ABSTRACT
The biobehavioral correlates of Adverse Childhood Experiences (ACEs) among Latinx youth have been strikingly understudied. The purpose of this study was to 1) examine the effects of T-ACEs (e.g., maltreatment, family dysfunction) and E-ACEs (e.g., family deportation, community violence) in alcohol use, 2) test whether social support moderated these associations and 3) explore whether ACEs and alcohol use were related via adrenocortical hormones (i.e., cortisol, dehydroepiandrosterone [DHEA]). A total of 100 Latinx youth, between the ages of 13 and 19, participated in this study (53% female). Community samples of United States (U.S.)-born (N = 54) and immigrant Latinx (N = 46) youth provided morning saliva samples and completed self-report questionnaires. Results highlighted that for immigrant youth, social support buffered the effects of E-ACEs on alcohol use, F(9,89)= 3.34, p = .01, R2 = .25. Although our mediation hypothesis was not supported, the direct effects of T-ACEs (ß = .25, t (94) = 2.21, p = .03) and E-ACES (ß = -.24, t (94) = -2.23, p = .03) on DHEA were significant for the entire sample. Preventing maltreatment and reducing community-level adversities seem critical for optimal child development, as exposure to these may increase alcohol use risk and affect HPA Axis functioning. Increasing extrafamilial support may be particularly salient for immigrant Latinx youth, as many experience extended immigration-related periods of separation from family members.
ABSTRACT
Alzheimer's disease and age-related dementias (AD/ADRD) are debilitating diseases that exact a significant physical, emotional, cognitive, and financial toll on the individual and their social network. While genetic risk factors for early-onset AD have been identified, the molecular and genetic drivers of late-onset AD, the most common subtype, remain a mystery. Current treatment options are limited for the 35 million people in the United States with AD/ADRD. Thus, it is critically important to identify novel molecular mechanisms of dementia-related pathology that may be targets for the development of new interventions. Here, we summarize the overarching concepts regarding AD/ADRD pathogenesis. Then, we highlight one potential molecular driver of AD/ADRD, the chromatin remodeling protein DEK. We discuss in vitro, in vivo, and ex vivo findings, from our group and others, that link DEK loss with the cellular, molecular, and behavioral signatures of AD/ADRD. These include associations between DEK loss and cellular and molecular hallmarks of AD/ADRD, including apoptosis, Tau expression, and Tau hyperphosphorylation. We also briefly discuss work that suggests sex-specific differences in the role of DEK in AD/ADRD pathogenesis. Finally, we discuss future directions for exploiting the DEK protein as a novel player and potential therapeutic target for the treatment of AD/ADRD.
ABSTRACT
DEK, a chromatin-remodelling phosphoprotein, is associated with various functions and biological pathways in the periphery, including inflammation, oncogenesis, DNA repair, and transcriptional regulation. We recently identified an association between DEK loss and central nervous system diseases, such as Alzheimer's. To understand DEK's potential role in disease, it is critical to characterize DEK in healthy human brain to distinguish between neural DEK expression and function in healthy versus diseased states like dementia. We utilized two public databases, BrainCloud and Human Brain Transcriptome, and analysed DEK mRNA expression across the lifespan in learning and memory relevant brain regions. Since DEK loss induces phenotypes associated with brain ageing (e.g., DNA damage and apoptosis), we hypothesized that neural DEK expression may be highest during foetal development and lower in elderly individuals. In agreement with this hypothesis, DEK was most prominently expressed during foetal development in all queried forebrain areas, relative to other ages. Consistent with its roles in the periphery, pathways related to DEK in the brain were associated with cellular proliferation, DNA replication and repair, apoptosis, and inflammation. We also found novel neural development-relevant pathways (e.g., synaptic transmission, neurite outgrowth, and myelination) to be enriched from genes correlated with DEK expression. These findings suggest that DEK is important for human brain development. Overall, we highlight age-related changes in neural DEK expression across the human lifespan and illuminate novel biological pathways associated with DEK that are distinct from normal brain ageing. These findings may further our understanding of how DEK impacts brain function and disease susceptibility.
