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Advances in Stress and Depression Research: Neurobiology, Models, Biomarkers and Therapies 2.0

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (31 December 2023) | Viewed by 10440

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Dr. Larisa Bobrovskaya

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Health and Biomedical Innovation, Clinical and Health Sciences, University of South Australia, Adelaide 5000, Australia
Interests: neurobiology of stress and depression; animal models of disease; neurochemical mechanisms; behaviour; neurodegeneration; nutritional interventions; hypoglycaemia-associated autonomic failure in diabetes
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Der Colleagues,

Depression is becoming increasingly prevalent, especially in the era of the COVID-19 pandemic. There are major challenges in managing people with depression due to the complexity and heterogeneity of the disorder, poor response of some sufferers to current treatments and lack of objective biological markers. Thus, a better understanding of the underlying biology of this disorder is of major importance.

Growing evidence supports the link between stressful life events and the development of depression. Animal models investigating the neurobiology of stress and depression have been a valuable tool for elucidating depression pathogenesis and testing novel therapies. However, the translatability of pre-clinical studies has been limited and raised controversies about the use of animal models in depression research. Thus, improved pre-clinical approaches to modelling specific aspects of depression are required to facilitate therapeutic developments.

This Special Issue will collate high-quality studies in stress and depression research focussing on the behavioural, hormonal, cellular and molecular mechanisms; sex differences; role of gut–brain connections and nutrition; biological markers; novel and/or improved approaches to modelling depression in animals; as well as therapeutic interventions. Both original research and review articles are welcome.

Dr. Larisa Bobrovskaya
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

depression
stress
pathogenesis
animal models
behaviour
molecular mechanisms
biomarkers
gut–brain connections
nutrition
sex differences
therapeutic interventions

Published Papers (7 papers)

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Research

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15 pages, 2108 KiB

Open AccessArticle

Biomarkers of Depression among Adolescent Girls: BDNF and Epigenetics

by Weronika Zwolińska, Karolina Bilska, Kateryna Tarhonska, Edyta Reszka, Maria Skibińska, Natalia Pytlińska, Agnieszka Słopień and Monika Dmitrzak-Węglarz

Int. J. Mol. Sci. 2024, 25(6), 3281; https://doi.org/10.3390/ijms25063281 - 14 Mar 2024

Viewed by 677

Abstract

Alterations in brain-derived neurotrophic factor (BDNF) expression have been suggested to mediate the influence of environmental factors on the emergence of depression through epigenetic modifications. However, research on this subject in the developmental population is lacking and the pathophysiology of adolescent depression remains unclear. We aimed to investigate the alterations in BDNF expression and global DNA methylation in depression among adolescent girls. Thirty female inpatients with the initial diagnosis of depression were assessed before and after the period of antidepressant treatment and compared with thirty age-matched healthy controls. The assessment involved BDNF and proBDNF serum levels, the BDNF gene exon IV promoter methylation, and global DNA methylation. The methylation level in the BDNF gene exon IV promoter was significantly lower in the studied group compared with the control and correlated negatively with the severity of depression. The test distinguished the studied group from the controls with a sensitivity of 37% and specificity of 90%. The differences were no longer present after the period of antidepressant treatment. No differences in the global DNA methylation, BDNF, and proBDNF levels were found. We concluded that decreased methylation in the BDNF exon IV promoter could be considered as a biomarker of a depression state among adolescent girls. Full article

(This article belongs to the Special Issue Advances in Stress and Depression Research: Neurobiology, Models, Biomarkers and Therapies 2.0)

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15 pages, 2833 KiB

Open AccessArticle

Methylation Patterns of the FKBP5 Gene in Association with Childhood Maltreatment and Depressive Disorders

by Nora L. Großmann, Antoine Weihs, Luise Kühn, Susann Sauer, Simone Röh, Tobias Wiechmann, Monika Rex-Haffner, Henry Völzke, Uwe Völker, Elisabeth B. Binder, Alexander Teumer, Georg Homuth, Johanna Klinger-König and Hans J. Grabe

Int. J. Mol. Sci. 2024, 25(3), 1485; https://doi.org/10.3390/ijms25031485 - 25 Jan 2024

Cited by 1 | Viewed by 1124

Abstract

Childhood maltreatment is an important risk factor for adult depression and has been associated with changes in the hypothalamic pituitary adrenal (HPA) axis, including cortisol secretion and methylation of the FKBP5 gene. Furthermore, associations between depression and HPA changes have been reported. This study investigated the associations of whole-blood FKBP5 mRNA levels, serum cortisol levels, childhood maltreatment, and depressive symptoms with the whole-blood methylation status (assessed via target bisulfite sequencing) of 105 CpGs at the FKBP5 locus using data from the general population-based Study of Health in Pomerania (SHIP) (N = 203). Both direct and interaction effects with the rs1360780 single-nucleotide polymorphism were investigated. Nominally significant associations of main effects on methylation of a single CpG site were observed at intron 3, intron 7, and the 3′-end of the gene. Additionally, methylation at two clusters at the 3′-end and intron 7 were nominally associated with childhood maltreatment × rs1360780 and depressive symptoms × rs1360780, respectively. The results add to the understanding of molecular mechanisms underlying the emergence of depression and could aid the development of personalised depression therapy and drug development. Full article

