part, from the hypothalamic-pituitary-adrenal (HPA) axis, which regulates the response to stress and can influence the perception of pain. Previous studies have shown that stress exposure in anxiety-prone rats can induce both pelvic and widespread hypersensitivity. Here, we exposed female A/J mice, an anxiety-prone inbred murine strain, to 10 days of foot shock stress to determine stress-induced effects on sensitivity, anhedonia, and HPA axis regulation and output in. At 1- and 28-days post-foot shock, A/J mice displayed significantly increased bladder sensitivity and hind paw mechanical allodynia. They also displayed anhedonic behavior, measured as reduced nest building scores and a decrease in sucrose preference during the 10-day foot shock exposure. Serum corticosterone was significantly increased at 1-day post-foot shock and bladder mast cell degranulation rates were similarly high in both sham- and shock-exposed mice. Bladder cytokine and growth factor mRNA levels indicated a persistent shift toward a pro-inflammatory environment following foot shock exposure. Together, these data suggest that chronic stress exposure in an anxiety-prone mouse strain may provide a useful translational model for understanding mechanisms that contribute to widespreadness of pain and increased comorbidity in a subset of UCPPS patients.

neuroscience↗