scholarly journals Impaired endogenous neurosteroid signaling contributes to behavioral deficits associated with chronic stress

2022 ◽  
Author(s):  
Najah L. Walton ◽  
Pantelis Antonoudiou ◽  
Lea Barros ◽  
Alyssa DiLeo ◽  
Jenah Gabby ◽  
...  
Keyword(s):  
Mood Disorders ◽  
Chronic Stress ◽  
Behavioral Outcomes ◽  
Behavioral Deficits ◽  
Pathophysiological Mechanisms ◽  
Psychiatric Illnesses ◽  
Fda Approval ◽  
Antidepressant Effects ◽  
Steroid Analog

Chronic stress is a major risk factor for psychiatric illnesses, including depression; however, the pathophysiological mechanisms whereby stress leads to mood disorders remain unclear. The recent FDA approval of antidepressants with novel mechanisms of action, like Zulresso®, a synthetic neuroactive steroid analog with molecular pharmacology similar to allopregnanolone, has spurred interest in new therapeutic targets and, potentially, novel pathophysiological mechanisms for depression. Allopregnanolone acts as a positive allosteric modulator of GABAA receptors (GABAARs), acting preferentially at δ subunit-containing receptors (δ-GABAARs). Accumulating clinical and preclinical evidence supports the antidepressant effects of exogenous administration of allopregnanolone and allopregnanolone analogs; however, the role of endogenous neurosteroids in the pathophysiology of depression remains unknown. Here, we examine whether altered neurosteroid signaling may contribute to behavioral deficits following chronic unpredictable stress (CUS) in mice. We first identified reductions in expression of δ-GABAARs, the predominant site of action of 5a-reduced neuroactive steroids, following CUS. Additionally, utilizing LC-MS/MS we discovered a decrease in levels of allopregnanolone in the BLA, but not plasma of mice following CUS, an indication of impaired neurosteroid synthesis. CRISPR knockdown the rate-limiting enzymes involved in allopregnanolone synthesis, 5α-reductase type 1 and 2, in the BLA mimicked the behavioral deficits associated with CUS in mice. Furthermore, overexpression expression of 5α-reductase type 1 and 2 in the BLA improved behavioral outcomes. Collectively, this suggests chronic stress impairs endogenous neurosteroid signaling in the BLA which is sufficient to induce behavioral deficits similar to those observed following CUS. Further, these studies suggest that the therapeutic efficacy of allopregnanolone-based treatments may be due to their ability to directly target the underlying pathophysiology of mood disorders. Therefore, targeting endogenous neurosteroidogenesis may offer a novel therapeutic strategy for the treatment of mood disorders.

scholarly journals 421 - Mood disorders and its relationship with cognitive impairment and dementia

2020 ◽  
Vol 32 (S1) ◽  
pp. 137-137
Author(s):  
Sandra Torres ◽  
Andreia Lopes
Keyword(s):  
Cognitive Impairment ◽  
Mood Disorders ◽  
Neuronal Loss ◽  
Neurocognitive Impairment ◽  
Attention And Memory ◽  
Psychiatric Illnesses ◽  
Neurocognitive Functions ◽  
The Many ◽  
The One ◽  
Published Research

ABSTRACT:Mood disorders are common psychiatric illnesses that represent a major cause of disability worldwide. With life expectancy and the percentage of elderly people rising in many developed and undeveloped countries around the globe, cognitive impairment and dementia are gaining a societal importance. The relation between mood disorders and cognitive function is a twofold. On the one hand, cognitive deficits within mood disorders have been studied extensively, in which there seems to be a persistent neurocognitive impairment, both in acute phases and in interepisodic euthymic phases. Although results have not always been consistent, an overall pattern of specific impairments – in executive function, attention and memory - has become evident. On the other hand, recent research suggests that mood disorders, in general, may be risk factors for the development of mild cognitive impairment and dementia. In this sense, of the many models for the association of mood disorders and dementia, two are favored by several authors. One suggests that mood disorders are a risk factor for earlier clinical manifestation of dementia. The second sees mood disorders as the cause of dementing states, for instance through neuronal loss via dysregulation of the glucocorticoid cascade. In fact, there is suggestion that impairment of neuroplasticity may underlie the pathophysiology of mood disorders as such, and not only of neurocognitive impairment. In some patients, specific neurocognitive functions may be present before the onset of mood disorder and may constitute a trait factor or even an endophenotype. The aim of the present work is to, through a basic narrative review of published research on the main databases, summarize the main evidences of the association of mood disorders and dementia.