Subject(s)
Brain , Chromosomal Proteins, Non-Histone , Oncogene Proteins , Poly-ADP-Ribose Binding Proteins , Aged , Brain/metabolism , Chromosomal Proteins, Non-Histone/genetics , Chromosomal Proteins, Non-Histone/metabolism , Gene Expression , Humans , Inflammation , Longevity , Oncogene Proteins/genetics , Oncogene Proteins/metabolism , Poly-ADP-Ribose Binding Proteins/genetics , Poly-ADP-Ribose Binding Proteins/metabolismABSTRACT
Alzheimer's disease (AD) is the most common cause of dementia and is characterized by the buildup of ß-amyloid plaques and neurofibrillary Tau tangles. This leads to decreased synaptic efficacy, cell death, and, consequently, brain atrophy in patients. Behaviorally, this manifests as memory loss and confusion. Using a gene ontology analysis, we recently identified AD and other age-related dementias as candidate diseases associated with the loss of DEK expression. DEK is a nuclear phosphoprotein with roles in DNA repair, cellular proliferation, and inhibiting apoptosis. Work from our laboratory determined that DEK is highly expressed in the brain, particularly in regions relevant to learning and memory, including the hippocampus. Moreover, we have also determined that DEK is highly expressed in neurons. Consistent with our gene ontology analysis, we recently reported that cortical DEK protein levels are inversely proportional to dementia severity scores in elderly female patients. However, the functional role of DEK in neurons is unknown. Thus, we knocked down DEK in an in vitro neuronal model, differentiated SH-SY5Y cells, hypothesizing that DEK loss would result in cellular and molecular phenotypes consistent with AD. We found that DEK loss resulted in increased neuronal death by apoptosis (i.e., cleaved caspases 3 and 8), decreased ß-catenin levels, disrupted neurite development, higher levels of total and phosphorylated Tau at Ser262, and protein aggregates. We have demonstrated that DEK loss in vitro recapitulates cellular and molecular phenotypes of AD pathology.
ABSTRACT
Stress confers risk for the development and progression of Alzheimer's disease (AD). Relative to men, women are disproportionately more likely to be diagnosed with this neurodegenerative disease. We hypothesized that sex differences in endocrine stress responsiveness may be a factor in this statistic. To test this hypothesis, we assessed basal and stress-induced corticosterone, social recognition, and coat state deterioration (surrogate for depression-like behavior) in male and female 3xTg-AD mice. Prior to reported amyloid plaque deposition, 3xTg females (4 months), but not 3xTg males, had heightened corticosterone responses to restraint exposure. Subsequently, only 3xTg females (6 months) displayed deficits in social memory concomitant with prominent ß-amyloid (Aß) immunostaining. These data suggest that elevated corticosterone stress responses may precede cognitive impairments in genetically vulnerable females. 3xTg mice of both sexes exhibited coat state deterioration relative to same-sex controls. Corticolimbic glucocorticoid receptor (GR) dysfunction is associated with glucocorticoid hypersecretion and cognitive impairment. Our findings indicate sex- and brain-region specific effects of genotype on hippocampal and amygdala GR protein expression. Because olfactory deficits may impede social recognition, in Experiment 2, we assessed olfaction and found no differences between genotypes. Notably, in this cohort, heightened corticosterone stress responses in 3xTg females was not accompanied by social memory deficits or coat state deterioration. However, coat state deterioration was consistent in 3xTg males. We report consistent heightened stress-induced corticosterone levels and Aß pathology in female 3xTg-AD mice. However, the behavioral findings illuminate unknown inconsistencies in certain phenotypes in this AD mouse model.
Subject(s)
Alzheimer Disease , Corticosterone/metabolism , Memory/physiology , Stress, Physiological/genetics , Alzheimer Disease/genetics , Alzheimer Disease/metabolism , Alzheimer Disease/physiopathology , Alzheimer Disease/psychology , Amyloid beta-Peptides/genetics , Amyloid beta-Peptides/metabolism , Animals , Disease Models, Animal , Female , Male , Mice , Mice, 129 Strain , Mice, Inbred C57BL , Mice, Transgenic , Recognition, Psychology/physiology , Sex Characteristics , Social BehaviorABSTRACT
Preclinical and clinical findings indicate that glucocorticoids (GC) induce lipid accumulation in visceral depots, while inhibiting lipid stores from subcutaneous depots. Whereas some suggest that this is due to adipose depot specific concentration of glucocorticoid receptors (GR) or 11beta-hydroxysteroid dehydrogenase 1 (11ß-HSD1), others demonstrate these events emerge from increases in interleukin-1 beta (IL-1ß) from macrophages within distinct depots. Regardless of the mechanisms, most of these studies occur in males and thus lack evaluation of sex differences. Here, we examined the impact of 2-week corticosterone (CORT) (3 mg/kg/day) or saline treatment on GR, 11ß-HSD1 and IL-1ß protein concentration in intra-abdominal (epididymal/parametrial, and visceral) and subcutaneous (inguinal) depots in male and female Sprague Dawley rats. The objective was to examine if factors that regulate GC-induced adipose depot metabolism and distribution, differ between males and females. CORT inhibited, but did not decrease, body weight gain in both sexes. 11ß-HSD1 was similar between the sexes in all adipose depots. CORT increased IL-1ß in both sexes only in gonadal adipose tissue. Overall, males had greater GR protein concentration in all adipose depots, whereas females had more IL-1ß in intra-abdominal adipose depots. Given the male-biased increase in intra-abdominal GR protein concentration, the data suggest that males may be more prone to CORT-induced increases in visceral obesity, which may have implications for increased risk for metabolic diseases. Overall, the data suggest that the effects of GC signaling in adipose tissue are multifaceted, dependent on sex, and the inherent adipocyte characteristics.Lay summaryResearch supports that glucocorticoids (GC) induce visceral adipose tissue accumulation, however few studies have examined if these GC-mediated outcomes are similar between males and females. This study investigates if female rats differentially respond to corticosterone treatment. Results indicate that male rats may have an increased susceptibility to CORT-induced accumulation of visceral adipose tissue compared with females, which may have implication for sex-specific risk for metabolic diseases.
Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1 , Glucocorticoids , Adipose Tissue , Animals , Female , Glucocorticoids/pharmacology , Male , Rats , Rats, Sprague-Dawley , Stress, PsychologicalABSTRACT
Eating tasty foods dampens responses to stress - an idea reflected in the colloquial term 'comfort foods'. To study the neurobiological mechanisms by which palatable foods provide stress relief, we previously characterized a limited sucrose intake (LSI) paradigm in which male rats are given twice-daily access to 4â¯ml of 30% sucrose solution (vs. water as a control), and subsequently have reduced hypothalamic-pituitary-adrenocortical (HPA) axis responsivity and anxiety-related behaviors. Notably, women may be more prone to 'comfort feeding' than men, and this may vary across the menstrual cycle, suggesting the potential for important sex and estrous cycle differences. In support of this idea, LSI reduces HPA axis responses in female rats during the proestrus/estrus (P/E), as opposed to the diestrus 1/diestrus 2 (D1/D2) estrous cycle stage. However, the effect of LSI on anxiety-related behaviors in females remains unknown. Here we show that LSI reduced stress-related behaviors in female rats in the elevated plus-maze and restraint tests, but not in the open field test, though only during P/E. LSI also decreased the HPA axis stress response primarily during P/E, consistent with prior findings. Finally, cFos immunolabeling (a marker of neuronal activation) revealed that LSI increased post-restraint cFos in the central amygdala medial subdivision (CeM) and the bed nucleus of the stria terminalis posterior subnuclei (BSTp) exclusively during P/E. These results suggest that in female rats, palatable food reduces both behavioral and neuroendocrine stress responses in an estrous cycle-dependent manner, and the CeM and BSTp are implicated as potential mediators of these effects.
Subject(s)
Adrenocorticotropic Hormone/metabolism , Anxiety/drug therapy , Behavior, Animal/physiology , Corticosterone/metabolism , Estrous Cycle/metabolism , Food , Stress, Psychological/drug therapy , Sucrose/pharmacology , Sweetening Agents/pharmacology , Animals , Female , Rats , Rats, Long-EvansABSTRACT
Psychological stress and excess glucocorticoids are associated with metabolic and cardiovascular diseases. Glucocorticoids act primarily through mineralocorticoid (MR) and glucocorticoid receptors (GR), and compounds modulating these receptors show promise in mitigating metabolic and cardiovascular-related phenotypes. CORT118335 (GR/MR modulator) prevents high-fat diet-induced weight gain and adiposity in mice, but the ability of this compound to reverse obesity-related symptoms is unknown. Adult male rats were subcutaneously administered CORT118335 (3, 10, or 30 mg/kg) or vehicle once daily. A 5-day treatment with CORT118335 at 30 mg/kg induced weight loss in rats fed a chow diet by decreasing food intake. However, lower doses of the compound attenuated body weight gain primarily because of decreased calorific efficiency, as there were no significant differences in food intake compared with vehicle. Notably, the body weight effects of CORT118335 persisted during a 2-wk treatment hiatus, suggesting prolonged effects of the compound. To our knowledge, we are the first to demonstrate a sustained effect of combined GR/MR modulation on body weight gain. These findings suggest that CORT118335 may have long-lasting effects, likely due to GR/MR-induced transcriptional changes. Prolonged (18 days) treatment of CORT118335 (10 mg/kg) reversed body weight gain and adiposity in animals fed a high-fat diet for 13 wk. Surprisingly, this occurred despite a worsening of the lipid profile and glucose homeostasis as well as a disrupted diurnal corticosterone rhythm, suggesting GR agonistic effects in the periphery. We conclude that species and tissue-specific targeting may result in promising leads for exploiting the metabolically beneficial aspects of GR/MR modulation.
