Molecular mechanisms of glucocorticoid receptor sensitivity and relevance to affective disorders

2003 ◽  
Vol 15 (6) ◽  
pp. 354-367 ◽  
Author(s):  
Mario F Juruena ◽  
Anthony J Cleare ◽  
Moisés E Bauer ◽  
Carmine M Pariante
Keyword(s):  
Glucocorticoid Receptor ◽  
Hpa Axis ◽  
Affective Disorders ◽  
Molecular Mechanisms ◽  
Antidepressant Treatment ◽  
Brain Regions ◽  
Suppression Test ◽  
Treatment Research ◽  
Second Messenger Pathways ◽  
The Impact

Changes in the hypothalamic–pituitary–adrenocortical (HPA) system are characteristic of depression, and in the majority of these patients these result in HPA axis hyperactivity. This is further supported by the reduced sensitivity to the inhibitory effects of the glucocorticoid, dexamethasone (DEX), on the production of adrenocorticotropic hormone (ACTH) and cortisol, during the DEX suppression test and the DEX-corticotropin-releasing hormone (DEX/CRH) test. Because the effects of glucocorticoids are mediated by intracellular receptors including, most notably, the glucocorticoid receptor (GR), several studies have examined the number and/or function of GRs in depressed patients. These studies have consistently demonstrated that GR function is impaired in major depression, resulting in reduced GR-mediated negative feedback on the HPA axis and increased production and secretion of CRH in various brain regions postulated to be involved in the causality of depression. This article summarizes the literature on GR in depression and on the impact of antidepressants on the GR in clinical and preclinical studies, and supports the concept that impaired GR signaling is a key mechanism in the pathogenesis of depression, in the absence of clear evidence of decreased GR expression. The data also indicate that antidepressants have direct effects on the GR, leading to enhanced GR function and increased GR expression. Hypotheses regarding the mechanism of these receptor changes involve non-steroid compounds that regulate GR function via second messenger pathways, such as cytokines and neurotransmitters. Moreover, we present recent evidence suggesting that membrane steroid transporters such as the multidrug resistance (MDR) p-glycoprotein, which regulate access of glucocorticoids to the brain, could be a fundamental target of antidepressant treatment. Research in this field will lead to new insights into the pathophysiology and treatment of affective disorders.

scholarly journals Aerobic Exercise Induces Alternative Splicing of Neurexins in Frontal Cortex

2021 ◽  
Vol 6 (2) ◽  
pp. 48
Author(s):  
Elisa Innocenzi ◽  
Ida Cariati ◽  
Emanuela De Domenico ◽  
Erika Tiberi ◽  
Giovanna D’Arcangelo ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Aerobic Exercise ◽  
Frontal Cortex ◽  
Molecular Mechanisms ◽  
Splice Variants ◽  
Brain Regions ◽  
Synaptic Function ◽  
Molecular Changes ◽  
Beneficial Effects ◽  
The Impact

Aerobic exercise (AE) is known to produce beneficial effects on brain health by improving plasticity, connectivity, and cognitive functions, but the underlying molecular mechanisms are still limited. Neurexins (Nrxns) are a family of presynaptic cell adhesion molecules that are important in synapsis formation and maturation. In vertebrates, three-neurexin genes (NRXN1, NRXN2, and NRXN3) have been identified, each encoding for α and β neurexins, from two independent promoters. Moreover, each Nrxns gene (1–3) has several alternative exons and produces many splice variants that bind to a large variety of postsynaptic ligands, playing a role in trans-synaptic specification, strength, and plasticity. In this study, we investigated the impact of a continuous progressive (CP) AE program on alternative splicing (AS) of Nrxns on two brain regions: frontal cortex (FC) and hippocampus. We showed that exercise promoted Nrxns1–3 AS at splice site 4 (SS4) both in α and β isoforms, inducing a switch from exon-excluded isoforms (SS4−) to exon-included isoforms (SS4+) in FC but not in hippocampus. Additionally, we showed that the same AE program enhanced the expression level of other genes correlated with synaptic function and plasticity only in FC. Altogether, our findings demonstrated the positive effect of CP AE on FC in inducing molecular changes underlying synaptic plasticity and suggested that FC is possibly a more sensitive structure than hippocampus to show molecular changes.

scholarly journals Developmental cannabidiol exposure increases anxiety and modifies genome-wide brain DNA methylation in adult female mice

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Nicole M. Wanner ◽  
Mathia Colwell ◽  
Chelsea Drown ◽  
Christopher Faulk
Keyword(s):  
Dna Methylation ◽  
Molecular Mechanisms ◽  
Coat Color ◽  
Brain Regions ◽  
Functional Enrichment ◽  
Positive Effects ◽  
Genome Wide ◽  
Nulliparous Female ◽  
The Impact ◽  
The Brain

