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The Role of Neurons in Human Health and Disease 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 (30 June 2024) | Viewed by 34394

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Dr. Yasemin M. Akay

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Department of Biomedical Engineering, University of Houston, Houston, TX 77204-5060, USA
Interests: coronary artery disease; stent; noninvasive monitoring; nonlinear dynamics analysis; approximate entropy; 3D co-culture; glioblastoma; astrocytes; tumor microenvironment; PEGDA; addiction; cancer research; data science in medicine
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Dear Colleagues,

The brain is the central regulator of the organism, responsible for maintaining homeostasis. Neurons are the most critical components of the central and peripheral nervous systems. The immune system protects us from all possible threats that could endanger the well-being of a human body. A strong immune system or a weakened one could make all the differences between the healthy and diseased conditions of a human body. The nervous and immune systems are both crucial for the survival of the human beings. The nervous system affects the activity of the immune system due to its unique anatomical structure and function. The brain can directly regulate the function of the most physiological systems. Neuronal regulation can improve the conditions under which the immune system works by synchronizing its activity with other physiological functions. The brain has the ability to perceive and evaluate the threats before they physically affect the organism. This predictive capacity also helps the immune system prepare for a possible danger in advance and could induce a more effective and faster response. One of the most prominent differences between the nervous and the immune systems is their speed of reaction. The nervous system can react within milliseconds, whereas immunological responses often require from several minutes up to weeks to develop. Although a slower immune reaction is mostly sufficient, a faster response can be beneficial in some cases. In this Special Issue, we focus mainly on how the brain and the nervous system affect immunity, specifically peripheral immunity, and how they play an essential role in human health and disease.

Dr. Yasemin M. Akay
Guest Editor

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Keywords

brain
nervous system
neurons
immune system
human health and disease

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The Role of Neurons in Human Health and Disease—3rd Edition in International Journal of Molecular Sciences (2 articles)

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10 pages, 16273 KiB

Open AccessArticle

Cell-Type-Specific Expression of Leptin Receptors in the Mouse Forebrain

by Cade R. Canepa, John A. Kara and Charles C. Lee

Int. J. Mol. Sci. 2024, 25(18), 9854; https://doi.org/10.3390/ijms25189854 - 12 Sep 2024

Cited by 2 | Viewed by 1231

Abstract

Leptin is a hormone produced by the small intestines and adipose tissue that promotes feelings of satiety. Leptin receptors (LepRs) are highly expressed in the hypothalamus, enabling central neural control of hunger. Interestingly, LepRs are also expressed in several other regions of the body and brain, notably in the cerebral cortex and hippocampus. These brain regions mediate higher-order sensory, motor, cognitive, and memory functions, which can be profoundly altered during periods of hunger and satiety. However, LepR expression in these regions has not been fully characterized on a cell-type-specific basis, which is necessary to begin assessing their potential functional impact. Consequently, we examined LepR expression on neurons and glia in the forebrain using a LepR-Cre transgenic mouse model. LepR-positive cells were identified using a ‘floxed’ viral cell-filling approach and co-labeling immunohistochemically for cell-type-specific markers, i.e., NeuN, VGlut2, GAD67, parvalbumin, somatostatin, 5-HT3R, WFA, S100β, and GFAP. In the cortex, LepR-positive cells were localized to lower layers (primarily layer 6) and exhibited non-pyramidal cellular morphologies. The majority of cortical LepR-positive cells were neurons, while the remainder were identified primarily as astrocytes or other glial cells. The majority of cortical LepR-positive neurons co-expressed parvalbumin, while none expressed somatostatin or 5-HT3R. In contrast, all hippocampal LepR-positive cells were neuronal, with none co-expressing GFAP. These data suggest that leptin can potentially influence neural processing in forebrain regions associated with sensation and limbic-related functions. Full article

(This article belongs to the Special Issue The Role of Neurons in Human Health and Disease 2.0)

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14 pages, 2454 KiB

Open AccessArticle

Exposure to Radiofrequency Induces Synaptic Dysfunction in Cortical Neurons Causing Learning and Memory Alteration in Early Postnatal Mice

by Ju Hwan Kim, Jun Young Seok, Yun-Hee Kim, Hee Jung Kim, Jin-Koo Lee and Hak Rim Kim