scholarly journals Chronic non-discriminatory social defeat stress reduces effort-related motivated behaviors in male and female mice

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Andrew Dieterich ◽  
Tonia Liu ◽  
Benjamin Adam Samuels
Keyword(s):  
Mood Disorders ◽  
Chronic Stress ◽  
Choice Behavior ◽  
Progressive Ratio ◽  
Social Defeat ◽  
Social Defeat Stress ◽  
Male And Female ◽  
Female Mice ◽  
High Reward ◽  
Motivated Behaviors

AbstractReward and motivation deficits are prominent symptoms in many mood disorders, including depression. Similar reward and effort-related choice behavioral tasks can be used to study aspects of motivation in both rodents and humans. Chronic stress can precipitate mood disorders in humans and maladaptive reward and motivation behaviors in male rodents. However, while depression is more prevalent in women, there is relatively little known about whether chronic stress elicits maladaptive behaviors in female rodents in effort-related motivated tasks and whether there are any behavioral sex differences. Chronic nondiscriminatory social defeat stress (CNSDS) is a variation of chronic social defeat stress that is effective in both male and female mice. We hypothesized that CNSDS would reduce effort-related motivated and reward behaviors, including reducing sensitivity to a devalued outcome, reducing breakpoint in progressive ratio, and shifting effort-related choice behavior. Separate cohorts of adult male and female C57BL/6 J mice were divided into Control or CNSDS groups, exposed to the 10-day CNSDS paradigm, and then trained and tested in instrumental reward or effort-related behaviors. CNSDS reduced motivation to lever press in progressive ratio and shifted effort-related choice behavior from a high reward to a more easily attainable low reward in both sexes. CNSDS caused more nuanced impairments in outcome devaluation. Taken together, CNSDS induces maladaptive shifts in effort-related choice and reduces motivated lever pressing in both sexes.

scholarly journals Allopregnanolone mediates affective switching through modulation of oscillatory states in the basolateral amygdala

2021 ◽  
Author(s):  
Pantelis Antonoudiou ◽  
Phillip LW Colmers ◽  
Najah L Walton ◽  
Grant L Weiss ◽  
Anne C Smith ◽  
...  
Keyword(s):  
Basolateral Amygdala ◽  
Post Partum ◽  
Critical Role ◽  
Behavioral Outcomes ◽  
Theta Oscillations ◽  
Allosteric Modulators ◽  
Post Partum Depression ◽  
Antidepressant Effects ◽  
Behavioral States ◽  
Network States

AbstractBrexanolone (allopregnanolone), was recently approved by the FDA for the treatment of post-partum depression, demonstrating long-lasting antidepressant effects. Despite our understanding of the mechanism of action of neurosteroids as positive allosteric modulators (PAMs) of GABAa receptors, we still do not fully understand how allopregnanolone exerts these persistent antidepressant effects. Here, we demonstrate that allopregnanolone and similar synthetic neuroactive steroid analogs, SGE-516 (tool-compound) and zuranolone (SAGE-217, investigational-compound), are capable of modulating oscillatory states across species, which we propose may contribute to long-lasting changes in behavioral states. We identified a critical role for interneurons in generating oscillations in the basolateral amygdala (BLA) and a role for delta-containing GABAaRs in mediating the ability of neurosteroids to modulate network and behavioral states. Actions of allopregnanolone in the BLA is sufficient to alter behavioral states and enhance BLA high-theta oscillations (6-12Hz) through delta-containing GABAa receptors, a mechanism distinct from other GABAa PAMs, such as benzodiazepines. Moreover, treatment with the allopregnanolone analog SGE-516 induces long-lasting protection from chronic stress-induced disruption of network states, which correlates with improved behavioral outcomes. Our findings demonstrate a novel molecular and cellular mechanism mediating the well-established anxiolytic and antidepressant effects of neuroactive steroids.