Subject(s)
Adiposity/drug effects , Energy Metabolism/drug effects , Lipid Metabolism/drug effects , Mineralocorticoid Receptor Antagonists/pharmacology , Receptors, Glucocorticoid/antagonists & inhibitors , Receptors, Mineralocorticoid/drug effects , Thymine/analogs & derivatives , Adipose Tissue/drug effects , Adipose Tissue/metabolism , Animals , Blood Glucose/metabolism , Diet, High-Fat , Eating/drug effects , Male , Organ Size/drug effects , Rats , Rats, Long-Evans , Rats, Sprague-Dawley , Receptors, Glucocorticoid/metabolism , Receptors, Mineralocorticoid/metabolism , Thymine/pharmacology , Weight Gain/drug effectsABSTRACT
DEK is a chromatin-remodeling phosphoprotein found in most human tissues, but its expression and function in the human brain is largely unknown. DEK depletion in vitro induces cellular and molecular anomalies associated with cognitive impairment, including down-regulation of the canonical Wnt/ß-catenin signaling pathway. ToppGene analyses link DEK loss to genes associated with various dementias and age-related cognitive decline. To examine the role of DEK in cognitive impairment in severe mental illness, DEK protein expression was assayed by immunoblot in the anterior cingulate cortex (ACC) of subjects with schizophrenia. Cognitive impairment is a core feature of schizophrenia and cognitive function in subjects was assessed antemortem using the clinical dementia rating (CDR) scale. DEK protein expression was not significantly altered in schizophrenia (nâ¯=â¯20) compared to control subjects (nâ¯=â¯20). Further analysis revealed significant reduction in DEK protein expression in women with schizophrenia, and a significant increase in expression in men with schizophrenia, relative to their same-sex controls. DEK protein expression levels were inversely correlated with dementia severity in women. Conversely, in men, DEK protein expression and dementia severity were positively correlated. Notably, there was no sex difference in DEK protein expression in the control group, suggesting that this sex difference is specific to schizophrenia and not due to inherent differences in DEK expression between males and females. These results suggest a novel, sex-specific role for DEK in cognitive performance and highlight a putative sex-specific link between central nervous system DEK protein expression and a neuropsychiatric disease that is commonly associated with cognitive impairment.
Subject(s)
Chromosomal Proteins, Non-Histone/metabolism , Dementia/metabolism , Gyrus Cinguli/metabolism , Oncogene Proteins/metabolism , Poly-ADP-Ribose Binding Proteins/metabolism , Schizophrenia/metabolism , Sex Characteristics , Aged , Dementia/pathology , Female , Gene Expression , Gyrus Cinguli/pathology , Humans , Immunoblotting , Male , Psychiatric Status Rating Scales , Schizophrenia/drug therapy , Schizophrenia/pathology , Severity of Illness IndexABSTRACT
Eating palatable foods can provide stress relief, but the mechanisms by which this occurs are unclear. We previously characterized a limited sucrose intake (LSI) paradigm in which twice-daily access to a small amount of 30% sucrose (vs. water as a control) reduces hypothalamic-pituitary-adrenocortical (HPA) axis responses to stress and alters neuronal activation in stress-regulatory brain regions in male rats. However, women may be more prone to 'comfort feeding' behaviors than men, and stress-related eating may vary across the menstrual cycle. This suggests that LSI effects may be sex- and estrous cycle-dependent. The present study therefore investigated the effects of LSI on HPA axis stress responsivity, as well as markers of neuronal activation/plasticity in stress- and reward-related neurocircuitry in female rats across the estrous cycle. We found that LSI reduced post-restraint stress plasma ACTH in female rats specifically during proestrus/estrus (P/E). LSI also increased basal (non-stress) FosB/deltaFosB- and pCREB-immunolabeling in the basolateral amygdala (BLA) and central amygdala specifically during P/E. Finally, Bayesian network modeling of the FosB/deltaFosB and pCREB expression data identified a neurocircuit that includes the BLA, nucleus accumbens, prefrontal cortex, and bed nucleus of the stria terminalis as likely being modified by LSI during P/E. When considered in the context of our prior results, the present findings suggest that palatable food reduces stress responses in female rats similar to males, but in an estrous cycle-dependent manner. Further, the BLA may contribute to the LSI effects in both sexes, whereas the involvement of other brain regions appears to be sex-dependent.
Subject(s)
Estrous Cycle/physiology , Food , Hypothalamo-Hypophyseal System/physiology , Pituitary-Adrenal System/physiology , Prosencephalon/physiology , Adrenal Glands/physiology , Adrenocorticotropic Hormone/blood , Animals , Corticosterone/blood , Estradiol/blood , Female , Neural Pathways/physiology , Rats , Rats, Long-Evans , Restraint, Physical , Stress, Physiological/physiology , Stress, Psychological/physiopathology , Sucrose/pharmacologyABSTRACT
Depression is commonly associated with hypothalamic-pituitary adrenal (HPA) axis dysfunction that primarily manifests as aberrant glucocorticoid secretion. Glucocorticoids act on Type I mineralocorticoid (MR) and Type II glucocorticoid receptors (GR) to modulate mood and endocrine responses. Successful antidepressant treatment normalizes HPA axis function, in part due to modulatory effects on MR and GR in cortico-limbic structures. Although women are twice as likely to suffer from depression, little is known about how antidepressants modulate brain, endocrine, and behavioral stress responses in females. Here, we assessed the impact of CORT118335 (GR modulator/MR antagonist) and imipramine (tricyclic antidepressant) on neuroendocrine and behavioral responses to restraint or forced swim stress (FST) in female rats (n=10-12/group). Increased immobility CORT118335 in the FST is purported to reflect passive coping or depression-like behavior. CORT118335 dampened adrenocorticotropic hormone (ACTH) and corticosterone responses to the FST, but did not affect immobility. Imipramine suppressed ACTH, but had minimal effects on corticosterone responses to FST. Despite these marginal effects, imipramine decreased immobility, suggesting antidepressant efficacy. In an effort to link brain-endocrine responses with behavior, c-Fos was assessed in HPA axis and mood modulatory regions in response to the FST. CORT118335 upregulated c-Fos expression in the paraventricular nucleus of the hypothalamus. Imipramine decreased c-Fos in the basolateral amygdala and hippocampus (CA1 and CA3), but increased c-Fos in the central amygdala. These data suggest the antidepressant-like (e.g., active coping) properties of imipramine may be due to widespread effects on cortico-limbic circuits that regulate emotional and cognitive processes.