Abstract Background Use of cannabidiol (CBD), the primary non-psychoactive compound found in cannabis, has recently risen dramatically, while relatively little is known about the underlying molecular mechanisms of its effects. Previous work indicates that direct CBD exposure strongly impacts the brain, with anxiolytic, antidepressant, antipsychotic, and other effects being observed in animal and human studies. The epigenome, particularly DNA methylation, is responsive to environmental input and can direct persistent patterns of gene regulation impacting phenotype. Epigenetic perturbation is particularly impactful during embryogenesis, when exogenous exposures can disrupt critical resetting of epigenetic marks and impart phenotypic effects lasting into adulthood. The impact of prenatal CBD exposure has not been evaluated; however, studies using the psychomimetic cannabinoid Δ9-tetrahydrocannabinol (THC) have identified detrimental effects on psychological outcomes in developmentally exposed adult offspring. We hypothesized that developmental CBD exposure would have similar negative effects on behavior mediated in part by the epigenome. Nulliparous female wild-type Agouti viable yellow (Avy) mice were exposed to 20 mg/kg CBD or vehicle daily from two weeks prior to mating through gestation and lactation. Coat color shifts, a readout of DNA methylation at the Agouti locus in this strain, were measured in F1 Avy/a offspring. Young adult F1 a/a offspring were then subjected to tests of working spatial memory and anxiety/compulsive behavior. Reduced-representation bisulfite sequencing was performed on both F0 and F1 cerebral cortex and F1 hippocampus to identify genome-wide changes in DNA methylation for direct and developmental exposure, respectively. Results F1 offspring exposed to CBD during development exhibited increased anxiety and improved memory behavior in a sex-specific manner. Further, while no significant coat color shift was observed in Avy/a offspring, thousands of differentially methylated loci (DMLs) were identified in both brain regions with functional enrichment for neurogenesis, substance use phenotypes, and other psychologically relevant terms. Conclusions These findings demonstrate for the first time that despite positive effects of direct exposure, developmental CBD is associated with mixed behavioral outcomes and perturbation of the brain epigenome.

scholarly journals Neuroendocrine Assessment of Dopaminergic Function during Antidepressant Treatment in Major Depressed Patients

2021 ◽  
Vol 11 (4) ◽  
pp. 425
Author(s):  
Fabrice Duval ◽  
Marie-Claude Mokrani ◽  
Alexis Erb ◽  
Felix Gonzalez Lopera ◽  
Vlad Danila ◽  
...  
Keyword(s):  
Hpa Axis ◽  
Antidepressant Treatment ◽  
Cortisol Response ◽  
Mesolimbic Pathway ◽  
Suppression Test ◽  
Pre Treatment ◽  
Hpa Axis Activity ◽  
Drug Free ◽  
Hypothalamic Level ◽  
Dexamethasone Suppression

The effects of antidepressants on dopamine (DA) receptor sensitivity in the mesolimbic–hypothalamic system have yielded contradictory results. The postsynaptic DA receptor function was evaluated by the cortisol response to apomorphine (APO; 0.75 mg SC) in 16 drug-free DSM-5 major depressed inpatients and 18 healthy hospitalized control (HC) subjects. Cortisol response to the dexamethasone suppression test (DST) was also measured. After two and four weeks of antidepressant treatment (ADT), the DST and APO test were repeated in all patients. Cortisol response to APO (∆COR) was not influenced by the hypothalamic–pituitary–adrenal (HPA) axis activity, as assessed by the DST. Pre-treatment ∆COR values did not differ significantly between patients and HCs. During ADT, ∆COR values were lower than in HCs at week 2 and 4. After four weeks of treatment, among the eight patients who had blunted ∆COR values, seven were subsequent remitters, while among the eight patients who had normal ∆COR values, seven were non-remitters. Considering the limitations of our study, the results suggest that following chronic ADT, the desensitization of postsynaptic DA receptors connected with the regulation of the HPA axis at the hypothalamic level is associated with clinical remission. These results could reflect increased DA levels in the mesolimbic pathway.