scholarly journals Chronic Stress Alters Astrocyte Morphology in Mouse Prefrontal Cortex

2021 ◽  
Author(s):  
Sierra A. Codeluppi ◽  
Dipashree Chatterjee ◽  
Thomas D. Prevot ◽  
Keith A. Misquitta ◽  
Etienne Sibille ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Chronic Stress ◽  
Fluorescent Protein ◽  
Glial Fibrillary Acid Protein ◽  
Behavioral Deficits ◽  
Sholl Analysis ◽  
Acid Protein ◽  
Potential Link ◽  
Green Fluorescent ◽  
Stress Models

AbstractBackgroundNeuromorphological changes are consistently reported in the prefrontal cortex (PFC) of patients with stress-related disorders and in rodent stress models, but the effects of stress on astrocyte morphology and potential link to behavioral deficits are relatively unknown.MethodsTo answer these questions, transgenic mice expressing green fluorescent protein (GFP) under the glial fibrillary acid protein (GFAP) promotor were subjected to 7, 21 or 35 days of chronic restraint stress (CRS). CRS behavioral effects on anhedonia- and anxiety-like behaviours were measured using the sucrose intake and the PhenoTyper tests, respectively. PFC GFP+ or GFAP+ cells morphology was assessed using Sholl analysis and associations with behavior were determined using correlation analysis.ResultsCRS-exposed mice displayed anxiety-like behavior at 7, 21 and 35 days and anhedonia-like behavior at 35 days. Analysis of GFAP+ cell morphology revealed significant atrophy of distal processes following 21 and 35 days of CRS. CRS induced similar decreases in intersections at distal radii for GFP+ cells, accompanied by increased proximal processes. Additionally, the number of intersections at the most distal radius step significantly correlated with time spent in the shelter zone in the PhenoTyper test (r=-0.581, p<0.01) for GFP+ cells and with behavioural emotionality calculated by z-scoring all behavioral measured deficits, for both GFAP+ and GFP+ cells (r=-0.400, p<0.05; r=-0.399, p<0.05).ConclusionChronic stress exposure induces a progressive atrophy of cortical astroglial cells, potentially contributing to maladaptive neuroplastic changes associated with stress-related disorders.

scholarly journals Social dominance mediates behavioral adaptation to chronic stress in a sex-specific manner

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Stoyo Karamihalev ◽  
Elena Brivio ◽  
Cornelia Flachskamm ◽  
Rainer Stoffel ◽  
Mathias V Schmidt ◽  
...  
Keyword(s):  
Chronic Stress ◽  
Social Dominance ◽  
Behavioral Outcomes ◽  
Group Living ◽  
Social Hierarchy ◽  
Behavioral Adaptation ◽  
The Social ◽  
Specific Manner ◽  
Behavioral Monitoring ◽  
Influence Behavior

Sex differences and social context independently contribute to the development of stress-related disorders. However, less is known about how their interplay might influence behavior and physiology. Here we focused on social hierarchy status, a major component of the social environment in mice, and whether it influences behavioral adaptation to chronic stress in a sex-specific manner. We used a high-throughput automated behavioral monitoring system to assess social dominance in same-sex, group-living mice. We found that position in the social hierarchy at baseline was a significant predictor of multiple behavioral outcomes following exposure to chronic stress. Crucially, this association carried opposite consequences for the two sexes. This work demonstrates the importance of recognizing the interplay between sex and social factors and enhances our understating of how individual differences shape the stress response.

