Neurobiology of Depression: Molecular and Cellular Mechanisms

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cells of the Nervous System".

Deadline for manuscript submissions: closed (31 December 2022) | Viewed by 30466

Special Issue Editors

Jagiellonian University, Krakow, Poland
Interests: stress; stress resilience; depression; miRNA; GPCR dimerization; preclinical studies Recent photo:
Department of Pharmacology, Maj Institute of Pharmacology, Polish Academy of Sciences, 31-343 Kraków, Poland
Interests: depression; treatment resistance; transmembrane receptors; dimerization; neuropeptides; animal models
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Special Issue Information

Dear Colleagues,

Neurobiology aims at understanding the brain activity via elucidation of mechanisms underlying means of mutual communication by billions of neuronal cells and other cells building the brain, orchestrating a coherent response to external stimuli. Neurobiology also aims at the elucidation of a biological basis of consciousness and psychological processes, which allow human beings to understand the surrounding world, to act, to learn, and to remember.

This Special Issue of Cells is dedicated to the neurobiology of depression, the disease which disturbs the understanding of the surrounding world by a depressed person. According to WHO, depression in 2030 will be the main reason of withdrawal from social and productive life. Despite decades of research and a plethora of various data obtained, we are still far from understanding the neurobiological basis of depression.

Great technological progress has produced new possibilities in the field of neurobiology. Genome-wide association studies (GWAS) and other high throughput approaches have become available, and new levels of gene expression regulation, like epigenetics or microRNAs, are being used in neurobiological studies. Animal models used in preclinical studies have become more advanced, e.g., using deep brain stimulation, sleep deprivation, or vagal nerve stimulation, followed by a modern biochemical and molecular approach, has helped us to get closer to understanding the drug-resistant forms of depression.

However, we are still far from the main goal, i.e., a full understanding of depression pathogenesis and efficient therapy. Even if we have ketamine—the discovery of its fast antidepressant effect has been a great achievement in itself—we do not know the actual mechanism underlying its beneficial action.

We are strongly convinced that new studies of depression and mechanism of action of antidepressant drugs are urgent. Therefore, we invite and encourage all authors who are in possession of interesting data to contribute original research to the Special Issue of Cells, or a review article. Help us make this Special Issue of Cells a breakthrough in the search for the molecular and cellular causes of depression.

We are looking forward to your contributions to this Special Issue.

Prof. Dr. Marta Dziedzicka-Wasylewska
Dr. Agata Faron-Górecka
Guest Editors

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Keywords

  • depression
  • treatment resistance
  • molecular and cellular mechanism
  • antidepressant drugs

Published Papers (9 papers)

