ABSTRACT
There is growing interest in the therapeutic potential of psilocybin for the treatment of a wide variety of medical problems, and even for the promotion of wellbeing among healthy individuals. Interestingly, among the many proposed indications, both obesity and anorexia nervosa (AN) have been discussed. However, the effect of psilocybin on appetitive behavior and metabolism is not well known. Here, we report the effects of psilocybin on body weight, intake and output, body composition, and metabolic function among lean male and female wild-type mice. In the days immediately following treatment, both male and female mice receiving a single intraperitoneal dose of psilocybin were consistently heavier than saline controls, with no effect of psilocybin on intake or output. Co-administration of the 5-HT2A/2C receptor antagonist ketanserin had no effect on this outcome. Body composition analysis revealed that psilocybin significantly increased lean and water mass among males, with a similar trend among females. A metabolic panel revealed increased creatine kinase (CK), aspartate aminotransferase (AST), and chloride among male and female psilocybin treated mice. Together, these findings begin to investigate the potential mechanisms of psilocybin's effects on body weight and metabolic measures. Such understanding will be critical for the safe, efficacious, and well-informed use of psilocybin in clinical and non-clinical settings.
Subject(s)
Body Composition , Body Weight , Psilocybin , Animals , Female , Male , Mice , Body Composition/drug effects , Psilocybin/pharmacology , Body Weight/drug effects , Mice, Inbred C57BL , Hallucinogens/pharmacology , Ketanserin/pharmacology , Eating/drug effects , Sex CharacteristicsABSTRACT
Individuals with anorexia nervosa (AN) exhibit dangerous weight loss due to restricted eating and hyperactivity. Those with AN are predominantly women and most cases have an age of onset during adolescence. Activity-based anorexia (ABA) is a rodent behavioral paradigm that recapitulates many of the features of AN including restricted food intake and hyperactivity, resulting in precipitous weight loss. In addition, there is enhanced sensitivity to the paradigm during adolescence. In ABA, animals are given time-restricted access to food and unlimited access to a running wheel. Under these conditions, most animals increase their running and decrease their food intake resulting in precipitous weight loss until they either die or researchers discontinue the paradigm. Some animals learn to balance their food intake and energy expenditure and are able to stabilize and eventually reverse their weight loss. For these studies, adolescent (postnatal day 33-42), female Sprague Dawley (n = 68) rats were placed under ABA conditions (unlimited access to a running wheel and 1.5 hrs access to food) until they either reached 25% body weight loss or for 7 days. 70.6% of subjects reached 25% body weight loss before 7 days and were designated susceptible to ABA while 29.4% animals were resistant to the paradigm and did not achieve the weight loss criterion. We used discrete time survival analysis to investigate the contribution of food intake and running behavior during distinct time periods both prior to and during ABA to the likelihood of reaching the weight loss criterion and dropping out of ABA. Our analyses revealed risk factors, including total running and dark cycle running, that increased the likelihood of dropping out of the paradigm, as well as protective factors, including age at the start of ABA, the percent of total running exhibited as food anticipatory activity (FAA), and food intake, that reduced the likelihood of dropping out. These measures had predictive value whether taken before or during exposure to ABA conditions. Our findings suggest that certain running and food intake behaviors may be indicative of a phenotype that predisposes animals to susceptibility to ABA. They also provide evidence that running during distinct time periods may reflect functioning of distinct neural circuitry and differentially influence susceptibility and resistance to the paradigm.
Subject(s)
Anorexia Nervosa , Anorexia , Adolescent , Rats , Female , Humans , Animals , Male , Rats, Sprague-Dawley , Motor Activity , Disease Models, Animal , Weight Loss , EatingABSTRACT
Anorexia Nervosa (AN) is associated with a high rate of morbidity and mortality as well as a high rate of relapse. The molecular mechanisms underlying the progression of the disorder or the relapses are largely unknown. Patients with AN have been shown to have increased oxidative stress, but its involvement in the development in the disease is unknown. We have previously shown that adolescent female rats undergoing the activity-based anorexia (ABA) paradigm also show signs of oxidative stress. Due to their role in the release of reactive oxygen species (ROS), mitochondria are of high interest in diseases exhibiting oxidative stress. In this study, the impact of ABA on brain mitochondrial dynamics was examined. We found transient changes in the medial prefrontal cortex, hypothalamus, and hippocampus following 25% weight loss and changes in the amygdala at a 10-day weight recovery timepoint. These changes point towards damage in the mitochondria contributing to the oxidative stress.