Assessment of the hypothalamic–pituitary–adrenal axis activity: glucocorticoid receptor and mineralocorticoid receptor function in depression with early life stress – a systematic review

2012 ◽  
Vol 24 (1) ◽  
pp. 4-15 ◽  
Author(s):  
Cristiane Von Werne Baes ◽  
Sandra M. de Carvalho Tofoli ◽  
Camila Maria S. Martins ◽  
Mario F. Juruena
Keyword(s):  
Systematic Review ◽  
Glucocorticoid Receptor ◽  
Hpa Axis ◽  
Life Stress ◽  
Early Life ◽  
Mineralocorticoid Receptor ◽  
Early Life Stress ◽  
Hypothalamic Pituitary Adrenal ◽  
Depressed Patients ◽  
Suppression Test

Objective:The mechanisms involved in the dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis, especially in the functioning of glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) in depressed patients, are not well elucidated. The objective of this study was to conduct a systematic review of articles that assess the HPA axis activity from GR and MR in depressed patients and healthy controls with or without early life stress.Methods:We conducted a systematic review of articles in PubMed, SCOPUS and SciELO published between 2000 and 2011, using the following search terms:child abuse,depression,HPA axis,dexamethasone,prednisolone,fludrocortisoneandspironolactone. Thirty-four papers were selected for this review.Results:Most studies identified in this review used the dexamethasone/corticotropin-releasing hormone test and dexamethasone suppression test. In these studies, hypercortisolaemia was associated with depression. We identified three studies with the Prednisolone suppression test, only one study with the use of fludrocortisone and one with spironolactone. This review found nine studies that evaluated the HPA axis in individuals with early life stress.Conclusions:The majority of the studies assessed in this review show that early life stress leads to permanent changes in the HPA axis and may lead to development of depression in adults. The most consistent findings in the literature show increased activity of the HPA axis in depression associated with hypercortisolaemia and reduced inhibitory feedback. These findings suggest that this dysregulation of the HPA axis is partially attributable to an imbalance between GR and MR. Evidences have consistently showed that GR function is impaired in major depression, but few studies have assessed the activity of MR in depression and early life stress.

Molecular Mechanisms Transducing the Anesthetic, Analgesic, and Organ-protective Actions of Xenon

2006 ◽  
Vol 105 (1) ◽  
pp. 187-197 ◽  
Author(s):  
Benedikt Preckel ◽  
Nina C. Weber ◽  
Robert D. Sanders ◽  
Mervyn Maze ◽  
Wolfgang Schlack ◽  
...  
Keyword(s):  
Cardiopulmonary Bypass ◽  
Molecular Mechanisms ◽  
Experimental Studies ◽  
Molecular Targets ◽  
Brain Regions ◽  
Clinical Settings ◽  
Analgesic Effects ◽  
Protective Actions ◽  
Pharmacokinetic Properties ◽  
The Impact

The anesthetic properties of xenon have been known for more than 50 yr, and the safety and efficacy of xenon inhalational anesthesia has been demonstrated in several recent clinical studies. In addition, xenon demonstrates many favorable pharmacodynamic and pharmacokinetic properties, which could be used in certain niche clinical settings such as cardiopulmonary bypass. This inert gas is capable of interacting with a variety of molecular targets, and some of them are also modulated in anesthesia-relevant brain regions. Besides these anesthetic and analgesic effects, xenon has been shown to exert substantial organoprotective properties, especially in the brain and the heart. Several experimental studies have demonstrated a reduction in cerebral and myocardial infarction after xenon application. Whether this translates to a clinical benefit must be determined because preservation of myocardial and cerebral function may outweigh the significant cost of xenon administration. Clinical trials to assess the impact of xenon in settings with a high probability of injury such as cardiopulmonary bypass and neonatal asphyxia should be designed and underpinned with investigation of the molecular targets that transduce these effects.

The impact of neuroinflammation and inflammatory cytokines in depression and suicidal behavior

2016 ◽  
Vol 33 (S1) ◽  
pp. S160-S160
Author(s):  
G. Serafini ◽  
M. Pompili ◽  
P. Girardi ◽  
M. Amore
Keyword(s):  
Suicidal Ideation ◽  
Major Depression ◽  
Inflammatory Cytokines ◽  
Suicidal Behavior ◽  
Affective Disorders ◽  
Molecular Mechanisms ◽  
Major Depressive ◽  
Competing Interest ◽  
Activation Pathways ◽  
The Impact

