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Molecular Effects of Stress in the Brain: Looking for New Drug Targets for Psychopathologies

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

Deadline for manuscript submissions: closed (28 February 2023) | Viewed by 13447

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Special Issue Editor

Dr. Laura Musazzi

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Guest Editor

Department of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy
Interests: neurobiology of acute and chronic stress in animal models; mechanism of action of rapid-acting antidepressants; epigenetics of stress and antidepressant activity

Special Issue Information

Dear Colleagues,

Psychiatric disorders are a worldwide plague, with an ever-increasing prevalence and dramatic socioeconomic impact. Despite the effort of research to elucidate the mechanisms involved in the etiopathogenesis, these remain a matter of discussion. Compelling evidence from both clinical and preclinical studies has converged in highlighting the role of environmental factors in shaping the risk of developing psychopathologies. In this context, exposure to stressful events has been recognized as the main environmental player in the exacerbation of psychiatric disorders.

With this Special Issue, we aim at collecting original as well as review papers dissecting mechanisms of acute and chronic stress in neurons and brain of human subjects or animal models, together with related functional and behavioral alterations. Papers analyzing sex differences or age-dependent changes in the stress response will be particularly welcome. The Special Issue will specifically focus on the study of mechanisms which could help in the identification of new pharmacological targets for the development of innovative therapeutic strategies for the treatment of stress-related psychiatric disorders.

Dr. Laura Musazzi
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

stress
psychiatric disorder
depression
antidepressant
animal model
synaptic mechanisms
synaptic plasticity
neuronal function

Published Papers (5 papers)

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Research

Jump to: Review

14 pages, 2051 KiB

Open AccessArticle

Chronic N-Acetyl-Cysteine Treatment Enhances the Expression of the Immediate Early Gene Nr4a1 in Response to an Acute Challenge in Male Rats: Comparison with the Antidepressant Venlafaxine

by Paola Brivio, Maria Teresa Gallo, Piotr Gruca, Magdalena Lason, Ewa Litwa, Fabio Fumagalli, Mariusz Papp and Francesca Calabrese

Int. J. Mol. Sci. 2023, 24(8), 7321; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24087321 - 15 Apr 2023

Cited by 3 | Viewed by 1783

Abstract

Despite several antidepressant treatments being available in clinics, they are not effective in all patients. In recent years, N-acetylcysteine (NAC) has been explored as adjunctive therapy for many psychiatric disorders, including depression, for its antioxidant properties. Given the promising efficacy of this compound for the treatment of such pathologies, it is fundamental to investigate, at the preclinical level, the ability of the drug to act in the modulation of neuroplastic mechanisms in basal conditions and during challenging events in order to highlight the potential features of the drug useful for clinical efficacy. To this aim, adult male Wistar rats were treated with the antidepressant venlafaxine (VLX) (10 mg/kg) or NAC (300 mg/kg) for 21 days and then subjected to 1 h of acute restraint stress (ARS). We found that NAC enhanced the expression of several immediate early genes, markers of neuronal plasticity in the ventral and dorsal hippocampus, prefrontal cortex and amygdala, and in particular it mediated the acute-stress-induced upregulation of Nr4a1 expression more than VLX. These data suggested the ability of NAC to induce coping strategies to face external challenges, highlighting its potential for the improvement of neuroplastic mechanisms for the promotion of resilience, in particular via the modulation of Nr4a1. Full article

(This article belongs to the Special Issue Molecular Effects of Stress in the Brain: Looking for New Drug Targets for Psychopathologies)

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12 pages, 2053 KiB

Open AccessArticle

Involvement of miR-135a-5p Downregulation in Acute and Chronic Stress Response in the Prefrontal Cortex of Rats

by Jessica Mingardi, Caterina Paoli, Luca La Via, Giulia Carini, Paulina Misztak, Carlo Cifani, Maurizio Popoli, Alessandro Barbon and Laura Musazzi

Int. J. Mol. Sci. 2023, 24(2), 1552; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24021552 - 13 Jan 2023

Cited by 2 | Viewed by 2796

Abstract

Stress is a key risk factor in the onset of neuropsychiatric disorders. The study of the mechanisms underlying stress response is important to understand the etiopathogenetic mechanisms and identify new putative therapeutic targets. In this context, microRNAs (miRNAs) have emerged as key regulators of the complex patterns of gene/protein expression changes in the brain, where they have a crucial role in the regulation of neuroplasticity, neurogenesis, and neuronal differentiation. Among them, miR-135a-5p has been associated with stress response, synaptic plasticity, and the antidepressant effect in different brain areas. Here, we used acute unavoidable foot-shock stress (FS) and chronic mild stress (CMS) on male rats to study whether miR-135a-5p was involved in stress-induced changes in the prefrontal cortex (PFC). Both acute and chronic stress decreased miR-135a-5p levels in the PFC, although after CMS the reduction was induced only in animals vulnerable to CMS, according to a sucrose preference test. MiR-135a-5p downregulation in the primary neurons reduced dendritic spine density, while its overexpression exerted the opposite effect. Two bioinformatically predicted target genes, Kif5c and Cplx1/2, were increased in FS rats 24 h after stress. Altogether, we found that miR-135a-5p might play a role in stress response in PFC involving synaptic mechanisms. Full article

(This article belongs to the Special Issue Molecular Effects of Stress in the Brain: Looking for New Drug Targets for Psychopathologies)

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21 pages, 2053 KiB

Open AccessArticle

Diet Prevents Social Stress-Induced Maladaptive Neurobehavioural and Gut Microbiota Changes in a Histamine-Dependent Manner

by Alessia Costa, Barbara Rani, Thomaz F. S. Bastiaanssen, Francesco Bonfiglio, Eoin Gunnigle, Gustavo Provensi, Moira Rossitto, Marcus Boehme, Conall Strain, Clara S. Martínez, Patrizio Blandina, John F. Cryan, Sophie Layé, Renato Corradetti and Maria Beatrice Passani