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Research

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16 pages, 4892 KiB  
Article
Long-Term Hyperglycemia Causes Depressive Behaviors in Mice with Hypoactive Glutamatergic Activity in the Medial Prefrontal Cortex, Which Is Not Reversed by Insulin Treatment
by Ji Hyeong Baek, Hyeonwi Son, Jae Soon Kang, Dae Young Yoo, Hye Jin Chung, Dong Kun Lee and Hyun Joon Kim
Cells 2022, 11(24), 4012; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11244012 - 12 Dec 2022
Cited by 2 | Viewed by 1491
Abstract
The etiology of hyperglycemic-induced depressive behaviors is unclear. We hypothesized that long-term hyperglycemia may induce long-lasting disturbances in glutamatergic signaling and neural damages, causing depressive behaviors. To prove our hypothesis, a C57BL/6N mouse model of hyperglycemia was maintained for 4 weeks (equivalent to [...] Read more.
The etiology of hyperglycemic-induced depressive behaviors is unclear. We hypothesized that long-term hyperglycemia may induce long-lasting disturbances in glutamatergic signaling and neural damages, causing depressive behaviors. To prove our hypothesis, a C57BL/6N mouse model of hyperglycemia was maintained for 4 weeks (equivalent to approximately 3 years in humans), after which insulin treatment was administered for an additional 4 weeks to normalize hyperglycemia-induced changes. Hyperglycemic mice showed depressive-like behaviors. Glutamatergic neurons and glial cells in the medial prefrontal cortex (mPFC) were affected by hyperglycemia. Insulin treatment improved blood glucose, water intake, and food intake to normoglycemic levels, but did not improve depressive-like behaviors. Glutamatergic signaling decreased with long-term hyperglycemia and did not normalize with insulin-induced normoglycemia. Importantly, hyperglycemia-induced changes in the mPFC were almost not reversed by the 4-week insulin treatment. In particular, levels of insulin receptor beta subunit (IRβ), IRS-1, vesicular glutamate transporter 1, glutamine transporter SNAT2, phosphate-activated glutaminase, and GLUT-3 were not changed by insulin. Nitration and the dephosphorylation of IRβ in the PFC also did not improve with insulin treatment. Therefore, our results suggest that hypoactive glutamatergic activity in the mPFC is involved in diabetic-associated depressive behaviors, and it is difficult to cure with glycemic regulation alone. Full article
(This article belongs to the Special Issue Neurobiology of Depression: Molecular and Cellular Mechanisms)
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13 pages, 2962 KiB  
Article
Dihydromyricetin Attenuates Depressive-like Behaviors in Mice by Inhibiting the AGE-RAGE Signaling Pathway
by Jun Huang, Bin Chen, Hao Wang, Sheng Hu, Xudong Yu, James Reilly, Zhiming He, Yong You and Xinhua Shu
Cells 2022, 11(23), 3730; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11233730 - 22 Nov 2022
Cited by 1 | Viewed by 1649
Abstract
Depression is a complex mental disorder, affecting approximately 280 million individuals globally. The pathobiology of depression is not fully understood, and the development of new treatments is urgently needed. Dihydromyricetin (DHM) is a natural flavanone, mainly distributed in Ampelopsis grossedentata. DHM has demonstrated [...] Read more.
Depression is a complex mental disorder, affecting approximately 280 million individuals globally. The pathobiology of depression is not fully understood, and the development of new treatments is urgently needed. Dihydromyricetin (DHM) is a natural flavanone, mainly distributed in Ampelopsis grossedentata. DHM has demonstrated a protective role against cardiovascular disease, diabetes, liver disease, cancer, kidney injury and neurodegenerative disorders. In the present study, we examined the protective effect of DHM against depression in a chronic depression mouse model induced by corticosterone (CORT). Animals exposed to CORT displayed depressive-like behaviors; DHM treatment reversed these behaviors. Network pharmacology analyses showed that DHM’s function against depression involved a wide range of targets and signaling pathways, among which the inflammation-linked targets and signaling pathways were critical. Western blotting showed that CORT-treated animals had significantly increased levels of the advanced glycation end product (AGE) and receptor of AGE (RAGE) in the hippocampus, implicating activation of the AGE-RAGE signaling pathway. Furthermore, enzyme-linked immunosorbent assay (ELISA) detected a marked increase in the production of proinflammatory cytokines, interleukin-1 beta (IL-1β), IL-6 and tumor necrosis factor-alpha (TNFα) in the hippocampus of CORT-treated mice. DHM administration significantly counteracted these CORT-induced changes. These findings suggest that protection against depression by DHM is mediated by suppression of neuroinflammation, predominantly via the AGE-RAGE signaling pathway. Full article
(This article belongs to the Special Issue Neurobiology of Depression: Molecular and Cellular Mechanisms)
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14 pages, 3943 KiB  
Article
P-Coumaric Acid Reverses Depression-Like Behavior and Memory Deficit Via Inhibiting AGE-RAGE-Mediated Neuroinflammation
by Xu-Dong Yu, Dan Zhang, Chu-Li Xiao, Yu Zhou, Xing Li, Le Wang, Zhiming He, James Reilly, Zhi-Yong Xiao and Xinhua Shu
Cells 2022, 11(10), 1594; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11101594 - 10 May 2022
Cited by 13 | Viewed by 2465
Abstract
Depression, a mood disorder, affects one in fifteen adults, has multiple risk factors and is associated with complicated underlying pathological mechanisms. P-coumaric acid (p-CA), a phenolic acid, is widely distributed in vegetables, fruits and mushrooms. P-CA has demonstrated a protective role against oxidative [...] Read more.
Depression, a mood disorder, affects one in fifteen adults, has multiple risk factors and is associated with complicated underlying pathological mechanisms. P-coumaric acid (p-CA), a phenolic acid, is widely distributed in vegetables, fruits and mushrooms. P-CA has demonstrated a protective role against oxidative stress and inflammation in various diseases, including cardiovascular disease, diabetes and cancer. In the current study, we investigated the protection of p-CA against depression and memory impairment in a corticosterone (CORT)-induced chronic depressive mouse model. CORT administration resulted in depression-like behaviors and memory impairment. P-CA treatment alleviated CORT-induced depression-related behaviors and memory impairment. Network pharmacology predicted that p-CA had multiple targets and mediated various signaling pathways, of which inflammation-associated targets and signaling pathways are predominant. Western blotting showed CORT-induced activation of the advanced glycation end product (AGE)-receptor of AGE (RAGE) (AGE-RAGE) signaling and increased expression of the proinflammatory cytokines interleukin-1 beta (IL-1β) and tumor necrosis factor-alpha (TNFα) in the hippocampus, while p-CA treatment inactivated AGE-RAGE signaling and decreased the levels of IL-1β and TNFα, suggesting that protection against depression and memory impairment by p-CA is mediated by the inhibition of inflammation, mainly via the AGE-RAGE signaling pathway. Our data suggest that p-CA treatment will benefit patients with depression. Full article
(This article belongs to the Special Issue Neurobiology of Depression: Molecular and Cellular Mechanisms)
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Review