Int. J. Mol. Sci. 2024, 25(16), 8589; https://doi.org/10.3390/ijms25168589 - 6 Aug 2024

Cited by 1 | Viewed by 1519

Abstract

The widespread use of wireless communication devices has necessitated unavoidable exposure to radiofrequency electromagnetic fields (RF-EMF). In particular, increasing RF-EMF exposure among children is primarily driven by mobile phone use. Therefore, this study investigated the effects of 1850 MHz RF-EMF exposure at a specific absorption rate of 4.0 W/kg on cortical neurons in mice at postnatal day 28. The results indicated a significant reduction in the number of mushroom-shaped dendritic spines in the prefrontal cortex after daily exposure for 4 weeks. Additionally, prolonged RF-EMF exposure over 9 days led to a gradual decrease in postsynaptic density 95 puncta and inhibited neurite outgrowth in developing cortical neurons. Moreover, the expression levels of genes associated with synapse formation, such as synaptic cell adhesion molecules and cyclin-dependent kinase 5, were reduced in the cerebral cortexes of RF-EMF-exposed mice. Behavioral assessments using the Morris water maze revealed altered spatial learning and memory after the 4-week exposure period. These findings underscore the potential of RF-EMF exposure during childhood to disrupt synaptic function in the cerebral cortex, thereby affecting the developmental stages of the nervous system and potentially influencing later cognitive function. Full article

(This article belongs to the Special Issue The Role of Neurons in Human Health and Disease 2.0)

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28 pages, 3095 KiB

Open AccessArticle

Differential Roles of Key Brain Regions: Ventral Tegmental Area, Locus Coeruleus, Dorsal Raphe, Nucleus Accumbens, Caudate Nucleus, and Prefrontal Cortex in Regulating Response to Methylphenidate: Insights from Neuronal and Behavioral Studies in Freely Behaving Rats

by Nachum Dafny, Catherine Claussen, Emilee Frazier and Yin Liu

Int. J. Mol. Sci. 2024, 25(11), 5938; https://doi.org/10.3390/ijms25115938 - 29 May 2024

Viewed by 1299

Abstract

A total of 3102 neurons were recorded before and following acute and chronic methylphenidate (MPD) administration. Acute MPD exposure elicits mainly increases in neuronal and behavioral activity in dose–response characteristics. The response to chronic MPD exposure, as compared to acute 0.6, 2.5, or 10.0 mg/kg MPD administration, elicits electrophysiological and behavioral sensitization in some animals and electrophysiological and behavioral tolerance in others when the neuronal recording evaluations were performed based on the animals’ behavioral responses, or amount of locomotor activity, to chronic MPD exposure. The majority of neurons recorded from those expressing behavioral sensitization responded to chronic MPD with further increases in firing rate as compared to the initial MPD responses. The majority of neurons recorded from animals expressing behavioral tolerance responded to chronic MPD with decreases in their firing rate as compared to the initial MPD exposures. Each of the six brain areas studied—the ventral tegmental area, locus coeruleus, dorsal raphe, nucleus accumbens, prefrontal cortex, and caudate nucleus (VTA, LC, DR, NAc, PFC, and CN)—responds significantly (p < 0.001) differently to MPD, suggesting that each one of the above brain areas exhibits different roles in the response to MPD. Moreover, this study demonstrates that it is essential to evaluate neuronal activity responses to psychostimulants based on the animals’ behavioral responses to acute and chronic effects of the drug from several brain areas simultaneously to obtain accurate information on each area’s role in response to the drug. Full article

(This article belongs to the Special Issue The Role of Neurons in Human Health and Disease 2.0)

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14 pages, 5215 KiB

Open AccessArticle

Disruption of Intranasal GnRH Neuronal Migration Route into the Brain Induced by Proinflammatory Cytokine IL-6: Ex Vivo and In Vivo Rodent Models

by Viktoria Sharova, Vasilina Ignatiuk, Marina Izvolskaia and Liudmila Zakharova

Int. J. Mol. Sci. 2023, 24(21), 15983; https://doi.org/10.3390/ijms242115983 - 5 Nov 2023