Subject(s)
Anorexia Nervosa , Anorexia , Rats , Female , Animals , Mitochondrial Dynamics , Hippocampus , BrainABSTRACT
This study assessed the impact of maternal diet during pregnancy versus lactation on offspring gut microbiota. Sprague-Dawley dams were fed high fat (HF) or Chow diets during pregnancy, and their male offspring were raised by a different dam consuming the same or opposite diet (Chow-Chow, Chow-HF, HF-Chow, and HF-HF). Microbiota analysis showed that maternal lactation diet, rather than pregnancy diet, determined offspring microbiota profiles at weaning. Increased abundances of Turicibacter, Staphylococcus , and Ruminococcus were characteristic of chow lactation groups. Lactococcus , Streptococcus , and Parabacteroides were characteristic of HF lactation groups and positively correlated with offspring body weight.
Subject(s)
Microbiota , Prenatal Exposure Delayed Effects , Pregnancy , Humans , Female , Rats , Animals , Male , Maternal Nutritional Physiological Phenomena , Rats, Sprague-Dawley , Diet , Lactation , Body Weight , Diet, High-Fat/adverse effectsABSTRACT
In rodents, early-life exposure to environmental stress or antidepressant medication treatment has been shown to induce similar long-term consequences on memory- and depression-related behavior in adulthood. To expand on this line of work, we evaluated how juvenile exposure to chronic variable stress (CVS) or the selective serotonin reuptake inhibitor fluoxetine (FLX) influences conditioned taste aversion (CTA) learning in adulthood. To do this, in Experiment 1, we examined how adolescent CVS alone (postnatal day [PND] 35-48), or with prenatal stress (PNS) history (PNS + CVS), influenced the acquisition and extinction of CTA in adult male Sprague Dawley rats. Specifically, at PND70+ (adulthood), rats were presented with 0.15 % saccharin followed by an intraperitoneal (i.p.) injection of lithium chloride (LiCl) to induce visceral malaise. A total of four saccharin (conditioned stimulus) and LiCl (unconditioned stimulus) pairings occurred across the CTA acquisition phase. Next, saccharin was presented without aversive consequences, and intake was measured across consecutive days of the extinction phase. No differences in body weight gain across the experimental days, rate of CTA acquisition, or extinction of CTA, were observed among the experimental groups (control, n = 7; CVS, n = 12; PNS + CVS, n = 9). In Experiment 2, we evaluated if early-life FLX exposure alters CTA learning in adulthood. Specifically, adolescent stress naïve male and female rats received FLX (0 or 20 mg/kg/i.p) once daily for 15 consecutive days (PND35-49). During antidepressant exposure, FLX decreased body weight gain in both male (n = 7) and female rats (n = 7), when compared to respective controls (male control, n = 8; female control, n = 8). However, juvenile FLX exposure decreased body weight-gain in adult male, but not female, rats. Lastly, adolescent FLX history had no effect on CTA acquisition or extinction in adulthood (PND70), in neither male nor female rats. Together, the data indicate that juvenile FLX exposure results in a long-term decrease of body weight-gain in a male-specific manner. Yet, independent of sex, neither early-life stress nor FLX exposure alters CTA learning in adulthood.