scholarly journals Increased Nitro-Oxidative Toxicity in Association With Metabolic Syndrome, Atherogenicity and Insulin Resistance in Patients With Affective Disorders

2021 ◽  
Author(s):  
Nayara Morelli ◽  
Michael Maes ◽  
Kamila Bonifacio ◽  
Heber Vargas ◽  
Sandra Nunes ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Mood Disorders ◽  
Lipid Hydroperoxides ◽  
Superoxide Dismutase 1 ◽  
Bipolar Type ◽  
Male Sex ◽  
Nitric Oxide Metabolites ◽  
Composite Scores

Background: There is a strong comorbidity between mood disorders and metabolic syndrome (MetS). Increased levels of reactive oxygen and nitrogen species (RONS) and nitro-oxidative stress toxicity (NOSTOX) partially underpin this comorbidity.Aims: To examine the associations of RONS/NOSTOX biomarkers with MetS after adjusting for the significant effects of mood disorders (major depression, and bipolar type 1 and 2), generalized anxiety disorder (GAD), tobacco use disorder (TUD), and male sex.Methods: The study included subjects with (n=65) and without (n=107) MetS and measured levels of superoxide dismutase 1 (SOD1), lipid hydroperoxides (LOOH), nitric oxide metabolites (NOx), malondialdehyde (MDA), and advanced oxidation protein products (AOPP) and computed z unit-weighted composite scores which reflect RONS/NOSTOX. The study included 105 patients with mood disorders, 46 with GAD, and 95 with TUD.Results: MetS was associated with increased levels of MDA and AOPP, independently from mood disorders, TUD, sex and GAD. Atherogenicity and insulin resistance (IR) were significantly associated with a NOSTOX composite score. Mood disorders, TUD, GAD, male sex and MetS independently contribute to increased RONS/NOSTOX. The RONS/NOSTOX profile of MetS was different from that of GAD, which showed increased SOD1 and NOx levels. TUD was accompanied by increased SOD1, LOOH and MDA, and male sex by increased LOOH and AOPP.Conclusions: MetS is characterized by increased lipid peroxidation with aldehyde formation and chlorinative stress, and atherogenicity and IR are strongly mediated by RONS/NOSTOX. Partially shared RONS/NOSTOX pathways underpin the comorbidity of MetS with mood disorders, GAD, and TUD.

scholarly journals Involvement of Hepatic SHIP2 and PI3K/Akt Signalling in the Regulation of Plasma Insulin by Xiaoyaosan in Chronic Immobilization-Stressed Rats

Molecules ◽  
2019 ◽  
Vol 24 (3) ◽  
pp. 480 ◽  
Author(s):  
Qiuxia Pan ◽  
Jiajia Wu ◽  
Yueyun Liu ◽  
Xiaojuan Li ◽  
Jiaxu Chen
Keyword(s):  
Blood Glucose ◽  
Chronic Stress ◽  
Plasma Insulin ◽  
Metabolic Disorders ◽  
Density Lipoprotein ◽  
Preference Test ◽  
Control Group ◽  
Sprague Dawley ◽  
Antidepressant Effects ◽  
Group A