Cited by 1 | Viewed by 1582

Abstract

Maternal immune activation results in altered levels of cytokines in the maternal–fetal system, which has a negative impact on fetal development, including the gonadotropin-releasing hormone (GnRH) system, which is crucial for the reproduction. Suppression of GnRH–neuron migration may be associated with cytokine imbalances, and primarily with proinflammatory cytokine interleukin (IL)-6. This study aimed to determine the effects of IL-6 and monoclonal antibody to IL-6 or IL-6R or polyclonal IgG on the formation of migration route of GnRH–neurons in ex vivo and in vivo rodent models on day 11.5 of embryonic development. The increased level of IL-6 in mouse nasal explants suppressed peripherin-positive fiber outgrowth, while this led to an increase in the number of GnRH–neurons in the nose and olfactory bulbs and a decrease in their number in the fetal brain. This effect is likely to be realized via IL-6 receptors along the olfactory nerves. The suppressive effect of IL-6 was diminished by monoclonal antibodies to IL-6 or its receptors and by IgG. Full article

(This article belongs to the Special Issue The Role of Neurons in Human Health and Disease 2.0)

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14 pages, 2467 KiB

Open AccessArticle

Neurotrophin Analog ENT-A044 Activates the p75 Neurotrophin Receptor, Regulating Neuronal Survival in a Cell Context-Dependent Manner

by Maria Anna Papadopoulou, Thanasis Rogdakis, Despoina Charou, Maria Peteinareli, Katerina Ntarntani, Achille Gravanis, Konstantina Chanoumidou and Ioannis Charalampopoulos

Int. J. Mol. Sci. 2023, 24(14), 11683; https://doi.org/10.3390/ijms241411683 - 20 Jul 2023

Cited by 1 | Viewed by 1880

Abstract

Neuronal cell fate is predominantly controlled based on the effects of growth factors, such as neurotrophins, and the activation of a variety of signaling pathways acting through neurotrophin receptors, namely Trk and p75 (p75NTR). Despite their beneficial effects on brain function, their therapeutic use is compromised due to their polypeptidic nature and blood–brain-barrier impermeability. To overcome these limitations, our previous studies have proven that DHEA-derived synthetic analogs can act like neurotrophins, as they lack endocrine side effects. The present study focuses on the biological characterization of a newly synthesized analog, ENT-A044, and its role in inducing cell-specific functions of p75NTR. We show that ENT-A044 can induce cell death and phosphorylation of JNK protein by activating p75NTR. Additionally, ENT-A044 can induce the phosphorylation of TrkB receptor, indicating that our molecule can activate both neurotrophin receptors, enabling the protection of neuronal populations that express both receptors. Furthermore, the present study demonstrates, for the first time, the expression of p75NTR in human-induced Pluripotent Stem Cells-derived Neural Progenitor Cells (hiPSC-derived NPCs) and receptor-dependent cell death induced via ENT-A044 treatment. In conclusion, ENT-A044 is proposed as a lead molecule for the development of novel pharmacological agents, providing new therapeutic approaches and research tools, by controlling p75NTR actions. Full article

(This article belongs to the Special Issue The Role of Neurons in Human Health and Disease 2.0)

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16 pages, 3762 KiB

Open AccessArticle

Sugar Beverage Habitation Relieves Chronic Stress-Induced Anxiety-like Behavior but Elicits Compulsive Eating Phenotype via vLS^GAD2 Neurons

by Dan Liu, Haohao Hu, Yuchuan Hong, Qian Xiao and Jie Tu

Int. J. Mol. Sci. 2023, 24(1), 661; https://doi.org/10.3390/ijms24010661 - 30 Dec 2022

Cited by 2 | Viewed by 3856

Abstract

Chronically stressed individuals are reported to overconsume tasty, palatable foods like sucrose to blunt the psychological and physiological impacts of stress. Negative consequences of high-sugar intake on feeding behavior include increased metabolic disease burdens like obesity. However, the neural basis underlying long-term high-sugar intake-induced overeating during stress is not fully understood. To investigate this question, we used the two-bottle sucrose choice paradigm in mice exposed to chronic unpredictable mild stressors (CUMS) that mimic those of daily life stressors. After 21 days of CUMS paralleled by consecutive sucrose drinking, we explored anxiety-like behavior using the elevated plus maze and open field tests. The normal water-drinking stressed mice displayed more anxiety than the sucrose-drinking stressed mice. Although sucrose-drinking displayed anxiolytic effects, the sucrose-drinking mice exhibited binge eating (chow) and a compulsive eating phenotype. The sucrose-drinking mice also showed a significant body-weight gain compared to the water-drinking control mice during stress. We further found that c-Fos expression was significantly increased in the ventral part of the lateral septum (vLS) of the sucrose-treated stressed mice after compulsive eating. Pharmacogenetic activation of the vLS glutamate decarboxylase 2(GAD2) neurons maintained plain chow intake but induced a compulsive eating phenotype in the naïve GAD2-Cre mice when mice feeding was challenged by flash stimulus, mimicking the negative consequences of excessive sucrose drinking during chronic stress. Further, pharmacogenetic activation of the vLS^GAD2 neurons aggravated anxiety of the stressed GAD2-Cre mice but did not alter the basal anxiety level of the naïve ones. These findings indicate the GABAergic neurons within the vLS may be a potential intervention target for anxiety comorbid eating disorders during stress. Full article