Int. J. Mol. Sci. 2022, 23(2), 862; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23020862 - 13 Jan 2022

Cited by 5 | Viewed by 2916

Abstract

Exposure to repeated social stress may cause maladaptive emotional reactions that can be reduced by healthy nutritional supplementation. Histaminergic neurotransmission has a central role in orchestrating specific behavioural responses depending on the homeostatic state of a subject, but it remains to be established if it participates in the protective effects against the insults of chronic stress afforded by a healthy diet. By using C57BL/6J male mice that do not synthesize histamine (Hdc^−/−) and their wild type (Hdc^+/+) congeners we evaluated if the histaminergic system participates in the protective action of a diet enriched with polyunsaturated fatty acids and vitamin A on the deleterious effect of chronic stress. Behavioural tests across domains relevant to cognition and anxiety were performed. Hippocampal synaptic plasticity, cytokine expression, hippocampal fatty acids, oxylipins and microbiota composition were also assessed. Chronic stress induced social avoidance, poor recognition memory, affected hippocampal long-term potentiation, changed the microbiota profile, brain cytokines, fatty acid and oxylipins composition of both Hdc^−/− and Hdc^+/+ mice. Dietary enrichment counteracted stress-induced deficits only in Hdc^+/+ mice as histamine deficiency prevented almost all the diet-related beneficial effects. Interpretation: Our results reveal a previously unexplored and novel role for brain histamine as a mediator of many favorable effects of the enriched diet. These data present long-reaching perspectives in the field of nutritional neuropsychopharmacology. Full article

(This article belongs to the Special Issue Molecular Effects of Stress in the Brain: Looking for New Drug Targets for Psychopathologies)

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Review

Jump to: Research

21 pages, 1829 KiB

Open AccessReview

Glucocorticoid-Responsive Tissue Plasminogen Activator (tPA) and Its Inhibitor Plasminogen Activator Inhibitor-1 (PAI-1): Relevance in Stress-Related Psychiatric Disorders

by Marie Mennesson and Jean-Michel Revest

Int. J. Mol. Sci. 2023, 24(5), 4496; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24054496 - 24 Feb 2023

Viewed by 2072

Abstract

Stressful events trigger a set of complex biological responses which follow a bell-shaped pattern. Low-stress conditions have been shown to elicit beneficial effects, notably on synaptic plasticity together with an increase in cognitive processes. In contrast, overly intense stress can have deleterious behavioral effects leading to several stress-related pathologies such as anxiety, depression, substance use, obsessive-compulsive and stressor- and trauma-related disorders (e.g., post-traumatic stress disorder or PTSD in the case of traumatic events). Over a number of years, we have demonstrated that in response to stress, glucocorticoid hormones (GCs) in the hippocampus mediate a molecular shift in the balance between the expression of the tissue plasminogen activator (tPA) and its own inhibitor plasminogen activator inhibitor-1 (PAI-1) proteins. Interestingly, a shift in favor of PAI-1 was responsible for PTSD-like memory induction. In this review, after describing the biological system involving GCs, we highlight the key role of tPA/PAI-1 imbalance observed in preclinical and clinical studies associated with the emergence of stress-related pathological conditions. Thus, tPA/PAI-1 protein levels could be predictive biomarkers of the subsequent onset of stress-related disorders, and pharmacological modulation of their activity could be a potential new therapeutic approach for these debilitating conditions. Full article

(This article belongs to the Special Issue Molecular Effects of Stress in the Brain: Looking for New Drug Targets for Psychopathologies)

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17 pages, 1168 KiB

Open AccessReview

Glutamatergic and N-Acetylaspartate Metabolites in Bipolar Disorder: A Systematic Review and Meta-Analysis of Proton Magnetic Resonance Spectroscopy Studies

by Jonathan Chabert, Etienne Allauze, Bruno Pereira, Carine Chassain, Ingrid De Chazeron, Jean-Yves Rotgé, Philippe Fossati, Pierre-Michel Llorca and Ludovic Samalin

Int. J. Mol. Sci. 2022, 23(16), 8974; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23168974 - 11 Aug 2022

Cited by 5 | Viewed by 2936

Abstract

The exact neurobiological mechanisms of bipolar disorder (BD) remain unknown. However, some neurometabolites could be implicated, including Glutamate (Glu), Glutamine (Gln), Glx, and N-acetylaspartate (NAA). Proton Magnetic Resonance Spectroscopy (¹H-MRS) allows one to quantify these metabolites in the human brain. Thus, we conducted a systematic review and meta-analysis of the literature to compare their levels between BD patients and healthy controls (HC). The main inclusion criteria for inclusion were ¹H-MRS studies comparing levels of Glu, Gln, Glx, and NAA in the prefrontal cortex (PFC), anterior cingulate cortex (ACC), and hippocampi between patients with BD in clinical remission or a major depressive episode and HC. Thirty-three studies were included. NAA levels were significantly lower in the left white matter PFC (wmPFC) of depressive and remitted BD patients compared to controls and were also significantly higher in the left dorsolateral PFC (dlPFC) of depressive BD patients compared to HC. Gln levels were significantly higher in the ACC of remitted BD patients compared to in HC. The decreased levels of NAA of BD patients may be related to the alterations in neuroplasticity and synaptic plasticity found in BD patients and may explain the deep white matter hyperintensities frequently observed via magnetic resonance imagery. Full article

(This article belongs to the Special Issue Molecular Effects of Stress in the Brain: Looking for New Drug Targets for Psychopathologies)

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