Subject(s)
Imipramine/pharmacology , Stress, Physiological/drug effects , Thymine/analogs & derivatives , Adrenocorticotropic Hormone/pharmacology , Animals , Antidepressive Agents/pharmacology , Antidepressive Agents, Tricyclic/pharmacology , Behavior, Animal/physiology , Brain/metabolism , Corticosterone/metabolism , Depression/physiopathology , Depressive Disorder/physiopathology , Female , Hippocampus/metabolism , Hypothalamo-Hypophyseal System/metabolism , Hypothalamus/metabolism , Imipramine/metabolism , Mineralocorticoid Receptor Antagonists/metabolism , Mineralocorticoid Receptor Antagonists/pharmacology , Pituitary-Adrenal System/metabolism , Proto-Oncogene Proteins c-fos/metabolism , Rats , Rats, Sprague-Dawley , Receptors, Glucocorticoid/antagonists & inhibitors , Stress, Physiological/physiology , Stress, Psychological/physiopathology , Thymine/metabolism , Thymine/pharmacologyABSTRACT
The late adolescent period is characterized by marked neurodevelopmental and endocrine fluctuations in the transition to early adulthood. Adolescents are highly responsive to the external environment, which enhances their ability to adapt and recover from challenges when given nurturing influences, but also makes them vulnerable to aberrant development when exposed to prolonged adverse situations. Female rats are particularly sensitive to the effects of chronic stress in adolescence, which manifests as passive coping strategies and blunted hypothalamo-pituitary adrenocortical (HPA) stress responses in adulthood. We sought to intervene by exposing adolescent rats to environmental enrichment (EE) immediately prior to and during chronic stress, hypothesizing that EE would minimize or prevent the long-term effects of stress that emerge in adult females. To test this, we exposed male and female rats to EE on postnatal days (PND) 33-60 and implemented chronic variable stress (CVS) on PND 40-60. CVS consisted of twice-daily unpredictable stressors. Experimental groups included: CVS/unenriched, unstressed/EE, CVS/EE and unstressed/unenriched (n = 10 of each sex/group). In adulthood, we measured behavior in the open field test and forced swim test (FST) and collected blood samples following the FST. We found that environmental enrichment given during the adolescent period prevented the chronic stress-induced transition to passive coping in the FST and reversed decreases in peak adrenocortical responsiveness observed in adult females. Adolescent enrichment had little to no effect on males or unstressed females tested in adulthood, indicating that beneficial effects are specific to females that were exposed to chronic stress.
Subject(s)
Hypothalamo-Hypophyseal System/physiopathology , Pituitary-Adrenal System/physiopathology , Stress, Physiological/physiology , Stress, Psychological/physiopathology , Animals , Behavior, Animal/physiology , Environment , Female , Housing, Animal , Male , Motor Activity/physiology , Rats , Rats, Sprague-Dawley , Sex FactorsABSTRACT
DEK, a chromatin-remodeling gene expressed in most human tissues, is known for its role in cancer biology and autoimmune diseases. DEK depletion in vitro reduces cellular proliferation, induces DNA damage subsequently leading to apoptosis, and down-regulates canonical Wnt/ß-catenin signaling, a molecular pathway essential for learning and memory. Despite a recognized role in cancer (non-neuronal) cells, DEK expression and function is not well characterized in the central nervous system. We conducted a gene ontology analysis (ToppGene), using a cancer database to identify genes associated with DEK deficiency, which pinpointed several genes associated with cognitive-related diseases (i.e., Alzheimer's disease, presenile dementia). Based on this information, we examined DEK expression in corticolimbic structures associated with learning and memory in adult male and female mice using immunohistochemistry. DEK was expressed throughout the brain in both sexes, including the medial prefrontal cortex (prelimbic, infralimbic and dorsal peduncular). DEK was also abundant in all amygdalar subdivisions (basolateral, central and medial) and in the hippocampus including the CA1, CA2, CA3, dentate gyrus (DG), ventral subiculum and entorhinal cortex. Of note, compared to males, females had significantly higher DEK immunoreactivity in the CA1, indicating a sex difference in this region. DEK was co-expressed with neuronal and microglial markers in the CA1 and DG, whereas only a small percentage of DEK cells were in apposition to astrocytes in these areas. Given the reported inverse cellular and molecular profiles (e.g., cell survival, Wnt pathway) between cancer and Alzheimer's disease, these findings suggest a potentially important role of DEK in cognition.