(This article belongs to the Special Issue The Role of Neurons in Human Health and Disease 2.0)

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25 pages, 13380 KiB

Open AccessArticle

Novel Small Molecule Positive Allosteric Modulator SPAM1 Triggers the Nuclear Translocation of PAC1-R to Exert Neuroprotective Effects through Neuron-Restrictive Silencer Factor

by Guangchun Fan, Shang Chen, Lili Liang, Huahua Zhang and Rongjie Yu

Int. J. Mol. Sci. 2022, 23(24), 15996; https://doi.org/10.3390/ijms232415996 - 15 Dec 2022

Cited by 3 | Viewed by 2307

Abstract

The neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) exerts effective neuroprotective activity through its specific receptor, PAC1-R. We accidentally discovered that as a positive allosteric modulator (PAM) of PAC1-R, the small-molecule PAM (SPAM1) has a hydrazide-like structure, but different binding characteristics, from hydrazide for the N-terminal extracellular domain of PAC1-R (PAC1-R-EC1). SPAM1 had a significant neuroprotective effect against oxidative stress, both in a cell model treated with hydrogen peroxide (H₂O₂) and an aging mouse model induced by D-galactose (D-gal). SPAM1 was found to block the decrease in PACAP levels in brain tissues induced by D-gal and significantly induced the nuclear translocation of PAC1-R in PAC1R-CHO cells and mouse retinal ganglion cells. Nuclear PAC1-R was subjected to fragmentation and the nuclear 35 kDa, but not the 15 kDa fragments, of PAC1-R interacted with SP1 to upregulate the expression of Huntingtin (Htt), which then exerted a neuroprotective effect by attenuating the binding availability of the neuron-restrictive silencer factor (NRSF) to the neuron-restrictive silencer element (NRSE). This resulted in an upregulation of the expression of NRSF-related neuropeptides, including PACAP, the brain-derived neurotrophic factor (BDNF), tyrosine hydroxylase (TH), and synapsin-1 (SYN1). The novel mechanism reported in this study indicates that SPAM1 has potential use as a drug, as it exerts a neuroprotective effect by regulating NRSF. Full article

(This article belongs to the Special Issue The Role of Neurons in Human Health and Disease 2.0)

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Review

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21 pages, 4225 KiB

Open AccessReview

Histone Deacetylases in Retinoblastoma

by Malwina Lisek, Julia Tomczak, Julia Swiatek, Aleksandra Kaluza and Tomasz Boczek

Int. J. Mol. Sci. 2024, 25(13), 6910; https://doi.org/10.3390/ijms25136910 - 24 Jun 2024

Viewed by 1948

Abstract

Retinoblastoma, a pediatric ocular malignancy, presents significant challenges in comprehending its molecular underpinnings and targeted therapeutic approaches. The dysregulated activity of histone deacetylases (HDACs) has been associated with retinoblastoma pathogenesis, influencing critical cellular processes like cell cycle regulation or retinal ganglion cell apoptosis. Through their deacetylase activity, HDACs exert control over key tumor suppressors and oncogenes, influencing the delicate equilibrium between proliferation and cell death. Furthermore, the interplay between HDACs and the retinoblastoma protein pathway, a pivotal aspect of retinoblastoma etiology, reveals a complex network of interactions influencing the tumor microenvironment. The examination of HDAC inhibitors, encompassing both established and novel compounds, offers insights into potential approaches to restore acetylation balance and impede retinoblastoma progression. Moreover, the identification of specific HDAC isoforms exhibiting varying expression in retinoblastoma provides avenues for personalized therapeutic strategies, allowing for interventions tailored to individual patient profiles. This review focuses on the intricate interrelationship between HDACs and retinoblastoma, shedding light on epigenetic mechanisms that control tumor development and progression. The exploration of HDAC-targeted therapies underscores the potential for innovative treatment modalities in the pursuit of more efficacious and personalized management strategies for this disease. Full article

