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Stress-Related Disorders and Depression: From Molecular Basis to Therapy (2nd Edition)

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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: 20 June 2025 | Viewed by 9647

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Prof. Dr. Irena Nalepa

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Department of Brain Biochemistry, Maj Institute of Pharmacology of the Polish Academy of Sciences, Smętna 12, 31-343 Krakow, Poland
Interests: neuroscience; neuropharmacology; stress-related disorders; depression; psychotropic drugs; GPCR signaling; noradrenergic system; neuroplasticity, neuroimmune interaction
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Dr. Agnieszka Zelek-Molik

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Department of Brain Biochemistry, Maj Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, 31-343 Kraków, Poland
Interests: neurobiology; pharmacology; stress; psychiatric disorders
Special Issues, Collections and Topics in MDPI journals

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Dear Colleagues,

Stress is defined as a challenge to the homeostasis of an organism by events coming from the environment. Two major systems are essential in the response to stressors: the sympathetic adrenomedullary system and the hypothalamic–pituitary–adrenal axis (HPA). Elevated by stress, noradrenaline and HPA axis-related hormones (including CRH, vasopressin, ACTH, corticosteroids) influence the gene transcription processes and the functioning of neurotransmitter systems. The immune system’s responsiveness is also affected. Via alterations to brain structure, chemistry, and function, chronic stress contributes to depression and various anxiety disorders, including posttraumatic stress disorder (PTSD). There is evidence demonstrating that chronic stress may also contribute to addiction and obesity.

The purpose of this Special Issue is to collect original research articles and review papers that concern the study of how the brain transduces environmental stress exposure into depression and stress-related diseases. We aim to bring together the most recent studies and use different experimental approaches, in vivo or in vitro, for the purpose of addressing:

molecular and cellular responses to stress;
stress-induced changes in the neurochemical cross-talk between signaling systems in the brain;
methods to study the effects of various stressors in psychiatric disease models;
stress vulnerability and resilience;
stress biomarkers;
therapies for stress-related disorders.

Prof. Dr. Irena Nalepa
Dr. Agnieszka Zelek-Molik
Guest Editors

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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.

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Keywords

psychobiology of stress
depression
posttraumatic stress disorder
anxiety disorders
animal models
biogenic monoamines
glucocorticoids
inflammation
antidepressant and anxiolytic drugs

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Published Papers (6 papers)

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17 pages, 10646 KiB

Open AccessArticle

Neuronal TCF7L2 in Lateral Habenula Is Involved in Stress-Induced Depression

by Xincheng Li, Xiaoyu Liu, Jiaxin Liu, Fei Zhou, Yunluo Li, Ye Zhao, Xueyong Yin, Yun Shi and Haishui Shi

Int. J. Mol. Sci. 2024, 25(22), 12404; https://doi.org/10.3390/ijms252212404 - 19 Nov 2024

Viewed by 632

Abstract

Depression is a complex psychiatric disorder that has substantial implications for public health. The lateral habenula (LHb), a vital brain structure involved in mood regulation, and the N-methyl-D-aspartate receptor (NMDAR) within this structure are known to be associated with depressive behaviors. Recent research has identified transcription factor 7-like 2 (TCF7L2) as a crucial transcription factor in the Wnt signaling pathway, influencing diverse neuropsychiatric processes. In this study, we explore the role of TCF7L2 in the LHb and its effect on depressive-like behaviors in mice. By using behavioral tests, AAV-mediated gene knockdown or overexpression, and pharmacological interventions, we investigated the effects of alterations in TCF7L2 expression in the LHb. Our results indicate that TCF7L2 expression is reduced in neurons within the LHb of male ICR mice exposed to chronic mild stress (CMS), and neuron-specific knockdown of TCF7L2 in LHb neurons leads to notable antidepressant activity, as evidenced by reduced immobility time in the tail suspension test (TST) and forced swimming test (FST). Conversely, the overexpression of TCF7L2 in LHb neurons induces depressive behaviors. Furthermore, the administration of the NMDAR agonist NMDA reversed the antidepressant activity of TCF7L2 knockdown, and the NMDAR antagonist memantine alleviated the depressive behaviors induced by TCF7L2 overexpression, indicating the involvement of NMDAR. These findings offer novel insights into the molecular mechanisms of depression, highlighting the potential of TCF7L2 as both a biomarker and a therapeutic target for depression. Exploring the relationship between TCF7L2 signaling and LHb function may lead to innovative therapeutic approaches for alleviating depressive symptoms. Full article