Subject(s)
Fluoxetine , Stress, Psychological , Animals , Male , Rats , Avoidance Learning , Body Weight , Fluoxetine/pharmacology , Lithium Chloride/pharmacology , Rats, Sprague-Dawley , Saccharin , Taste , Female , Prenatal Exposure Delayed EffectsABSTRACT
Recent evidence in humans and animals indicates an association between maternal obesity and offspring behavioral outcomes. In humans, increased maternal body mass index has been linked to an increased risk of children receiving a diagnosis of early-emerging neurodevelopmental disorders such as Attention Deficit/Hyperactivity Disorder (ADHD) and/or Autism Spectrum Disorder (ASD). However, a limited number of preclinical studies have examined associations between maternal Western-Style Diet (mWSD) exposure and offspring social behavior. To our knowledge, this is the first study to investigate relationships between mWSD exposure and social behavior in non-human primates. Since aberrant social behavior is a diagnostic criterion for several neurodevelopmental disorders, the current study focuses on examining the influence of maternal nutrition and metabolic state on offspring social behavior in Japanese macaques (Macaca fuscata). We found that mWSD offspring initiated less affiliative social behaviors as well as proximity to a peer. Using path analysis, we found that the association between mWSD consumption and reduced offspring social engagement was statistically mediated by increased maternal interleukin (IL)-12 during the third trimester of pregnancy. Additionally, mWSD offspring displayed increased idiosyncratic behavior, which was related to alterations in maternal adiposity and leptin in the third trimester. Together, these results suggest that NHP offspring exposed to mWSD exhibit behavioral phenotypes similar to what is described in some early-emerging neurodevelopmental disorders. These results provide evidence that mWSD exposure during gestation may be linked to increased risk of neurodevelopmental disorders and provides targets for prevention and intervention efforts.
Subject(s)
Autism Spectrum Disorder , Prenatal Exposure Delayed Effects , Animals , Diet, Western/adverse effects , Female , Humans , Macaca fuscata , Pregnancy , Prenatal Exposure Delayed Effects/metabolism , Social ParticipationABSTRACT
OBJECTIVE: As patients with anorexia nervosa tend to "like" palatable tastants less than controls, we set out to model this preclinically by using the taste reactivity test (TRT) to assess hedonic state in rats following weight restoration from a bout of activity-based anorexia (ABA). METHOD: Female rats (n = 31) were surgically implanted with an intraoral catheter, which allowed experimenters to assess baseline TRT to six tastants. Following baseline TRT, animals were either exposed to the activity-based anorexia condition (ABA; 1.5HR chow/ad lib wheel until 25% weight loss), kept sedentary (SED; ad lib chow/locked wheel), given access to running wheels with ad lib chow access (RW; ad lib chow/wheel), or were body weight matched to the ABA group (BWM; restricted chow/locked wheel). Following 25% weight loss, wheels were locked and food returned to ABA rats. Paired RW groups had their wheels locked and paired BWM rats were given ad lib access to food. Animals were given 10 days to recover prior to a second TRT. Videos were analyzed for liking (tongue protrusions) and disliking (gape) behaviors. RESULTS: The ABA group displayed a significant within-subject reduction in cumulative lick responses to water and 1 M sucrose. Additionally, we found the SED and ABA group displayed a significant within-subject reduction in cumulative lick responses to .1 M sucrose. Positive hedonic responses did not decline in either the BWM or the RW groups. DISCUSSION: The data show a novel phenomenon that a history of ABA results in an anhedonia phenotype that mirrors aspects of AN. SIGNIFICANCE STATEMENT: Patients recovered from anorexia nervosa report anhedonia, or the lack of pleasure in consuming palatable foods. Unfortunately, the biological mechanism underpinning anhedonia in anorexia nervosa is not well understood. The current study assessed hedonic state in adolescent female rats prior to and 10 days recovered following the activity-based anorexia paradigm. Age-matched, running wheel-matched and body weight-matched control groups were also tested at the same time points.