(This article belongs to the Special Issue The Role of Neurons in Human Health and Disease 2.0)

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22 pages, 2269 KiB

Open AccessReview

Targeting Progranulin as an Immuno-Neurology Therapeutic Approach

by Maria A. Boylan, Andrew Pincetic, Gary Romano, Nadine Tatton, Sara Kenkare-Mitra and Arnon Rosenthal

Int. J. Mol. Sci. 2023, 24(21), 15946; https://doi.org/10.3390/ijms242115946 - 3 Nov 2023

Cited by 5 | Viewed by 5133

Abstract

Immuno-neurology is an emerging therapeutic strategy for dementia and neurodegeneration designed to address immune surveillance failure in the brain. Microglia, as central nervous system (CNS)-resident myeloid cells, routinely perform surveillance of the brain and support neuronal function. Loss-of-function (LOF) mutations causing decreased levels of progranulin (PGRN), an immune regulatory protein, lead to dysfunctional microglia and are associated with multiple neurodegenerative diseases, including frontotemporal dementia caused by the progranulin gene (GRN) mutation (FTD-GRN), Alzheimer’s disease (AD), Parkinson’s disease (PD), limbic-predominant age-related transactivation response deoxyribonucleic acid binding protein 43 (TDP-43) encephalopathy (LATE), and amyotrophic lateral sclerosis (ALS). Immuno-neurology targets immune checkpoint-like proteins, offering the potential to convert aging and dysfunctional microglia into disease-fighting cells that counteract multiple disease pathologies, clear misfolded proteins and debris, promote myelin and synapse repair, optimize neuronal function, support astrocytes and oligodendrocytes, and maintain brain vasculature. Several clinical trials are underway to elevate PGRN levels as one strategy to modulate the function of microglia and counteract neurodegenerative changes associated with various disease states. If successful, these and other immuno-neurology drugs have the potential to revolutionize the treatment of neurodegenerative disorders by harnessing the brain’s immune system and shifting it from an inflammatory/pathological state to an enhanced physiological/homeostatic state. Full article

(This article belongs to the Special Issue The Role of Neurons in Human Health and Disease 2.0)

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20 pages, 1809 KiB

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Neurons, Nose, and Neurodegenerative Diseases: Olfactory Function and Cognitive Impairment

by Irene Fatuzzo, Giovanni Francesco Niccolini, Federica Zoccali, Luca Cavalcanti, Mario Giuseppe Bellizzi, Gabriele Riccardi, Marco de Vincentiis, Marco Fiore, Carla Petrella, Antonio Minni and Christian Barbato

Int. J. Mol. Sci. 2023, 24(3), 2117; https://doi.org/10.3390/ijms24032117 - 20 Jan 2023

Cited by 42 | Viewed by 11561

Abstract

Olfactory capacity declines with aging, but increasing evidence shows that smell dysfunction is one of the early signs of prodromal neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease. The study of olfactory ability and its role in neurodegenerative diseases arouses much interest in the scientific community. In neurology, olfactory impairment is a potential early marker for the onset of neurodegenerative diseases, but the underlying mechanism is poorly understood. The loss of smell is considered a clinical sign of early-stage disease and a marker of the disease’s progression and cognitive impairment. Highlighting the importance of biological bases of smell and molecular pathways could be fundamental to improve neuroprotective and therapeutic strategies. We focused on the review articles and meta-analyses on olfactory and cognitive impairment. We depicted the neurobiology of olfaction and the most common olfactory tests in neurodegenerative diseases. In addition, we underlined the close relationship between the olfactory and cognitive deficit due to nasal neuroepithelium, which is a direct extension of the CNS in communication with the external environment. Neurons, Nose, and Neurodegenerative diseases highlights the role of olfactory dysfunction as a clinical marker for early stages of neurodegenerative diseases when it is associated with molecular, clinical, and neuropathological correlations. Full article

(This article belongs to the Special Issue The Role of Neurons in Human Health and Disease 2.0)

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