Subject(s)
Cerebral Cortex/metabolism , DNA-Binding Proteins/metabolism , Learning/physiology , Limbic System/metabolism , Memory/physiology , Oncogene Proteins/metabolism , Poly-ADP-Ribose Binding Proteins/metabolism , Animals , Astrocytes/cytology , Astrocytes/metabolism , Cerebral Cortex/cytology , DNA-Binding Proteins/genetics , Female , Immunohistochemistry , Limbic System/cytology , Male , Mice, Inbred C57BL , Mice, Knockout , Microglia/cytology , Microglia/metabolism , Neural Pathways/cytology , Neural Pathways/metabolism , Neurons/cytology , Neurons/metabolism , Oncogene Proteins/genetics , Poly-ADP-Ribose Binding Proteins/geneticsABSTRACT
Declining estradiol (E2), as occurs during menopause, increases risk for obesity and psychopathology (i.e., depression, anxiety). E2 modulates mood and energy homeostasis via binding to estrogen receptors (ER) in the brain. The often comorbid and bidirectional relationship between mood and metabolic disorders suggests shared hormonal and/or brain networks. The medial amygdala (MeA) is abundant in ERs and regulates mood, endocrine, and metabolic stress responses; therefore we tested the hypothesis that E2 in the MeA mitigates emotional and metabolic dysfunction in a rodent model of surgical menopause. Adult female rats were ovariectomized (OVX) and received bilateral implants of E2 or cholesterol micropellets aimed at the MeA. E2-MeA decreased anxiety-like (center entries, center time) and depression-like (immobility) behaviors in the open field and forced swim tests (FST), respectively in ovariectomized rats. E2-MeA also prevented hyperphagia, body weight gain, increased visceral adiposity, and glucose intolerance in ovariectomized rats. E2-MeA decreased caloric efficiency, suggestive of increased energy expenditure. E2-MeA also modulated c-Fos neural activity in amygdalar (central and medial) and hypothalamic (paraventricular and arcuate) brain regions that regulate mood and energy homeostasis in response to the FST, a physically demanding task. Given the shared neural circuitry between mood and body weight regulation, c-Fos expression in discrete brain regions in response to the FST may be due to the psychologically stressful and/or metabolic demands of the task. Together, these findings suggest that the MeA is a critical node for mediating estrogenic effects on mood and energy homeostasis.
Subject(s)
Amygdala/drug effects , Estradiol/pharmacology , Obesity/psychology , Stress, Psychological , Amygdala/metabolism , Animals , Body Weight/drug effects , Brain/drug effects , Brain/metabolism , Corticomedial Nuclear Complex/drug effects , Corticomedial Nuclear Complex/metabolism , Female , Hypothalamus/drug effects , Hypothalamus/metabolism , Obesity/complications , Obesity/metabolism , Ovariectomy , Rats , Rats, Long-Evans , Signal Transduction/drug effects , Stress, Physiological/drug effects , Stress, Physiological/physiology , Stress, Psychological/metabolism , Stress, Psychological/physiopathologyABSTRACT
Chronic stress-associated pathologies frequently associate with alterations in the structure and activity of the medial prefrontal cortex (mPFC). However, the influence of infralimbic cortex (IL) projection neurons on hypothalamic-pituitary-adrenal (HPA) axis activity is unknown, as is the involvement of these cells in chronic stress-induced endocrine alterations. In the current study, a lentiviral-packaged vector coding for a small interfering RNA (siRNA) targeting vesicular glutamate transporter (vGluT) 1 messenger RNA (mRNA) was microinjected into the IL of male rats. vGluT1 is responsible for presynaptic vesicular glutamate packaging in cortical neurons, and knockdown reduces the amount of glutamate available for synaptic release. After injection, rats were either exposed to chronic variable stress (CVS) or remained in the home cage as unstressed controls. Fifteen days after the initiation of CVS, all animals were exposed to a novel acute stressor (30-minute restraint) with blood collection for the analysis of adrenocorticotropic hormone (ACTH) and corticosterone. Additionally, brains were collected for in situ hybridization of corticotrophin-releasing hormone mRNA. In previously unstressed rats, vGluT1 siRNA significantly enhanced ACTH and corticosterone secretion. Compared with CVS animals receiving the green fluorescent protein control vector, the vGluT1 siRNA further increased basal and stress-induced corticosterone release. Further analysis revealed enhanced adrenal responsiveness in CVS rats treated with vGluT1 siRNA. Collectively, our results suggest that IL glutamate output inhibits HPA responses to acute stress and restrains corticosterone secretion during chronic stress, possibly at the level of the adrenal. Together, these findings pinpoint a neurochemical mechanism linking mPFC dysfunction with aberrant neuroendocrine responses to chronic stress.