(This article belongs to the Special Issue Stress-Related Disorders and Depression: From Molecular Basis to Therapy (2nd Edition))

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11 pages, 505 KiB

Open AccessArticle

Relationship Between the Occurrence of Depression and DROSHA (rs6877842, rs10719) and XPO5 (rs11077) Single-Nucleotide Polymorphisms in the Polish Population: A Case–Control Study

by Mateusz Kowalczyk, Edward Kowalczyk, Monika Talarowska, Ireneusz Majsterek, Maciej Skrzypek, Tomasz Popławski, Monika Sienkiewicz, Anna Wiktorowska-Owczarek, Paulina Sokołowska and Marta Jóźwiak-Bębenista

Int. J. Mol. Sci. 2024, 25(22), 12204; https://doi.org/10.3390/ijms252212204 - 14 Nov 2024

Viewed by 780

Abstract

Although the epidemiology and symptoms of major depressive disorder (MDD) have been well-documented, the etiology and pathophysiology of the disease have not yet been fully explained. Depression arises from intricate interplay among social, psychological, and biological factors. Recently, there has been growing focus on the involvement of miRNAs in depression, with suggestions that abnormal miRNA processing locally at the synapse contributes to MDD. Changes in miRNAs may result from altered expression and/or function of the miRNA biogenesis machinery at the synapse. The aim of our research was to assess the relationship between the occurrence of depression and single-nucleotide polymorphisms (SNP) in the following genes in the Polish population: DROSHA (rs6877842; rs10719) and XPO5 (rs11077). This study involved 200 individuals, including 100 with depressive disorders in the study group (SG) and 100 healthy people without MDD in the control group (CG). All participants were unrelated native Caucasian Poles from central Poland. Blood samples were collected to evaluate the single-nucleotide polymorphism of the genes. Findings indicated that within our patient cohort, the risk of depression is increased by polymorphic variants of the rs10719/DROSHA and rs11077/XPO5 genes and lowered by rs6877842/DROSHA. Our study sheds light on the understanding of the genetic basis of depression, which can be used in the rapid diagnosis of this disease. Full article

(This article belongs to the Special Issue Stress-Related Disorders and Depression: From Molecular Basis to Therapy (2nd Edition))

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16 pages, 4753 KiB

Open AccessArticle

Single Intranasal Administration of Ucn3 Affects the Development of PTSD Symptoms in an Animal Model

by Andrej Tillinger, Alexandra Zvozilová, Mojmír Mach, Ľubica Horváthová, Lila Dziewiczová and Jana Osacká

Int. J. Mol. Sci. 2024, 25(22), 11908; https://doi.org/10.3390/ijms252211908 - 6 Nov 2024