Subject(s)
Anorexia Nervosa , Anorexia , Anhedonia , Animals , Anorexia/etiology , Disease Models, Animal , Eating/physiology , Female , Humans , Motor Activity/physiology , Rats , Sucrose , Weight LossABSTRACT
Children born to women who experience stress during pregnancy have an increased risk of atherosclerosis in later life, but few animal models have explored mechanisms. To study this phenomenon, timed-bred ApoE knockout mice were determined pregnant with ultrasound and randomly assigned on gestation day 8.5 to either a control (no stress) or prenatal stress (PS) group using 2 h of restraint for five consecutive days. PS significantly increased plasma corticosterone levels in pregnant mice. The litters from PS mice showed increased neonatal mortality within the first week of life. Body weights (at euthanasia) of adult offspring at 25 wk from the PS group were significantly increased compared with weights of controls. Adult offspring from these pregnancies were serially imaged with ultrasound to measure plaque thickness and were compared with plaque macroscopic and microscopic pathology. PS groups had increased plaque thickness determined by ultrasound, gross, histological evaluation and increased aortic root and valve macrophage infiltration at 25 wk. Five-week-old mice from PS group had significant decrease in mean arterial pressure, yet blood pressure normalized by 10 wk. As prenatal stress induced increased atherosclerosis, and telomeres are susceptible to stress, aortas from 10-wk-old mice were compared for telomere lengths and were found to be significantly shorter in PS mice compared with control mice. These studies support future investigation of how stress impacts telomere shortening in animal models and human aortas. This model could be further used to investigate the role of prenatal stress, telomere biology, and atherosclerosis pathogenesis in adults.
Subject(s)
Atherosclerosis , Prenatal Exposure Delayed Effects , Animals , Aorta , Apolipoproteins E/genetics , Atherosclerosis/genetics , Atherosclerosis/pathology , Female , Humans , Mice , Mice, Knockout , Pregnancy , Stress, Psychological , Telomere ShorteningABSTRACT
OBJECTIVE: Anhedonia, which in part involves the lack of pleasure in consuming palatable food, is a long-lasting symptom observed in patients both when acutely ill and when long term recovered from Anorexia Nervosa. The neurocircuitry underlying this phenomenon is not well understood. Here we use the preclinical activity-based anorexia (ABA) model in adolescent female rats to assess the impact of excessive exercise, limited food intake and acute weight loss, on adolescent female rat orofacial responding to intraoral sucrose, as measured by the taste reactivity test (TRT). Animals were identified as either prone or resistant to this paradigm based on a weight loss criterion. Measures of food intake, running wheel activity, taste reactivity and medial prefrontal cortex astrocyte expression were compared across groups. METHODS: Adolescent female rats implanted with an intraoral catheter were given a TRT using 1 M (M) sucrose at baseline, max weight loss (25% weight loss from start of ABA or 7 full days on the paradigm) or 10 days recovered from the ABA paradigm. Animals were sacrificed after the final TRT and astrocyte density was measured via immunohistochemistry. RESULTS: Animals resistant to the ABA paradigm ran less than prone animals during the ABA period. Additionally, we found that resistant animals displayed more cumulative 'liking' responses to sucrose compared to prone animals at maximum weight loss. Finally, we found prone animals 10-days recovered from ABA had reduced medial prefrontal cortex astrocyte density compared to levels in resistant animals. DISCUSSION: Rats presented with the physiological challenge of the ABA paradigm either adapt their behavior to stabilize their body weight (i.e. resistant), or rapidly lose weight (i.e. prone). Furthermore, we found that prone animals have reduced orofacial responding to 1 M sucrose at maximum weight loss compared to responses in resistant animals, and this anhedonia-like behavior may be a result of reduced astrocyte density that affects cortical function.