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20 pages, 693 KiB  
Review
Understanding the Links among Maternal Diet, Myelination, and Depression: Preclinical and Clinical Overview
by Irena Smaga
Cells 2022, 11(3), 540; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11030540 - 04 Feb 2022
Cited by 4 | Viewed by 2621
Abstract
Depression is one of the most common mental disorders in the general population, and multiple mechanisms are involved in the etiology of this disease, including myelination. According to the Developmental Origins of Health and Disease (DOHaD) hypothesis, maternal diet affects the lifetime of [...] Read more.
Depression is one of the most common mental disorders in the general population, and multiple mechanisms are involved in the etiology of this disease, including myelination. According to the Developmental Origins of Health and Disease (DOHaD) hypothesis, maternal diet affects the lifetime of the individual during adulthood and may contribute to the development of neuropsychiatric disorders. Additionally, the intensive processes of myelination contribute to the development of the central nervous system in the perinatal period, while any alterations during this crucial process providing the physiological functioning of neurons may lead to neuropsychiatric disorders in the next generation. The present review summarizes the current knowledge on the role of the myelin-related changes in depression, as well as the crosstalk among maternal malnutrition, myelination, and depression in preclinical and clinical settings. Full article
(This article belongs to the Special Issue Neurobiology of Depression: Molecular and Cellular Mechanisms)
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14 pages, 632 KiB  
Review
Neuromolecular Underpinnings of Negative Cognitive Bias in Depression
by Karolina Noworyta, Agata Cieslik and Rafal Rygula
Cells 2021, 10(11), 3157; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10113157 - 13 Nov 2021
Cited by 14 | Viewed by 3026
Abstract
This selective review aims to summarize the recent advances in understanding the neuromolecular underpinnings of biased cognition in depressive disorder. We begin by considering the cognitive correlates of depressed mood and the key brain systems implicated in its development. We then review the [...] Read more.
This selective review aims to summarize the recent advances in understanding the neuromolecular underpinnings of biased cognition in depressive disorder. We begin by considering the cognitive correlates of depressed mood and the key brain systems implicated in its development. We then review the core findings across two domains of biased cognitive function in depression: pessimistic judgment bias and abnormal response to negative feedback. In considering their underlying substrates, we focus on the neurochemical mechanisms identified by genetic, molecular and pharmacological challenge studies. We conclude by discussing experimental approaches to the treatment of depression, which are derived largely from an improved understanding of its cognitive substrates. Full article
(This article belongs to the Special Issue Neurobiology of Depression: Molecular and Cellular Mechanisms)
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16 pages, 852 KiB  
Review
Neurobiological Basis of Increased Risk for Suicidal Behaviour
by Aleksandra Wisłowska-Stanek, Karolina Kołosowska and Piotr Maciejak
Cells 2021, 10(10), 2519; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10102519 - 23 Sep 2021
Cited by 27 | Viewed by 4411
Abstract
According to the World Health Organization (WHO), more than 700,000 people die per year due to suicide. Suicide risk factors include a previous suicide attempt and psychiatric disorders. The highest mortality rate in suicide worldwide is due to depression. Current evidence suggests that [...] Read more.
According to the World Health Organization (WHO), more than 700,000 people die per year due to suicide. Suicide risk factors include a previous suicide attempt and psychiatric disorders. The highest mortality rate in suicide worldwide is due to depression. Current evidence suggests that suicide etiopathogenesis is associated with neuroinflammation that activates the kynurenine pathway and causes subsequent serotonin depletion and stimulation of glutamate neurotransmission. These changes are accompanied by decreased BDNF (brain-derived neurotrophic factor) levels in the brain, which is often linked to impaired neuroplasticity and cognitive deficits. Most suicidal patients have a hyperactive hypothalamus–pituitary–adrenal (HPA) axis. Epigenetic mechanisms control the above-mentioned neurobiological changes associated with suicidal behaviour. Suicide risk could be attenuated by appropriate psychological treatment, electroconvulsive treatment, and drugs: lithium, ketamine, esketamine, clozapine. In this review, we present the etiopathogenesis of suicide behaviour and explore the mechanisms of action of anti-suicidal treatments, pinpointing similarities among them. Full article