Viewed by 573

Abstract

Post-traumatic stress disorder (PTSD) is a multifactorial psychological disorder that affects different neurotransmitter systems, including the central CRH system. CRH acts via the CRHR1 and CRHR2 receptors, which exert opposite effects, i.e., anxiogenic or anxiolytic. The aim of this work was to investigate how intranasal administration of the CRHR2-specific agonist urocortin 2 (Ucn2) or urocortin 3 (Ucn3) affects manifestations of PTSD in a single prolonged stress (SPS) animal model of PTSD. Elevated plus maze (EPM) and open field (OF) tests were used to assess anxiety-like behavior. Changes in the gene expressions of CRH, CRHR1, CRHR2, glucocorticoid receptor (GR), and FKBP5 were measured in brain regions (BNST, amygdala, and PVN) responsible for modulating the stress response. The SPS animals spent less time in the OF central zone and were less mobile than the controls; however, the Ucn3 treatment reversed this effect. SPS decreased the GR and FKPB5 mRNA levels in the PVN. Ucn3 suppressed the effect of SPS on FKBP5 mRNA expression in the PVN and increased FKBP5 mRNA in the BNST and PVN compared to the stressed animals. We demonstrate that Ucn3 has the potential to ameliorate anxiety-like behavior in SPS animals and also to affect the neuroendocrine system in the BNST and PVN. In addition, we confirm the important role of CRHR2 signaling in mediating the stress response. Full article

(This article belongs to the Special Issue Stress-Related Disorders and Depression: From Molecular Basis to Therapy (2nd Edition))

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23 pages, 2417 KiB

Open AccessArticle

Postpartum Oxytocin Treatment via the Mother Reprograms Long-Term Behavioral Disorders Induced by Early Life Stress on the Plasma and Brain Metabolome in the Rat

by Sara Morley-Fletcher, Alessandra Gaetano, Vance Gao, Eleonora Gatta, Gilles Van Camp, Hammou Bouwalerh, Pierre Thomas, Ferdinando Nicoletti and Stefania Maccari

Int. J. Mol. Sci. 2024, 25(5), 3014; https://doi.org/10.3390/ijms25053014 - 5 Mar 2024

Cited by 1 | Viewed by 1539

Abstract

The rat model of perinatal stress (PRS), in which exposure of pregnant dams to restraint stress reduces maternal behavior, is characterized by a metabolic profile that is reminiscent of the “metabolic syndrome”. We aimed to identify plasma metabolomic signatures linked to long-term programming induced by PRS in aged male rats. This study was conducted in the plasma and frontal cortex. We also investigated the reversal effect of postpartum carbetocin (Cbt) on these signatures, along with its impact on deficits in cognitive, social, and exploratory behavior. We found that PRS induced long-lasting changes in biomarkers of secondary bile acid metabolism in the plasma and glutathione metabolism in the frontal cortex. Cbt treatment demonstrated disease-dependent effects by reversing the metabolite alterations. The metabolomic signatures of PRS were associated with long-term cognitive and emotional alterations alongside endocrinological disturbances. Our findings represent the first evidence of how early life stress may alter the metabolomic profile in aged individuals, thereby increasing vulnerability to CNS disorders. This raises the intriguing prospect that the pharmacological activation of oxytocin receptors soon after delivery through the mother may rectify these alterations. Full article

(This article belongs to the Special Issue Stress-Related Disorders and Depression: From Molecular Basis to Therapy (2nd Edition))

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22 pages, 1054 KiB

Open AccessReview

Bridging Neurobiological Insights and Clinical Biomarkers in Postpartum Depression: A Narrative Review

by Keyi Zhang, Lingxuan He, Zhuoen Li, Ruxuan Ding, Xiaojiao Han, Bingqing Chen, Guoxin Cao, Jiang-Hong Ye, Tian Li and Rao Fu

Int. J. Mol. Sci. 2024, 25(16), 8835; https://doi.org/10.3390/ijms25168835 - 14 Aug 2024