Subject(s)
Anorexia Nervosa , Anorexia , Animals , Astrocytes , Disease Models, Animal , Female , Humans , Rats , Weight LossABSTRACT
We recently identified a nuclear-encoded miRNA (miR-181c) in cardiomyocytes that can translocate into mitochondria to regulate mitochondrial gene mt-COX1 and influence obesity-induced cardiac dysfunction through the mitochondrial pathway. Because liver plays a pivotal role during obesity, we hypothesized that miR-181c might contribute to the pathophysiological complications associated with obesity. Therefore, we used miR-181c/d-/- mice to study the role of miR-181c in hepatocyte lipogenesis during diet-induced obesity. The mice were fed a high-fat (HF) diet for 26 weeks, during which indirect calorimetric measurements were made. Quantitative PCR (qPCR) was used to examine the expression of genes involved in lipid synthesis. We found that miR-181c/d-/- mice were not protected against all metabolic consequences of HF exposure. After 26 weeks, the miR-181c/d-/- mice had a significantly higher body fat percentage than did wild-type (WT) mice. Glucose tolerance tests showed hyperinsulinemia and hyperglycemia, indicative of insulin insensitivity in the miR-181c/d-/- mice. miR-181c/d-/- mice fed the HF diet had higher serum and liver triglyceride levels than did WT mice fed the same diet. qPCR data showed that several genes regulated by isocitrate dehydrogenase 1 (IDH1) were more upregulated in miR-181c/d-/- liver than in WT liver. Furthermore, miR-181c delivered in vivo via adeno-associated virus attenuated the lipogenesis by downregulating these same lipid synthesis genes in the liver. In hepatocytes, miR-181c regulates lipid biosynthesis by targeting IDH1. Taken together, the data indicate that overexpression of miR-181c can be beneficial for various lipid metabolism disorders.
Subject(s)
Diet, High-Fat/adverse effects , Hepatocytes/metabolism , Lipogenesis , Liver/metabolism , MicroRNAs/metabolism , Obesity , Triglycerides , Animals , Lipogenesis/drug effects , Lipogenesis/genetics , Male , Mice , Mice, Knockout , MicroRNAs/genetics , Obesity/chemically induced , Obesity/genetics , Obesity/metabolism , Triglycerides/biosynthesis , Triglycerides/geneticsABSTRACT
The adverse effects of stress on brain and behavior have long been known and well-studied, with abundant evidence linking stress to, among other things, mood and anxiety disorders. Likewise, many have investigated potential treatments for stress-related mood and anxiety phenotypes and demonstrated good response to standard antidepressant medications like selective serotonin reuptake inhibitors (SSRIs), as well as environmental manipulations like exercise or enrichment. However, the extent to which stress and various treatments act on overlapping pathways in the brain is less well understood. Here, we used a widely studied social defeat stress paradigm to induce a robust depression- and anxiety-like phenotype and chronic corticosterone elevation that persisted for at least 4 weeks in wild type male mice. When mice were treated with either the SSRI fluoxetine or an enriched environment, both led to similar behavioral recovery from social defeat. We then focused on the amygdala and assessed the effects of social defeat, fluoxetine, and enrichment on 168 genes broadly related to synaptic plasticity or oxidative stress. We found 24 differentially expressed genes in response to social defeat stress. Interestingly, fluoxetine led to broad normalization of the stress-induced expression pattern while enrichment led to expression changes in a separate set of genes. Together, this study provides additional insight into the chronic effects of social defeat stress on behavior and gene expression in the amygdala. The findings also suggest that, for a subset of genes assessed, fluoxetine and environmental enrichment have strikingly divergent effects on expression in the amygdala, despite leading to similar behavioral outcomes.
ABSTRACT
Despite the high prevalence of obesity, little is known about its potential impact on the pharmacokinetics of psychotropic drugs. In the course of investigating the role of the microRNA system on neuronal signaling, we found that mice lacking the translin/trax microRNA-degrading enzyme display an exaggerated locomotor response to amphetamine. As these mice display robust adiposity in the context of normal body weight, we checked whether this phenotype might reflect elevated brain levels of amphetamine. To assess this hypothesis, we compared plasma and brain amphetamine levels of wild type and Tsn KO mice. Furthermore, we checked the effect of diet-induced increases in adiposity on plasma and brain amphetamine levels in wild type mice. Brain amphetamine levels were higher in Tsn KO mice than in wild type littermates and correlated with adiposity. Analysis of the effect of diet-induced increases in adiposity in wild type mice on brain amphetamine levels also demonstrated that brain amphetamine levels correlate with adiposity. Increased adiposity displayed by Tsn KO mice or by wild type mice fed a high-fat diet correlates with elevated brain amphetamine levels. As amphetamine and its analogues are widely used to treat attention deficit disorder, which is associated with obesity, further studies are warranted to assess the impact of adiposity on amphetamine levels in these patients.
