Research

14 pages, 1920 KiB

Open AccessArticle

The Hypothalamus of the Beaked Whales: The Paraventricular, Supraoptic, and Suprachiasmatic Nuclei

by Simona Sacchini, Cristiano Bombardi, Manuel Arbelo and Pedro Herráez

Biology 2023, 12(10), 1319; https://doi.org/10.3390/biology12101319 - 09 Oct 2023

Viewed by 1563

The hypothalamus is the body’s control coordinating center. It is responsible for maintaining the body’s homeostasis by directly influencing the autonomic nervous system or managing hormones. Beaked whales are the longest divers among cetaceans and their brains are rarely available for study. Complete [...] Read more.

The hypothalamus is the body’s control coordinating center. It is responsible for maintaining the body’s homeostasis by directly influencing the autonomic nervous system or managing hormones. Beaked whales are the longest divers among cetaceans and their brains are rarely available for study. Complete hypothalamic samples from a female Cuvier’s beaked whale and a male Blainville’s beaked whale were processed to investigate the paraventricular (PVN) and supraoptic (SON) nuclei, using immunohistochemical staining against vasopressin. The PVN occupied the preoptic region, where it reached its maximum size, and then regressed in the anterior or suprachiasmatic region. The SON was located from the preoptic to the tuberal hypothalamic region, encompassing the optical structures. It was composed of a retrochiasmatic region (SONr), which bordered and infiltrated the optic tracts, and a principal region (SONp), positioned more medially and dorsally. A third vasopressin-positive nucleus was also detected, i.e., the suprachiasmatic nucleus (SCN), which marked the end of the SON. This is the first description of the aforementioned nuclei in beaked whales—and in any marine mammals—as well as their rostro-caudal extent and immunoreactivity. Moreover, the SCN has been recognized for the first time in any marine mammal species. Full article

(This article belongs to the Special Issue New Era in Neuroscience)

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20 pages, 3296 KiB

Open AccessArticle

Iguratimod Ameliorates the Severity of Secondary Progressive Multiple Sclerosis in Model Mice by Directly Inhibiting IL-6 Production and Th17 Cell Migration via Mitigation of Glial Inflammation

by Satoshi Nagata, Ryo Yamasaki, Ezgi Ozdemir Takase, Kotaro Iida, Mitsuru Watanabe, Katsuhisa Masaki, Marion Heleen Cathérine Wijering, Hiroo Yamaguchi, Jun-ichi Kira and Noriko Isobe

Biology 2023, 12(9), 1217; https://doi.org/10.3390/biology12091217 - 07 Sep 2023

Cited by 1 | Viewed by 1345

Abstract

We previously reported a novel secondary progressive multiple sclerosis (SPMS) model, progressive experimental autoimmune encephalomyelitis (pEAE), in oligodendroglia-specific Cx47-inducible conditional knockout (Cx47 icKO) mice. Based on our prior study showing the efficacy of iguratimod (IGU), an antirheumatic drug, for acute EAE [...] Read more.

We previously reported a novel secondary progressive multiple sclerosis (SPMS) model, progressive experimental autoimmune encephalomyelitis (pEAE), in oligodendroglia-specific Cx47-inducible conditional knockout (Cx47 icKO) mice. Based on our prior study showing the efficacy of iguratimod (IGU), an antirheumatic drug, for acute EAE treatment, we aimed to elucidate the effect of IGU on the SPMS animal model. We induced pEAE by immunizing Cx47 icKO mice with myelin oligodendrocyte glycoprotein peptide 35–55. IGU was orally administered from 17 to 50 days post-immunization. We also prepared a primary mixed glial cell culture and measured cytokine levels in the culture supernatant after stimulation with designated cytokines (IL-1α, C1q, TNF-α) and lipopolysaccharide. A migration assay was performed to evaluate the effect of IGU on the migration ability of T cells toward mixed glial cell cultures. IGU treatment ameliorated the clinical signs of pEAE, decreased the demyelinated area, and attenuated glial inflammation on immunohistochemical analysis. Additionally, IGU decreased the intrathecal IL-6 level and infiltrating Th17 cells. The migration assay revealed reduced Th17 cell migration and IL-6 levels in the culture supernatant after IGU treatment. Collectively, IGU successfully mitigated the clinical signs of pEAE by suppressing Th17 migration through inhibition of IL-6 production by proinflammatory-activated glial cells. Full article

(This article belongs to the Special Issue New Era in Neuroscience)

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22 pages, 6394 KiB

Open AccessArticle

Temozolomide, Simvastatin and Acetylshikonin Combination Induces Mitochondrial-Dependent Apoptosis in GBM Cells, Which Is Regulated by Autophagy

by Sima Hajiahmadi, Shahrokh Lorzadeh, Rosa Iranpour, Saeed Karima, Masoumeh Rajabibazl, Zahra Shahsavari and Saeid Ghavami

Biology 2023, 12(2), 302; https://doi.org/10.3390/biology12020302 - 14 Feb 2023

Cited by 8 | Viewed by 2102

Abstract

Glioblastoma multiforme (GBM) is one of the deadliest cancers. Temozolomide (TMZ) is the most common chemotherapy used for GBM patients. Recently, combination chemotherapy strategies have had more effective antitumor effects and focus on slowing down the development of chemotherapy resistance. A combination of [...] Read more.