Viewed by 3407

Abstract

Postpartum depression (PPD) affects 174 million women worldwide and is characterized by profound sadness, anxiety, irritability, and debilitating fatigue, which disrupt maternal caregiving and the mother–infant relationship. Limited pharmacological interventions are currently available. Our understanding of the neurobiological pathophysiology of PPD remains incomplete, potentially hindering the development of novel treatment strategies. Recent hypotheses suggest that PPD is driven by a complex interplay of hormonal changes, neurotransmitter imbalances, inflammation, genetic factors, psychosocial stressors, and hypothalamic–pituitary–adrenal (HPA) axis dysregulation. This narrative review examines recent clinical studies on PPD within the past 15 years, emphasizing advancements in neuroimaging findings and blood biomarker detection. Additionally, we summarize recent laboratory work using animal models to mimic PPD, focusing on hormone withdrawal, HPA axis dysfunction, and perinatal stress theories. We also revisit neurobiological results from several brain regions associated with negative emotions, such as the amygdala, prefrontal cortex, hippocampus, and striatum. These insights aim to improve our understanding of PPD’s neurobiological mechanisms, guiding future research for better early detection, prevention, and personalized treatment strategies for women affected by PPD and their families. Full article

(This article belongs to the Special Issue Stress-Related Disorders and Depression: From Molecular Basis to Therapy (2nd Edition))

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Figure 1
Tryptophan metabolism in the brain. Tryptophan is mainly metabolized through the kynurenine pathway (95%) and less so through the serotonin pathway (<5%). In the kynurenine pathway, tryptophan is converted to kynurenine by IDO (in the brain) or TDO (in other tissues). This pathway splits into two branches: the KMO branch, where KMO (primarily in microglia) produces 3HK, 3HAA, QUIN, and NAD+, and the KAT branch, where KAT (mainly in astrocytes) converts kynurenine to KYNA. KYNA is neuroprotective, while QUIN is neurotoxic, with distinct effects on brain function. Full article ">Figure 2
Laboratory Animal models of PPD: (1) Hormone withdrawal models. Ovariectomized female rats were injected with a low dose of estradiol benzoate and a high dose of progesterone dissolved in sesame oil daily for 16 consecutive days. From day 17 to 23, the dose of estradiol was increased to mimic the levels observed in pregnancy. From day 24 to 27, which is considered the postpartum period, mice only received vehicle (sesame oil) daily. (2) Chronic corticosterone treatment model. Dams were injected with high CORT during the postpartum period (postpartum day 2–24). (3) Gestational stress model. Depression is induced by exposing pregnant female mice to gestational stress from days 10 to 20 during pregnancy. (4) The chronic social stress model. A novel male was placed in their home cage for 1 h each day from days 2 to 16 of lactation, resulting in depressive behaviors. (5) The repeated maternal separation model. Depression is induced by separating the mothers from their pups for periods that last 3–6 h daily during the first 1–3 weeks postpartum. Full article ">Figure 3
This review provides a comprehensive examination of postpartum depression (PPD) across four aspects: (1) Basic information, including clinical characteristics, brain imaging, and biomarkers, to offer an initial understanding. (2) Biological mechanisms, detailing PPD pathology with an emphasis on serotonin and kynurenine pathways, where kynurenine branches into neuroprotective KYNA and neurotoxic QUIN. (3) Laboratory animal models focused on hormone manipulation and stress, with model variations. (4) Neuronal mechanisms, involving key brain regions such as the PFC, AMY, HIPP, and striatum. Abbreviations: fMRI: functional magnetic resonance imaging; PET-CT: positron emission tomography-computed tomography; MRS: magnetic resonance spectroscopy; OXT: oxytocin; KYNA: kynurenic acid; QUIN: quinolinic acid; Cort: corticosterone; PFC: prefrontal cortex; AMY: amygdala; HIPP: hippocampus. Full article ">

18 pages, 1456 KiB

Open AccessReview

(R)-(-)-Ketamine: The Promise of a Novel Treatment for Psychiatric and Neurological Disorders

by Hana Shafique, Julie C. Demers, Julia Biesiada, Lalit K. Golani, Rok Cerne, Jodi L. Smith, Marta Szostak and Jeffrey M. Witkin

Int. J. Mol. Sci. 2024, 25(12), 6804; https://doi.org/10.3390/ijms25126804 - 20 Jun 2024