Subject(s)
Adiposity , Amphetamine , Adipose Tissue , Amphetamine/pharmacology , Animals , Brain , Diet, High-Fat , Humans , Mice , Mice, Inbred C57BL , Mice, Knockout , ObesityABSTRACT
OBJECTIVE: Gastrointestinal (GI) concerns are often presumed to complicate nutritional rehabilitation for restrictive eating disorders, yet their relationship to weight restoration outcomes is unclear. This retrospective chart review examined GI history and weight-related discharge outcomes in primarily adult, underweight inpatients with anorexia nervosa (AN, N = 107) or avoidant/restrictive food intake disorder (ARFID, N = 22) treated in a meal-based, behavioral eating disorder program. METHOD: Lifetime GI symptomatology, diagnoses, diagnostic tests, and procedures were abstracted from medical records. Generalized linear models examined associations of GI diagnoses, tests, and procedures with discharge BMI and rate of weight gain. RESULTS: Ninety-nine percent of patients reported GI symptomatology and 83% had one or more GI diagnoses; with constipation and GERD most common. GI diagnoses (p <.01) and testing (p <.001) were more common in ARFID than AN. Average inpatient weight gain (1.59 kg/week), and discharge BMI (18.5 kg/m2 ), did not differ by group. Slower weight gain in patients with (1.3 kg/week), versus without (1.7 kg/week), history of tube feeding (p = .02), accounted for a main effect of GI procedures on inpatient rate of gain (p = .01). DISCUSSION: Despite ubiquitous GI symptomatology, meal-based weight restoration achieved average weekly weight gain above recommended APA guidelines for hospitalized patients with an eating disorder. History of tube feeding was associated with slower mean weight gain, which remained, however, within recommended APA guidelines.
Subject(s)
Anorexia Nervosa , Avoidant Restrictive Food Intake Disorder , Feeding and Eating Disorders , Adult , Anorexia Nervosa/diagnosis , Anorexia Nervosa/therapy , Eating , Feeding and Eating Disorders/diagnosis , Feeding and Eating Disorders/therapy , Humans , Retrospective Studies , ThinnessABSTRACT
Functional dyspepsia (FD) is associated with chronic gastrointestinal distress and with anxiety and depression. Here, we hypothesized that aberrant gastric signals, transmitted by the vagus nerve, may alter key brain regions modulating affective and pain behavior. Using a previously validated rat model of FD characterized by gastric hypersensitivity, depression-like behavior, and anxiety-like behavior, we found that vagal activity - in response to gastric distention - was increased in FD rats. The FD phenotype was associated with gastric mast cell hyperplasia and increased expression of corticotrophin-releasing factor (Crh) and decreased brain-derived neurotrophic factor genes in the central amygdala. Subdiaphragmatic vagotomy reversed these changes and restored affective behavior to that of controls. Vagotomy partially attenuated pain responses to gastric distention, which may be mediated by central reflexes in the periaqueductal gray, as determined by local injection of lidocaine. Ketotifen, a mast cell stabilizer, reduced vagal hypersensitivity, normalized affective behavior, and attenuated gastric hyperalgesia. In conclusion, vagal activity, partially driven by gastric mast cells, induces long-lasting changes in Crh signaling in the amygdala that may be responsible for enhanced pain and enhanced anxiety- and depression-like behaviors. Together, these results support a "bottom-up" pathway involving the gut-brain axis in the pathogenesis of both gastric pain and psychiatric comorbidity in FD.