(This article belongs to the Special Issue Neurobiology of Depression: Molecular and Cellular Mechanisms)
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8 pages, 260 KiB  
Review
What Do the Animal Studies of Stress Resilience Teach Us?
by Marta Dziedzicka-Wasylewska, Joanna Solich, Agata Korlatowicz and Agata Faron-Górecka
Cells 2021, 10(7), 1630; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10071630 - 29 Jun 2021
Cited by 9 | Viewed by 2765
Abstract
Long-lasting stress factors, both biological and psychological, are commonly accepted as the main cause of depressive disorders. Several animal models, using various stressful stimuli, have been used to find biochemical and molecular alterations that could help us understand the etiopathogenesis of depression. However, [...] Read more.
Long-lasting stress factors, both biological and psychological, are commonly accepted as the main cause of depressive disorders. Several animal models, using various stressful stimuli, have been used to find biochemical and molecular alterations that could help us understand the etiopathogenesis of depression. However, recent sophisticated studies indicate that the most frequently used animal models of stress only capture a portion of the molecular features associated with complex human disorders. On the other hand, some of these models generate groups of animals resilient to stress. Studies of the mechanisms of stress resilience bring us closer to understanding the process of adapting to aversive stimuli and the differences between stress-susceptible vs. resilient phenotypes. Especially interesting in this context is the chronic mild stress (CMS) experimental paradigm, most often using rats. Studies using this animal model have revealed that biochemical (e.g., the dopamine D2 receptor) and molecular (e.g., microRNA) alterations are dynamic (i.e., depend on stress duration, 2 vs. 7 weeks) and much more pronounced in stress-resilient than stress-susceptible groups of animals. We strongly suggest that studies aimed at understanding the molecular and biochemical mechanisms of depression must consider these dynamics. A good candidate to serve as a biomarker in such studies might be serum microRNA, since it can be obtained relatively easily from living individuals at various time points. Full article
(This article belongs to the Special Issue Neurobiology of Depression: Molecular and Cellular Mechanisms)
29 pages, 3136 KiB  
Review
Major Depression: One Brain, One Disease, One Set of Intertwined Processes
by Elena V. Filatova, Maria I. Shadrina and Petr A. Slominsky
Cells 2021, 10(6), 1283; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10061283 - 21 May 2021
Cited by 43 | Viewed by 7234
Abstract
Major depressive disorder (MDD) is a heterogeneous disease affecting one out of five individuals and is the leading cause of disability worldwide. Presently, MDD is considered a multifactorial disease with various causes such as genetic susceptibility, stress, and other pathological processes. Multiple studies [...] Read more.
Major depressive disorder (MDD) is a heterogeneous disease affecting one out of five individuals and is the leading cause of disability worldwide. Presently, MDD is considered a multifactorial disease with various causes such as genetic susceptibility, stress, and other pathological processes. Multiple studies allowed the formulation of several theories attempting to describe the development of MDD. However, none of these hypotheses are comprehensive because none of them can explain all cases, mechanisms, and symptoms of MDD. Nevertheless, all of these theories share some common pathways, which lead us to believe that these hypotheses depict several pieces of the same big puzzle. Therefore, in this review, we provide a brief description of these theories and their strengths and weaknesses in an attempt to highlight the common mechanisms and relationships of all major theories of depression and combine them together to present the current overall picture. The analysis of all hypotheses suggests that there is interdependence between all the brain structures and various substances involved in the pathogenesis of MDD, which could be not entirely universal, but can affect all of the brain regions, to one degree or another, depending on the triggering factor, which, in turn, could explain the different subtypes of MDD. Full article
(This article belongs to the Special Issue Neurobiology of Depression: Molecular and Cellular Mechanisms)
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Other