Cited by 6 | Viewed by 1900

Abstract

NMDA receptor antagonists have potential for therapeutics in neurological and psychiatric diseases, including neurodegenerative diseases, epilepsy, traumatic brain injury, substance abuse disorder (SUD), and major depressive disorder (MDD). (S)-ketamine was the first of a novel class of antidepressants, rapid-acting antidepressants, to be approved for medical use. The stereoisomer, (R)-ketamine (arketamine), is currently under development for treatment-resistant depression (TRD). The compound has demonstrated efficacy in multiple animal models. Two clinical studies disclosed efficacy in TRD and bipolar depression. A study by the drug sponsor recently failed to reach a priori clinical endpoints but post hoc analysis revealed efficacy. The clinical value of (R)-ketamine is supported by experimental data in humans and rodents, showing that it is less sedating, does not produce marked psychotomimetic or dissociative effects, has less abuse potential than (S)-ketamine, and produces efficacy in animal models of a range of neurological and psychiatric disorders. The mechanisms of action of the antidepressant effects of (R)-ketamine are hypothesized to be due to NMDA receptor antagonism and/or non-NMDA receptor mechanisms. We suggest that further clinical experimentation with (R)-ketamine will create novel and improved medicines for some of the neurological and psychiatric disorders that are underserved by current medications. Full article

(This article belongs to the Special Issue Stress-Related Disorders and Depression: From Molecular Basis to Therapy (2nd Edition))

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Figure 1
Structures of racemic ketamine and its (R)- and (S)-enantiomers. Full article ">Figure 2
Effects of (R)-ketamine on overall withdrawal scores in rats undergoing naloxone-precipitated withdrawal from subchronic morphine. Each bar represents the mean + SEM of data from eight rats V: vehicle; Nal: naloxone; R-ket: R-ketamine; ** p < 0.01, *** p < 0.001 compared to mor + nal group by Newman–Keuls multiple comparison test. Figure is modified from [<a href="#B54-ijms-25-06804" class="html-bibr">54</a>] with permission. Full article ">Figure 3
(R)-ketamine (10 and 20 mg/kg) blocks the conditioned place preference engendered by 5 mg/kg morphine. * p < 0.05 compared to vehicle + morphine treatment by Dunnett’s test. Each bar represents the mean + SEM of data from 9 to 13 mice/group. Figure is modified from [<a href="#B54-ijms-25-06804" class="html-bibr">54</a>] with permission. Full article ">Figure 4
Frequency-rate response curves for the effects of (R)-ketamine (left panel) or (S)-ketamine (right panel) in rats responding under a schedule of electrical stimulation of the medial forebrain bundle (intracranial self-stimulation). Values represent the mean normalized response rate (% of maximum control responding) across 10 frequency presentations (1.75–2.20 log/Hz) of 10 rats. Error bars are omitted for clarity. Significant differences compared to vehicle at the respective frequencies are denoted by asterisks (* p < 0.05; **** p < 0.0001; N = 10). Data are from [<a href="#B54-ijms-25-06804" class="html-bibr">54</a>] with permission. Full article ">Figure 5
(R)-ketamine did not fully substitute for the training dose of (S)-ketamine in (S)-ketamine-trained rats. Ns for vehicle and (S)-ketamine were eight, whereas eight rats were tested with (R)-ketamine (17.5 mg/kg). Symbols: * p < 0.05, *** p < 0.001 vs. vehicle, ### p < 0.001 vs. training dose of (S)-ketamine. Dotted lines represent 25 and 75% accuracy. Data are from [<a href="#B76-ijms-25-06804" class="html-bibr">76</a>] with permission. Full article ">Figure 6
(R)-ketamine at 10 and 20 mg/kg does not induce a conditioned place preference when given alone (+vehicle). Each bar represents the mean + SEM of data from 10 mice/group. Veh: vehicle or saline; R-ket: (R)-ketamine. Data are from [<a href="#B54-ijms-25-06804" class="html-bibr">54</a>] with permission. Full article ">

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