(This article belongs to the Special Issue Advances in Stress and Depression Research: Neurobiology, Models, Biomarkers and Therapies 2.0)

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17 pages, 2441 KiB

Open AccessArticle

Embers of the Past: Early Childhood Traumas Interact with Variation in P2RX7 Gene Implicated in Neuroinflammation on Markers of Current Suicide Risk

by Zsuliet Kristof, Zsofia Gal, Dora Torok, Nora Eszlari, Sara Sutori, Beata Sperlagh, Ian M. Anderson, Bill Deakin, Gyorgy Bagdy, Gabriella Juhasz and Xenia Gonda

Int. J. Mol. Sci. 2024, 25(2), 865; https://doi.org/10.3390/ijms25020865 - 10 Jan 2024

Viewed by 1168

Abstract

Both early childhood traumatic experiences and current stress increase the risk of suicidal behaviour, in which immune activation might play a role. Previous research suggests an association between mood disorders and P2RX7 gene encoding P2X7 receptors, which stimulate neuroinflammation. We investigated the effect of P2RX7 variation in interaction with early childhood adversities and traumas and recent stressors on lifetime suicide attempts and current suicide risk markers. Overall, 1644 participants completed questionnaires assessing childhood adversities, recent negative life events, and provided information about previous suicide attempts and current suicide risk-related markers, including thoughts of ending their life, death, and hopelessness. Subjects were genotyped for 681 SNPs in the P2RX7 gene, 335 of which passed quality control and were entered into logistic and linear regression models, followed by a clumping procedure to identify clumps of SNPs with a significant main and interaction effect. We identified two significant clumps with a main effect on current suicidal ideation with top SNPs rs641940 and rs1653613. In interaction with childhood trauma, we identified a clump with top SNP psy_rs11615992 and another clump on hopelessness containing rs78473339 as index SNP. Our results suggest that P2RX7 variation may mediate the effect of early childhood adversities and traumas on later emergence of suicide risk. Full article

(This article belongs to the Special Issue Advances in Stress and Depression Research: Neurobiology, Models, Biomarkers and Therapies 2.0)

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18 pages, 6935 KiB

Open AccessArticle

Sex Differences in Brain Region-Specific Activation of c-Fos following Kappa Opioid Receptor Stimulation or Acute Stress in Mice

by Qianhan Ma, Susan Wonnacott, Sarah J. Bailey and Christopher P. Bailey

Int. J. Mol. Sci. 2023, 24(20), 15098; https://doi.org/10.3390/ijms242015098 - 11 Oct 2023

Cited by 1 | Viewed by 1261

Abstract

Kappa opioid receptors (KOPr) are involved in the response to stress. KOPr are also targets for the treatment of stress-related psychiatric disorders including depression, anxiety, and addiction although effects of KOPr are often sex-dependent. Here we investigated c-Fos expression in a range of brain regions in male and female mice following an acute stressor, and a single injection of KOPr agonist. Using adult C57BL/6 c-Fos-GFP transgenic mice and quantitative fluorescence microscopy, we identified brain regions activated in response to a challenge with the KOPr agonist U50,488 (20 mg/kg) or an acute stress (15 min forced swim stress, FSS). In male mice, U50,488 increased expression of c-Fos in the prelimbic area of the prefrontal cortex (PFCx), nucleus accumbens (NAcc), and basolateral nuclei of the amygdala (BLA). In contrast, in female mice U50,488 only activated the BLA but not the PFCx or the NAcc. FSS increased activation of PFCx, NAcc, and BLA in males while there was no activation of the PFCx in female mice. In both sexes, the KOPr antagonist norBNI significantly blocked U50,488-induced, but not stress-induced activation of brain regions. In separate experiments, activated cells were confirmed as non-GABAergic neurons in the PFCx and NAcc. Together these data demonstrate sex differences in activation of brain regions that are key components of the ‘reward’ circuitry. These differential responses may contribute to sex differences in stress-related psychiatric disorders and in the treatment of depression, anxiety, and addiction. Full article

(This article belongs to the Special Issue Advances in Stress and Depression Research: Neurobiology, Models, Biomarkers and Therapies 2.0)

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38 pages, 7761 KiB

Open AccessArticle

The Effects of Chronic Unpredictable Mild Stress and Semi-Pure Diets on the Brain, Gut and Adrenal Medulla in C57BL6 Mice

by Mauritz Frederick Herselman and Larisa Bobrovskaya

Int. J. Mol. Sci. 2023, 24(19), 14618; https://doi.org/10.3390/ijms241914618 - 27 Sep 2023