Subject(s)
Adrenocorticotropic Hormone/metabolism , Corticosterone/metabolism , Corticotropin-Releasing Hormone/genetics , Prefrontal Cortex/metabolism , RNA, Messenger/metabolism , Stress, Psychological/metabolism , Vesicular Glutamate Transport Protein 1/genetics , Animals , Gene Knockdown Techniques , Hypothalamo-Hypophyseal System/metabolism , Immunohistochemistry , In Situ Hybridization , Male , Pituitary-Adrenal System/metabolism , RNA, Small Interfering , Radioimmunoassay , Rats , Rats, Sprague-Dawley , Restraint, PhysicalABSTRACT
Aberrant glucocorticoid secretion is implicated in the pathophysiology of stress-related disorders (i.e., depression, anxiety). Glucocorticoids exert biological effects via mineralocorticoid (MR) and glucocorticoid (GR) receptors. Previous data from our laboratory indicate that GR antagonism/modulation (i.e., mifepristone, CORT 108297) regulate endocrine, behavioral, and central stress responses. Because of the dynamic interplay between MR and GR on HPA axis regulation and emotionality, compounds targeting both receptors are of interest for stress-related pathology. We investigated the effects of CORT 118335 (a dual selective GR modulator/MR antagonist) on endocrine, behavioral, and central (c-Fos) stress responses in male rats. Rats were treated for five days with CORT 118335, imipramine (positive control), or vehicle and exposed to restraint or forced swim stress (FST). CORT 118335 dampened corticosterone responses to both stressors, without a concomitant antidepressant-like effect in the FST. Imipramine decreased corticosterone responses to restraint stress; however, the antidepressant-like effect of imipramine in the FST was independent of circulating glucocorticoids. These findings indicate dissociation between endocrine and behavioral stress responses in the FST. CORT 118335 decreased c-Fos expression only in the CA1 division of the hippocampus. Imipramine decreased c-Fos expression in the basolateral amygdala and CA1 and CA3 divisions of the hippocampus. Overall, the data indicate differential effects of CORT 118335 and imipramine on stress-induced neuronal activity in various brain regions. The data also highlight a complex relationship between neuronal activation in stress and mood regulatory brain regions and the ensuing impact on endocrine and behavioral stress responses.
Subject(s)
Corticosterone/metabolism , Hippocampus/drug effects , Hormones/pharmacology , Psychotropic Drugs/pharmacology , Stress, Psychological/drug therapy , Thymine/analogs & derivatives , Amygdala/drug effects , Amygdala/metabolism , Amygdala/pathology , Animals , Depression/drug therapy , Depression/metabolism , Depression/pathology , Hippocampus/metabolism , Hippocampus/pathology , Imipramine/pharmacology , Male , Motor Activity/drug effects , Motor Activity/physiology , Neurons/drug effects , Neurons/metabolism , Neurons/pathology , Paraventricular Hypothalamic Nucleus/drug effects , Paraventricular Hypothalamic Nucleus/metabolism , Paraventricular Hypothalamic Nucleus/pathology , Prefrontal Cortex/drug effects , Prefrontal Cortex/metabolism , Prefrontal Cortex/pathology , Proto-Oncogene Proteins c-fos/metabolism , Random Allocation , Rats, Sprague-Dawley , Receptors, Glucocorticoid/metabolism , Receptors, Mineralocorticoid/metabolism , Stress, Psychological/metabolism , Stress, Psychological/pathology , Thymine/pharmacologyABSTRACT
Social conflict is a predominant stressor in humans and is associated with increased risk for developing psychological illnesses including depression and anxiety. Overwhelmingly, more women suffer from these disorders, which may be due to increased stress sensitivity. Like humans, rodents experience a myriad of physiological and behavioral sequelae due to prolonged stress exposure. Although the motivation for social conflict may differ between humans and rodents, female rodents may provide an opportunity to explore the underlying mechanisms by which stress confers risk for psychopathology in women. Because most female rodents do not express spontaneous aggression, the majority of basic research examines the physiological and behavioral outcomes of social conflict in male rodents. However, there are instances where female rodents exhibit territorial (California mice and Syrian hamsters) and maternal aggression (rats, mice, and hamsters) creating a venue to examine sex differences in physiology and behavior in response to stress. While many studies rely upon nonsocial behavioral assays (e.g., elevated plus maze, forced swim test) to assess the impact of stress on emotionality, here we primarily focus on behavioral outcomes in social-based assays in rodents. This is critically important given that disruptions in social relationships can be a cause and consequence of neuropsychiatric diseases. Next, we briefly discuss how sex differences in the recruitment of neural circuitry and/or neurochemistry in response to stress may underlie sex differences in neuroendocrine and behavioral stress responses. Finally, the translational value of females in rodent stress models and considerations regarding behavioral interpretations of these models are discussed. © 2016 Wiley Periodicals, Inc.