Glioblastoma multiforme (GBM) is one of the deadliest cancers. Temozolomide (TMZ) is the most common chemotherapy used for GBM patients. Recently, combination chemotherapy strategies have had more effective antitumor effects and focus on slowing down the development of chemotherapy resistance. A combination of TMZ and cholesterol-lowering medications (statins) is currently under investigation in in vivo and clinical trials. In our current investigation, we have used a triple-combination therapy of TMZ, Simvastatin (Simva), and acetylshikonin, and investigated its apoptotic mechanism in GBM cell lines (U87 and U251). We used viability, apoptosis, reactive oxygen species, mitochondrial membrane potential (MMP), caspase-3/-7, acridine orange (AO) and immunoblotting autophagy assays. Our results showed that a TMZ/Simva/ASH combination therapy induced significantly more apoptosis compared to TMZ, Simva, ASH, and TMZ/Simva treatments in GBM cells. Apoptosis via TMZ/Simva/ASH treatment induced mitochondrial damage (increase of ROS, decrease of MMP) and caspase-3/7 activation in both GBM cell lines. Compared to all single treatments and the TMZ/Simva treatment, TMZ/Simva/ASH significantly increased positive acidic vacuole organelles. We further confirmed that the increase of AVOs during the TMZ/Simva/ASH treatment was due to the partial inhibition of autophagy flux (accumulation of LC3β-II and a decrease in p62 degradation) in GBM cells. Our investigation also showed that TMZ/Simva/ASH-induced cell death was depended on autophagy flux, as further inhibition of autophagy flux increased TMZ/Simva/ASH-induced cell death in GBM cells. Finally, our results showed that TMZ/Simva/ASH treatment potentially depends on an increase of Bax expression in GBM cells. Our current investigation might open new avenues for a more effective treatment of GBM, but further investigations are required for a better identification of the mechanisms. Full article

(This article belongs to the Special Issue New Era in Neuroscience)

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13 pages, 1917 KiB

Open AccessArticle

KDM6B Variants May Contribute to the Pathophysiology of Human Cerebral Folate Deficiency

by Xiao Han, Xuanye Cao, Robert M. Cabrera, Paula Andrea Pimienta Ramirez, Cuilian Zhang, Vincent T. Ramaekers, Richard H. Finnell and Yunping Lei

Biology 2023, 12(1), 74; https://doi.org/10.3390/biology12010074 - 31 Dec 2022

Cited by 4 | Viewed by 1685

Abstract

(1) Background: The genetic etiology of most patients with cerebral folate deficiency (CFD) remains poorly understood. KDM6B variants were reported to cause neurodevelopmental diseases; however, the association between KDM6B and CFD is unknown; (2) Methods: Exome sequencing (ES) was performed on 48 isolated [...] Read more.

(1) Background: The genetic etiology of most patients with cerebral folate deficiency (CFD) remains poorly understood. KDM6B variants were reported to cause neurodevelopmental diseases; however, the association between KDM6B and CFD is unknown; (2) Methods: Exome sequencing (ES) was performed on 48 isolated CFD cases. The effect of KDM6B variants on KDM6B protein expression, Histone H3 lysine 27 epigenetic modification and FOLR1 expression were examined in vitro. For each patient, serum FOLR1 autoantibodies were measured; (3) Results: Six KDM6B variants were identified in five CFD patients, which accounts for 10% of our CFD cohort cases. Functional experiments indicated that these KDM6B variants decreased the amount of KDM6B protein, which resulted in elevated H3K27me2, lower H3K27Ac and decreased FOLR1 protein concentrations. In addition, FOLR1 autoantibodies have been identified in serum; (4) Conclusion: Our study raises the possibility that KDM6B may be a novel CFD candidate gene in humans. Variants in KDM6B could downregulate FOLR1 gene expression, and might also predispose carriers to the development of FOLR1 autoantibodies. Full article

(This article belongs to the Special Issue New Era in Neuroscience)

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10 pages, 2686 KiB

Open AccessArticle

A Mouse Model of Neurodegeneration Induced by Blade Penetrating Stab Wound to the Hippocampus

by Bao-Dong He, Chang-Mei Liu and Zhao-Qian Teng

Biology 2022, 11(9), 1365; https://doi.org/10.3390/biology11091365 - 18 Sep 2022

Cited by 4 | Viewed by 2684

Abstract

Traumatic brain injury (TBI) is closely associated with the later development of neurodegenerative and psychiatric diseases which are still incurable. Although various animal TBI models have been generated, they usually have weaknesses in standardization, survivability and/or reproducibility. In the present study, we investigated [...] Read more.