Cited by 1 | Viewed by 1531

Abstract

Chronic stress is known to perturb serotonergic regulation in the brain, leading to mood, learning and memory impairments and increasing the risk of developing mood disorders. The influence of the gut microbiota on serotonergic regulation in the brain has received increased attention recently, justifying the investigation of the role of diet on the gut and the brain in mood disorders. Here, using a 4-week chronic unpredictable mild stress (CUMS) model in mice, we aimed to investigate the effects of a high-fat high-glycaemic index (HFD) and high-fibre fruit & vegetable “superfood” (SUP) modifications of a semi-pure AIN93M diet on behaviour, serotonin synthesis and metabolism pathway regulation in the brain and the gut, as well as the gut microbiota and the peripheral adrenal medullary system. CUMS induced anxiety-like behaviour, dysregulated the tryptophan and serotonin metabolic pathways in the hippocampus, prefrontal cortex, and colon, and altered the composition of the gut microbiota. CUMS reduced the catecholamine synthetic capacity of the adrenal glands. Differential effects were found in these parameters in the HFD and SUP diet. Thus, dietary modifications may profoundly affect the multiple dynamic systems involved in mood disorders. Full article

(This article belongs to the Special Issue Advances in Stress and Depression Research: Neurobiology, Models, Biomarkers and Therapies 2.0)

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18 pages, 3415 KiB

Open AccessArticle

Serum Extracellular Vesicle-Derived hsa-miR-2277-3p and hsa-miR-6813-3p Are Potential Biomarkers for Major Depression: A Preliminary Study

by Issei Seki, Hiroto Izumi, Naomichi Okamoto, Atsuko Ikenouchi, Yasuo Morimoto, Seichi Horie and Reiji Yoshimura

Int. J. Mol. Sci. 2023, 24(18), 13902; https://doi.org/10.3390/ijms241813902 - 9 Sep 2023

Cited by 2 | Viewed by 1201

Abstract

The aim of the present study was to examine the association between miRNA levels in extracellular vesicles (EVs) from serum and the severity of Major Depression (MD). Patient sera from 16 MD cases were collected at our university hospital. The miRNAs contained in EVs were extracted using a nanofiltration method, and their expression levels were analyzed using miRNA microarrays. Intergroup comparisons were performed to validate the diagnostic performance of miRNAs in EVs. Furthermore, candidate miRNAs in EVs were added to neural progenitor cells, astrocytes, and microglial cells in vitro, and the predicted target genes of the candidate miRNAs were extracted. The predicted target genes underwent enrichment analysis. The expression levels of hsa-miR-6813-3p and hsa-miR-2277-3p were significantly downregulated with increasing depression severity of MD. The pathway enrichment analysis suggests that hsa-miR-6813-3p may be involved in glucocorticoid receptor and gamma-aminobutyric acid receptor signaling. Additionally, hsa-miR-2277-3p was found to be involved in the dopaminergic neural pathway. The analysis of serum miRNAs in EVs suggests that hsa-miR-6813-3p and hsa-miR-2277-3p could serve as novel biomarkers for MD, reflecting its severity. Moreover, these miRNAs in EVs could help understand MD pathophysiology. Full article

(This article belongs to the Special Issue Advances in Stress and Depression Research: Neurobiology, Models, Biomarkers and Therapies 2.0)

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Review

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26 pages, 784 KiB

Open AccessReview

Potential of Circulating miRNAs as Molecular Markers in Mood Disorders and Associated Suicidal Behavior

by Bhaskar Roy, Shinichiro Ochi and Yogesh Dwivedi

Int. J. Mol. Sci. 2023, 24(5), 4664; https://doi.org/10.3390/ijms24054664 - 28 Feb 2023

Cited by 7 | Viewed by 2737

Abstract

Mood disorders are the most prevalent psychiatric disorders associated with significant disability, morbidity, and mortality. The risk of suicide is associated with severe or mixed depressive episodes in patients with mood disorders. However, the risk of suicide increases with the severity of depressive episodes and is often presented with higher incidences in bipolar disorder (BD) patients than in patients with major depression (MDD). Biomarker study in neuropsychiatric disorders is critical for developing better treatment plans by facilitating more accurate diagnosis. At the same time, biomarker discovery also provides more objectivity to develop state-of-the-art personalized medicine with increased accuracy through clinical interventions. Recently, colinear changes in miRNA expression between brain and systemic circulation have added great interest in examining their potential as molecular markers in mental disorders, including MDD, BD, and suicidality. A present understanding of circulating miRNAs in body fluids implicates their role in managing neuropsychiatric conditions. Most notably, their use as prognostic and diagnostic markers and their potential role in treatment response have significantly advanced our knowledge base. The present review discusses circulatory miRNAs and their underlying possibilities to be used as a screening tool for assessing major psychiatric conditions, including MDD, BD, and suicidal behavior. Full article

(This article belongs to the Special Issue Advances in Stress and Depression Research: Neurobiology, Models, Biomarkers and Therapies 2.0)

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