Background: Long-term exposure to chronic stress is thought to be a factor closely correlated with the development of metabolic disorders, such as diabetes mellitus and metabolic syndrome. Xiaoyaosan, a Chinese herbal formula, has been described in many previous studies to exert anxiolytic-like or antidepressant effects in chronically stressed rats. However, few studies have observed the effects of Xiaoyaosan on the metabolic disorders induced by chronic stress. Objective: We sought to investigate the effective regulation of Xiaoyaosan on 21-day chronic immobility stress (CIS, which is 3 h of restraint immobilization every day)-induced behavioural performance and metabolic responses and to further explore whether the effects of Xiaoyaosan were related to SHIP2 expression in the liver. Methods: Sixty male Sprague Dawley rats were randomly divided into a control group, a CIS group, a Xiaoyaosan group and a rosiglitazone group. The latter three groups were subjected to 21 days of CIS to generate the stress model. After 21 days of CIS, the effects of Xiaoyaosan on body weight, food intake, and behaviour in the open field test, the sucrose preference test and the forced swimming test were observed following chronic stress. Plasma insulin, cholesterol (CHOL), triglyceride (TG), low-density lipoprotein (LDL-C) and high-density lipoprotein (HDL-C) concentrations and blood glucose were examined, and the protein and mRNA expression levels of SHIP2, p85 and Akt in the liver were measured using RT-qPCR and immunohistochemical staining. Results: Rats exposed to CIS exhibited depression-like behaviours, decreased levels of plasma insulin, CHOL, LDL-C, TG and HDL-C, and increased blood glucose. Increased SHIP2 expression and reduced Akt, p-Akt and p85 expression were also observed in the liver. Xiaoyaosan exerted antidepressant effects and effectively reversed the changes caused by CIS. Conclusions: These results suggest that Xiaoyaosan attenuates depression-like behaviours and ameliorates stress-induced abnormal levels of insulin, blood glucose, CHOL, LDL-C and HDL-C in the plasma of stressed rats, which may be associated with the regulation of SHIP2 expression to enhance PI3K/Akt signalling activity in the liver.

Effects of single and combined gabapentin use in elevated plus maze and forced swimming tests

2014 ◽  
Vol 26 (5) ◽  
pp. 307-314 ◽  
Author(s):  
Fatma Sultan Kilic ◽  
Sule Ismailoglu ◽  
Bilgin Kaygisiz ◽  
Setenay Oner
Keyword(s):  
Elevated Plus Maze ◽  
Anxiolytic Effect ◽  
Experimental Models ◽  
Forced Swimming ◽  
Anxiety And Depression ◽  
Antidepressant Effect ◽  
Control Group ◽  
Psychiatric Illnesses ◽  
Plus Maze ◽  
Antidepressant Effects

BackgroundGabapentin, a third-generation antiepileptic drug, is a structural analogue of γ-aminobutyric acid, which is an important mediator of central nervous system. There is clinical data indicating its effectiveness in the treatment of psychiatric illnesses such as bipolar disorder and anxiety disorders.ObjectivesWe aimed to investigate the antidepressant and anxiolytic-like effects and mechanisms of gabapentin in rats.Material and MethodsFemale Spraque–Dawley rats weighing 250±20 g were used. A total of 13 groups were formed, each containing 8 rats: gabapentin (5, 10, 20, 40 mg/kg), amitriptyline (10 mg/kg), sertraline (5 mg/kg), diazepam (5 mg/kg), ketamine (10 mg/kg), gabapentin 20 mg/kg was also combined with amitriptyline (10 mg/kg), sertraline (5 mg/kg), diazepam (5 mg/kg) and ketamine (10 mg/kg). All the drugs were used intraperitoneally as single dose. Saline was administered to the control group. Elevated plus maze and forced swimming tests were used as experimental models of anxiety and depression, respectively.ResultsIt was observed that gabapentin showed an anxiolytic-like and antidepressant-like effect in all doses in rats. Its antidepressant effect was found to be the same as the antidepressant effects of amitriptyline and sertraline. There was no change in the antidepressant effect when gabapentin was combined with amitriptyline and ketamine, but there was an increase when combined with sertraline and diazepam. Gabapentin and amitriptyline showed similar anxiolytic effect, whereas ketamine and diazepam had more potent anxiolytic effect compared with them.ConclusionsThese data suggest that gabapentin may possess antidepressant- and anxiolytic-like effects.

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