Traumatic brain injury (TBI) is closely associated with the later development of neurodegenerative and psychiatric diseases which are still incurable. Although various animal TBI models have been generated, they usually have weaknesses in standardization, survivability and/or reproducibility. In the present study, we investigated whether applying a blade penetrating stab wound to the hippocampus would create an animal model of cognitive deficits. Open-field, Morris water maze and Barnes maze tests were used to evaluate the animal behaviors. The immunofluorescence staining of NeuN, GFAP, IBA1, and TUNEL was conducted to analyze the changes in neurons, astrocytes, and microglia, as well as cell death. Mice with a hippocampal blade stab injury (HBSI) displayed the activation of microglia and astrocytes, inflammation, neuronal apoptosis, and deficits in spatial learning and memory. These findings suggest that HBSI is an easy approach to generate a reliable in vivo model of TBI to capture hemorrhage, neuroinflammation, reactive gliosis, and neural death, as well as cognitive deficits observed in human patients. Full article

(This article belongs to the Special Issue New Era in Neuroscience)

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12 pages, 4123 KiB

Open AccessArticle

Doublecortin in the Fish Visual System, a Specific Protein of Maturing Neurons

by Laura DeOliveira-Mello, Isabel Vicente, Veronica Gonzalez-Nunez, Adrian Santos-Ledo, Almudena Velasco, Rosario Arévalo, Juan M. Lara and Andreas F. Mack

Biology 2022, 11(2), 248; https://doi.org/10.3390/biology11020248 - 06 Feb 2022

Viewed by 2431

Abstract

Doublecortin (DCX) is a microtubule associated protein, essential for correct central nervous system development and lamination in the mammalian cortex. It has been demonstrated to be expressed in developing—but not in mature—neurons. The teleost visual system is an ideal model to study mechanisms [...] Read more.

Doublecortin (DCX) is a microtubule associated protein, essential for correct central nervous system development and lamination in the mammalian cortex. It has been demonstrated to be expressed in developing—but not in mature—neurons. The teleost visual system is an ideal model to study mechanisms of adult neurogenesis due to its continuous life-long growth. Here, we report immunohistochemical, in silico, and western blot analysis to detect the DCX protein in the visual system of teleost fish. We clearly determined the expression of DCX in newly generated cells in the retina of the cichlid fish Astatotilapia burtoni, but not in the cyprinid fish Danio rerio. Here, we show that DCX is not associated with migrating cells but could be related to axonal growth. This work brings to light the high conservation of DCX sequences between different evolutionary groups, which make it an ideal marker for maturing neurons in various species. The results from different techniques corroborate the absence of DCX expression in zebrafish. In A. burtoni, DCX is very useful for identifying new neurons in the transition zone of the retina. In addition, this marker can be applied to follow axons from maturing neurons through the neural fiber layer, optic nerve head, and optic nerve. Full article

(This article belongs to the Special Issue New Era in Neuroscience)

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Review

Jump to: Research, Other

11 pages, 1330 KiB

Open AccessReview

Metabolic Reprogramming toward Aerobic Glycolysis and the Gut Microbiota Involved in the Brain Amyloid Pathology

by Toshiyuki Murai and Satoru Matsuda

Biology 2023, 12(8), 1081; https://doi.org/10.3390/biology12081081 - 03 Aug 2023

Viewed by 2499

Abstract

Alzheimer’s disease (AD) is characterized by the formation of senile plaques consisting of fibrillated amyloid-β (Aβ), dystrophic neurites, and the neurofibrillary tangles of tau. The oligomers/fibrillar Aβ damages the neurons or initiates an intracellular signaling cascade for neuronal cell death leading to Aβ [...] Read more.