IntroductionIt has been suggested that neuroinflammation and inflammatory mediators may play a crucial role in the pathophysiology of both major depression and suicidal behavior. Immunological differences have been reported between both subjects with major affective disorders and suicidal behavior.ObjectivesThe main objective of this review was to deeply investigate the nature of the association between inflammatory cytokines in depression and suicidal behavior. Aims: The study aimed to conduct a systematic review of the current literature to investigate the association between inflammatory cytokines, depression, and suicidal behavior.ResultsGenerally, an imbalance between pro-inflammatory and anti-inflammatory cytokines has been documented in both major depression and suicidal behavior. The presence of major depressive disorder (MDD) with suicidal ideation/attempts was associated with differences in inflammatory cytokine profile when compared to that without suicidal ideation/attempts. However, not all studies demonstrated a positive correlation between inflammatory cytokines and suicidal behavior.ConclusionsThe mentioned association between inflammatory cytokines, depression, and suicidal behavior does not imply the existence of a causal relationship. Further additional studies should clarify the molecular mechanisms of the immune activation pathways underlying depression and suicidality.Disclosure of interestThe authors have not supplied their declaration of competing interest.

scholarly journals Postnatal Glucocorticoid Excess Due to Pituitary Glucocorticoid Receptor Deficiency: Differential Short- and Long-Term Consequences

Endocrinology ◽  
2009 ◽  
Vol 150 (6) ◽  
pp. 2709-2716 ◽  
Author(s):  
Mathias V. Schmidt ◽  
Vera Sterlemann ◽  
Klaus Wagner ◽  
Bertram Niederleitner ◽  
Karin Ganea ◽  
...  
Keyword(s):  
Glucocorticoid Receptor ◽  
Hpa Axis ◽  
Negative Feedback ◽  
Molecular Mechanisms ◽  
Forced Swim Test ◽  
Conditional Knockout ◽  
Negative Feedback Regulation ◽  
Long Term Consequences ◽  
Hpa Axis Activity

A tight regulation of hypothalamic-pituitary-adrenal (HPA) axis activity is essential for successful adaptation to stressful stimuli. Disruption of normal HPA axis development is a main risk factor for diseases such as posttraumatic stress disorder or depression, but the molecular mechanisms that lead to these long-term consequences are poorly understood. Here, we test the hypothesis that the pituitary glucocorticoid receptor (GR) is involved in regulating HPA axis function in neonatal and adult animals. Furthermore, we investigate whether postnatal hypercortisolism induced by pituitary GR deficiency is a main factor contributing to the persistent effects of early-life stress. Conditional knockout mice with a deletion of the GR at the pituitary (GRPOMCCre) show excessive basal corticosterone levels during postnatal development, but not in adulthood. The hypercortisolemic state of neonatal GRPOMCCre mice is accompanied by central gene expression changes of CRH and vasopressin in the paraventricular nucleus, but these alterations normalize at later ages. In adult mice, pituitary GR deficiency results in impaired glucocorticoid negative feedback. Furthermore, adult GRPOMCCre mice display a more active coping strategy in the forced swim test, with no alterations in anxiety like behavior or cognitive functions. Postnatal GR antagonist treatment is able to prevent the long-term behavioral effects in GRPOMCCre mice. In conclusion, we show that pituitary GRs are centrally involved in regulating HPA axis activity in neonates and mediate negative feedback regulation in adult animals. Postnatal glucocorticoid excess results in an altered stress-coping behavior in adult animals, with no effects on anxiety like behavior or cognition.

scholarly journals Neuromolecular and behavioral effects of ethanol deprivation in Drosophila

2021 ◽  
Author(s):  
Natalie M. D’Silva ◽  
Katie S. McCullar ◽  
Ashley Conard ◽  
Tyler Blackwater ◽  
Reza Azanchi ◽  
...  
Keyword(s):  
Neural Plasticity ◽  
Molecular Mechanisms ◽  
Social Behaviors ◽  
Alcohol Exposure ◽  
Brain Regions ◽  
Exposure Model ◽  
Brain Gene Expression ◽  
Expression Of Genes ◽  
Sensory Responses ◽  
The Impact

AbstractAlcohol use disorder (AUD) is characterized by loss of control in limiting alcohol intake. This may involve intermittent periods of abstinence followed by alcohol seeking and, consequently, relapse. However, little is understood of the molecular mechanisms underlying the impact of alcohol deprivation on behavior. Using a new Drosophila melanogaster repeated intermittent alcohol exposure model, we sought to identify how ethanol deprivation alters spontaneous behavior, determine the associated neural structures, and reveal correlated changes in brain gene expression. We found that repeated intermittent ethanol exposures followed by ethanol-deprivation dynamically induces behaviors associated with a negative affect state. Although behavioral states broadly mapped to many brain regions, persistent changes in social behaviors mapped to the mushroom body and surrounding neuropil. This occurred concurrently with changes in expression of genes associated with sensory responses, neural plasticity, and immunity. Like social behaviors, immune response genes were upregulated following three-day repeated intermittent ethanol-exposures and persisted with one or two days of ethanol-deprivation, suggesting an enduring change in molecular function. Our study provides a framework for identifying how ethanol deprivation alters behavior with correlated underlying circuit and molecular changes.