Subject(s)
Affect , Amygdala/physiopathology , Brain-Gut Axis , Dyspepsia/physiopathology , Pain/physiopathology , Signal Transduction , Vagus Nerve/metabolism , Amygdala/metabolism , Animals , Dyspepsia/metabolism , Female , Pain/metabolism , Rats , Rats, Sprague-DawleyABSTRACT
Maternal stressors during the prenatal and perinatal periods are associated with increased susceptibility for and severity of chronic disease phenotypes in adult offspring. In this study, we used a rat model of maternal high-fat diet (HFD) exposure during pregnancy and lactation to investigate the impact on skeletal homeostasis in offspring. In the distal femur, young male and female offspring (up to 3 weeks of age) from dams fed a HFD exhibited marked increases in trabecular bone volume relative to offspring from dams fed a chow diet, but this was followed by sustained bone loss. By 15 weeks of age, male offspring of HFD fed dams exhibited a 33% reduction in trabecular bone volume fraction that histomorphometric analyses revealed was due to a nearly threefold increase in the abundance of bone-resorbing osteoclasts, while there were no differences between female control and HFD offspring by 15 weeks of age. The osteoblastic differentiation of male offspring-derived bone marrow stromal cells was not affected by maternal diet. However, osteoclastic precursors isolated from the male offspring of HFD fed dams exhibited enhanced differentiation in vitro, forming larger osteoclasts with higher expression of the fusion marker DC-STAMP. This effect appears to be mediated by a cell autonomous increase in the sensitivity of precursors to RANKL. Taken together, these results suggest that maternal stressors like HFD exposure have persistent consequences for the skeletal health of offspring that may ultimately lead to a predisposition for osteopenia/osteoporosis.
Subject(s)
Diet, High-Fat , Prenatal Exposure Delayed Effects , Animals , Diet, High-Fat/adverse effects , Female , Lactation , Male , Osteogenesis , Pregnancy , RatsABSTRACT
The ANK3 locus has been repeatedly found to confer an increased risk for bipolar disorder. ANK3 codes for Ankyrin-G (Ank-G), a scaffold protein concentrated at axon initial segments, nodes of Ranvier, and dendritic spines, where it organizes voltage-gated sodium and potassium channels and cytoskeletal proteins. Mice with homozygous conditional knockout of Ank-G in the adult forebrain display hyperactivity and reduced anxiety-like behaviors, responsive to mood stabilizers. Their behavior switches to a depression-like phenotype when exposed to chronic social defeat stress (SDS), and then spontaneously reverts to baseline hyperactivity. Ank-G heterozygous conditional knockouts (Ank-G Het cKO) have not previously been characterized. Here, we describe the behavior of Ank-G Het cKO mice compared to littermate controls in the open field, elevated plus maze, and forced swim test, under both unstressed and stressed conditions. We found that Ank-G Het cKO is not significantly different from controls at baseline or after chronic SDS. The chronic stress-induced "depression-like" behavioral phenotype is persistent for at least 28 days and is responsive to fluoxetine. Strikingly, Ank-G Het cKO mice display increased sensitivity to a short duration SDS, which does not affect controls. The heterozygous Ank-G genetic model may provide novel insights into the role of Ank-G in the pathophysiology of stress sensitivity and "depression-like" phenotypes and could be useful for studying Ank-G-related gene-environment interactions.
ABSTRACT
OBJECTIVE: Patients with Anorexia Nervosa (AN) display increased levels of oxidative stress that correlates with disease severity. Unfortunately, the biological ramifications of AN-induced oxidative stress on the brain are largely unknown. Our lab uses the preclinical activity-based anorexia (ABA) paradigm to model symptoms of AN. The goal of the present study was to determine how ABA experience affects oxidative state and its consequences in adolescent female rats. METHOD: We compared systemic glutathione and cysteine plasma concentrations and medial prefrontal cortex (mPFC) mitochondrial fission in ABA animals at maximum weight loss or following 10-days of weight recovery to levels in age-matched sedentary (SED) control rats. RESULTS: ABA animals at maximum weight loss had significantly lower plasma levels of cysteine and glutathione compared to SED controls. Additionally, ABA animals at max weight loss have significantly more mPFC mitochondrial fission. There were no significant differences in plasma analyte levels or mitochondrial fission between weight recovered ABA animals and SED controls. DISCUSSION: These data suggest that ABA experience results in oxidative stress that is remedied after weight restoration. The long-lasting ramifications of transient periods of increased oxidative stress are unknown and can lead to significant consequences on brain function and behavior.