Subject(s)
Disease Models, Animal , Psychopathology , Sex Characteristics , Stress, Psychological/diagnosis , Stress, Psychological/physiopathology , Animals , Female , Male , MiceABSTRACT
Significant loss produces the highest degree of stress and compromised well-being in humans. Current rodent models of stress involve the application of physically or psychologically aversive stimuli, but do not address the concept of loss. We developed a rodent model for significant loss, involving removal of long-term access to a rewarding enriched environment. Our results indicate that removal from environmental enrichment produces a profound behavioral and physiological phenotype with depression-like qualities, including helplessness behavior, hypothalamo-pituitary-adrenocortical axis dysregulation and overeating. Importantly, this enrichment removal phenotype was prevented by antidepressant treatment. Furthermore, the effects of enrichment removal do not occur following relief from chronic stress and are not duplicated by loss of exercise or social contact.
Subject(s)
Behavior, Animal/physiology , Depression/physiopathology , Environment , Feeding Behavior/physiology , Hypothalamo-Hypophyseal System/physiopathology , Pituitary-Adrenal System/physiopathology , Animals , Antidepressive Agents/pharmacology , Antidepressive Agents/therapeutic use , Behavior, Animal/drug effects , Depression/drug therapy , Diet , Disease Models, Animal , Housing, Animal , Hypothalamo-Hypophyseal System/drug effects , Pituitary-Adrenal System/drug effects , Rats , Reward , Social Behavior , Stress, Psychological/drug therapy , Stress, Psychological/physiopathologyABSTRACT
Epilepsy is a common neurological disease, affecting 2.4million people in the US. Among the many different forms of the disease, temporal lobe epilepsy (TLE) is one of the most frequent in adults. Recent studies indicate the presence of a hyperactive hypothalamopituitary- adrenocortical (HPA) axis and elevated levels of glucocorticoids in TLE patients. Moreover, in these patients, stress is a commonly reported trigger of seizures, and stress-related psychopathologies, including depression and anxiety, are highly prevalent. Elevated glucocorticoids have been implicated in the development of stress-related psychopathologies. Similarly, excess glucocorticoids have been found to increase neuronal excitability, epileptiform activity and seizure susceptibility. Thus, patients with TLE may generate abnormal stress responses that both facilitate ictal discharges and increase vulnerability for the development of comorbid psychopathologies. Here, we will examine the evidence that the HPA axis is disrupted in TLE, consider potential mechanisms by which this might occur, and discuss the implications of HPA dysfunction for seizuretriggering and psychiatric comorbidities.
Subject(s)
Endocrine System Diseases/etiology , Epilepsy/complications , Hypothalamo-Hypophyseal System/physiopathology , Pituitary-Adrenal System/physiopathology , Endocrine System Diseases/epidemiology , Epilepsy/epidemiology , HumansABSTRACT
The posterior hypothalamic nucleus (PH) stimulates autonomic stress responses. However, the role of the PH in behavioral correlates of psychiatric illness, such as social and anxiety-like behavior, is largely unexplored, as is the neurochemistry of PH connectivity with limbic and neuroendocrine systems. Thus, the current study tested the hypothesis that GABAergic signaling within the PH is a critical link between forebrain behavior-regulatory nuclei and the neuroendocrine hypothalamus, integrating social and anxiety-related behaviors with physiological stress reactivity. To address this hypothesis, GABAA receptor pharmacology was used to locally inhibit or disinhibit the PH immediately before behavioral measures of social and anxiety-like behavior in rats. Limbic connectivity of the PH was then established by simultaneous co-injection of anterograde and retrograde tracers. Further, the role of PH GABAergic signaling in neuroendocrine stress responses was tested via inhibition/disinhibition of the PH. These studies determined a prominent role for the PH in the expression of anxiety-related behaviors and social withdrawal. Histological analyses revealed divergent stress-activated limbic input to the PH, emanating predominantly from the prefrontal cortex, lateral septum, and amygdala. PH projections also targeted both parvicellular and magnocellular peptidergic neurons in the paraventricular and supraoptic hypothalamus. Further, GABAA receptor pharmacology determined an excitatory effect of the PH on neuroendocrine responses to stress. These data indicate that the PH represents an important stress-integrative center, regulating behavioral processes and connecting the limbic forebrain with neuroendocrine systems. Moreover, the PH appears to be uniquely situated to have a role in stress-related pathologies associated with limbic-hypothalamic dysfunction.