Stress and the Serotonergic System, Observations from Pet Imaging

2017 ◽  
Vol 41 (S1) ◽  
pp. S19-S19
Author(s):  
M. Spies ◽  
R. Lanzenberger
Keyword(s):  
Hpa Axis ◽  
Acute Stress ◽  
Antidepressant Treatment ◽  
Brain Regions ◽  
The Other ◽  
Serotonergic System ◽  
Other Hand ◽  
Positron Emission ◽  
Hpa Axis Activity

IntroductionStress response and the neuroendocrinologic factors through which it is mediated are disturbed in anxiety and in affective disorders. While acute stress is thought to result in hypothalamus-pituitary-adrenal- (HPA) axis hyperactivity (Varghese 2001), chronic stress may result in decreased HPA-response (Booji 2013). Antidepressant treatment, on the other hand, is thought to realign HPA–axis activity (Schüle 2007).On the other hand, dysregulation within the serotonergic neurotransmitter system is understood as a central moderator in the pathophysiology of affective and anxiety disorders. Serotonergic transmission both regulates- and is regulated by- glucocortocoids. Cortisol results in an increase in serotonin synthesis and release while serotonergic transmission is thought to downregulate HPA-axis activity (Lanfumey, 2008). Positron emission tomography (PET) studies have demonstrated the link between the serotonergic system and the HPA-axis in humans in vivo. For example, a negative correlation between cortisol and 5HT1A receptor levels in various brain regions has been shown (Lanzenberger, 2010). SERT expression, on the other hand, was shown using PET to be positively related to HPA-axis reactivity (Frokjaer 2013).Methodsn.a.AimsAvailable literature on interactions between the HPA-axis and the serotonergic system will be discussed with a focus on data acquired via PET studies.Resultsn.a.ConclusionsThe interaction between the serotonergic system and the HPA-axis is likely bilateral and may be understood as a neurobiological link by which stress may foster the development of depression and anxiety.Disclosure of interestM. Spies has received travel grants from AOP Orphan Pharmaceuticals AG, Janssen-Cilag Pharma Gmbh, and Eli Lilly, workshop participation from Eli Lilly, and speaker honoraria from Janssen-Cilag Pharma Gmbh. R. Lanzenberger received travel grants and conference speaker honoraria from AstraZeneca, Lundbeck A/S, Roche Austria GmbH, Dr. Willmar Schwabe GmbH & Co. KG, AOP Orphan Pharmaceuticals, and Janssen-Cilag Pharma Gmbh.

scholarly journals MicroRNA-dependent control of neuroplasticity in affective disorders

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Helena Caria Martins ◽  
Gerhard Schratt
Keyword(s):  
Affective Disorders ◽  
Gene Networks ◽  
Molecular Mechanisms ◽  
Brain Regions ◽  
Functional Studies ◽  
Brain Functions ◽  
Small Regulatory Rnas ◽  
Therapeutic Tools ◽  
Mood And Cognition

AbstractAffective disorders are a group of neuropsychiatric disorders characterized by severe mood dysregulations accompanied by sleep, eating, cognitive, and attention disturbances, as well as recurring thoughts of suicide. Clinical studies consistently show that affective disorders are associated with reduced size of brain regions critical for mood and cognition, neuronal atrophy, and synaptic loss in these regions. However, the molecular mechanisms that mediate these changes and thereby increase the susceptibility to develop affective disorders remain poorly understood. MicroRNAs (miRNAs or miRs) are small regulatory RNAs that repress gene expression by binding to the 3ʹUTR of mRNAs. They have the ability to bind to hundreds of target mRNAs and to regulate entire gene networks and cellular pathways implicated in brain function and plasticity, many of them conserved in humans and other animals. In rodents, miRNAs regulate synaptic plasticity by controlling the morphology of dendrites and spines and the expression of neurotransmitter receptors. Furthermore, dysregulated miRNA expression is frequently observed in patients suffering from affective disorders. Together, multiple lines of evidence suggest a link between miRNA dysfunction and affective disorder pathology, providing a rationale to consider miRNAs as therapeutic tools or molecular biomarkers. This review aims to highlight the most recent and functionally relevant studies that contributed to a better understanding of miRNA function in the development and pathogenesis of affective disorders. We focused on in vivo functional studies, which demonstrate that miRNAs control higher brain functions, including mood and cognition, in rodents, and that their dysregulation causes disease-related behaviors.

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