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14 pages, 932 KiB  
Systematic Review
Kir4.1 Dysfunction in the Pathophysiology of Depression: A Systematic Review
by Stefania Della Vecchia, Maria Marchese, Filippo Maria Santorelli and Federico Sicca
Cells 2021, 10(10), 2628; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10102628 - 01 Oct 2021
Cited by 4 | Viewed by 3161
Abstract
A serotonergic dysfunction has been largely postulated as the main cause of depression, mainly due to its effective response to drugs that increase the serotonergic tone, still currently the first therapeutic line in this mood disorder. However, other dysfunctional pathomechanisms are likely involved [...] Read more.
A serotonergic dysfunction has been largely postulated as the main cause of depression, mainly due to its effective response to drugs that increase the serotonergic tone, still currently the first therapeutic line in this mood disorder. However, other dysfunctional pathomechanisms are likely involved in the disorder, and this may in part explain why some individuals with depression are resistant to serotonergic therapies. Among these, emerging evidence suggests a role for the astrocytic inward rectifier potassium channel 4.1 (Kir4.1) as an important modulator of neuronal excitability and glutamate metabolism. To discuss the relationship between Kir4.1 dysfunction and depression, a systematic review was performed according to the PRISMA statement. Searches were conducted across PubMed, Scopus, and Web of Science by two independent reviewers. Twelve studies met the inclusion criteria, analyzing Kir4.1 relationships with depression, through in vitro, in vivo, and post-mortem investigations. Increasing, yet not conclusive, evidence suggests a potential pathogenic role for Kir4.1 upregulation in depression. However, the actual contribution in the diverse subtypes of the disorder and in the comorbid conditions, for example, the epilepsy-depression comorbidity, remain elusive. Further studies are needed to better define the clinical phenotype associated with Kir4.1 dysfunction in humans and the molecular mechanisms by which it contributes to depression and implications for future treatments. Full article
(This article belongs to the Special Issue Neurobiology of Depression: Molecular and Cellular Mechanisms)
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