Subject(s)
Anorexia Nervosa , Anorexia , Animals , Disease Models, Animal , Female , Humans , Mitochondrial Dynamics , Oxidative Stress , Rats , Weight LossABSTRACT
OBJECTIVE: Deletion of Translin (Tsn) from mice induces an unusual metabolic profile characterized by robust adiposity, normal body weight and glucose tolerance. Translin (TN) protein and its partner, trax (TX), form the TN/TX microRNA-degrading enzyme. Since the microRNA system plays a prominent role in regulating metabolism, we reasoned that the metabolic profile displayed by Tsn KO mice might reflect dysregulation of microRNA signaling. METHODS: To test this hypothesis, we inserted a mutation, E126A, in Tsnax, the gene encoding TX, that abolishes the microRNA-degrading enzymatic activity of the TN/TX complex. In addition, to help define the cell types that drive the adiposity phenotype, we have also generated mice with floxed alleles of Tsn or Tsnax. RESULTS: Introduction of the E126A mutation in Tsnax does not impair expression of TN or TX proteins or their co-precipitation. Furthermore, these mice display selective increases in microRNAs that match those induced by Tsn deletion, confirming that this mutation in Tsnax inactivates the microRNA-degrading activity of the TN/TX complex. Mice homozygous for the Tsnax (E126A) mutation display a metabolic profile that closely mimics that of Tsn KO mice. Selective deletion of Tsn or Tsnax from either adipocytes or hepatocytes, two candidate cell types, does not phenocopy the elevated adiposity displayed by mice with constitutive Tsn deletion or the Tsnax (E126A) mutation. Furthermore, global, conditional deletion of Tsn in adulthood does not elicit increased adiposity. CONCLUSION: Taken together, these findings indicate that inactivation of the TN/TX microRNA-degrading enzyme during development is necessary to drive the robust adiposity displayed by Tsn KO mice.
Subject(s)
Adiposity/genetics , DNA-Binding Proteins/metabolism , RNA-Binding Proteins/metabolism , Adiposity/physiology , Animals , DNA-Binding Proteins/genetics , Female , Glucose/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , MicroRNAs/genetics , MicroRNAs/metabolism , Obesity/genetics , Obesity/metabolism , Phenotype , RNA-Binding Proteins/genetics , Signal TransductionABSTRACT
Children born to women who experience stress during pregnancy have an increased risk of cancer in later life, but no previous animal studies have tested such a link. We questioned whether prenatal stress (PS) in A/J mice affected the development of lung tumors after postnatal response to tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Timed-bred A/J mice were randomly assigned on gestation day 12.5 to PS by restraint for 5 consecutive days or control (no restraint). Adult offspring of control and stressed pregnancies were all treated with three NNK injections (50 mg/kg every other day) and euthanized 16 weeks later to examine their lungs. Compared with controls, PS dams exhibited significantly increased levels of plasma corticosterone, increased adrenal weights and decreased fetus weights without fetal loss. Prenatally stressed litters had a significantly higher neonatal death rate within first week of life, and surviving male and female offspring developed lung epithelial proliferations with increase multiplicity, increased area and aggressive morphology. PS also induced more advanced atypical adenomatous hyperplasia lesions. We found no difference in lung NNK-derived methyl DNA adducts, but PS did significantly enhance CD3+ T cell and Foxp3+ T cell tumor infiltration. PS significantly increases multiplicity, area of NNK-induced lung tumors and advanced morphology. PS did not affect production of NNK-derived methyl DNA adducts but did increase lymphocytic infiltration of lung tumors. To our knowledge, this is the first animal model of PS with evaluation of cancer development in offspring.