Alzheimer’s disease (AD) is characterized by the formation of senile plaques consisting of fibrillated amyloid-β (Aβ), dystrophic neurites, and the neurofibrillary tangles of tau. The oligomers/fibrillar Aβ damages the neurons or initiates an intracellular signaling cascade for neuronal cell death leading to Aβ toxicity. The Aβ is a 4 kDa molecular weight peptide originating from the C-terminal region of the amyloid precursor protein via proteolytic cleavage. Apart from the typical AD hallmarks, certain deficits in metabolic alterations have been identified. This study describes the emerging features of AD from the aspect of metabolic reprogramming in the main pathway of carbohydrate metabolism in the human brain. Particularly, the neurons in patients with AD favor glycolysis despite a normal mitochondrial function indicating a Warburg-like effect. In addition, certain dietary patterns are well known for their properties in preventing AD. Among those, a ketogenic diet may substantially improve the symptoms of AD. An effective therapeutic method for the treatment, mitigation, and prevention of AD has not yet been established. Therefore, the researchers pursue the development and establishment of novel therapies effective in suppressing AD symptoms and the elucidation of their underlying protective mechanisms against neurodegeneration aiming for AD therapy in the near future. Full article

(This article belongs to the Special Issue New Era in Neuroscience)

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24 pages, 1723 KiB

Open AccessReview

Neural Field Continuum Limits and the Structure–Function Partitioning of Cognitive–Emotional Brain Networks

by Kevin B. Clark

Biology 2023, 12(3), 352; https://doi.org/10.3390/biology12030352 - 23 Feb 2023

Cited by 1 | Viewed by 2148

Abstract

In The cognitive-emotional brain, Pessoa overlooks continuum effects on nonlinear brain network connectivity by eschewing neural field theories and physiologically derived constructs representative of neuronal plasticity. The absence of this content, which is so very important for understanding the dynamic structure-function embedding [...] Read more.

In The cognitive-emotional brain, Pessoa overlooks continuum effects on nonlinear brain network connectivity by eschewing neural field theories and physiologically derived constructs representative of neuronal plasticity. The absence of this content, which is so very important for understanding the dynamic structure-function embedding and partitioning of brains, diminishes the rich competitive and cooperative nature of neural networks and trivializes Pessoa’s arguments, and similar arguments by other authors, on the phylogenetic and operational significance of an optimally integrated brain filled with variable-strength neural connections. Riemannian neuromanifolds, containing limit-imposing metaplastic Hebbian- and antiHebbian-type control variables, simulate scalable network behavior that is difficult to capture from the simpler graph-theoretic analysis preferred by Pessoa and other neuroscientists. Field theories suggest the partitioning and performance benefits of embedded cognitive-emotional networks that optimally evolve between exotic classical and quantum computational phases, where matrix singularities and condensations produce degenerate structure-function homogeneities unrealistic of healthy brains. Some network partitioning, as opposed to unconstrained embeddedness, is thus required for effective execution of cognitive-emotional network functions and, in our new era of neuroscience, should be considered a critical aspect of proper brain organization and operation. Full article

(This article belongs to the Special Issue New Era in Neuroscience)

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15 pages, 2593 KiB

Open AccessReview

Single-Cell Labeling Strategies to Dissect Neuronal Structures and Local Functions

by Keigo Kohara and Masayoshi Okada

Biology 2023, 12(2), 321; https://doi.org/10.3390/biology12020321 - 16 Feb 2023

Cited by 2 | Viewed by 2401

Abstract

The brain network consists of ten billion neurons and is the most complex structure in the universe. Understanding the structure of complex brain networks and neuronal functions is one of the main goals of modern neuroscience. Since the seminal invention of Golgi staining, [...] Read more.

The brain network consists of ten billion neurons and is the most complex structure in the universe. Understanding the structure of complex brain networks and neuronal functions is one of the main goals of modern neuroscience. Since the seminal invention of Golgi staining, single-cell labeling methods have been among the most potent approaches for dissecting neuronal structures and neural circuits. Furthermore, the development of sparse single-cell transgenic methods has enabled single-cell gene knockout studies to examine the local functions of various genes in neural circuits and synapses. Here, we review non-transgenic single-cell labeling methods and recent advances in transgenic strategies for sparse single neuronal labeling. These methods and strategies will fundamentally contribute to the understanding of brain structure and function. Full article

(This article belongs to the Special Issue New Era in Neuroscience)

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19 pages, 3200 KiB

Open AccessReview

Tau; One Protein, So Many Diseases

by Parisa Tabeshmehr and Eftekhar Eftekharpour

Biology 2023, 12(2), 244; https://doi.org/10.3390/biology12020244 - 03 Feb 2023

Cited by 6 | Viewed by 3148

Abstract

Tau, a member of the microtubule-associated proteins, is a known component of the neuronal cytoskeleton; however, in the brain tissue, it is involved in other vital functions beyond maintaining the cellular architecture. The pathologic tau forms aggregates inside the neurons and ultimately forms [...] Read more.

Tau, a member of the microtubule-associated proteins, is a known component of the neuronal cytoskeleton; however, in the brain tissue, it is involved in other vital functions beyond maintaining the cellular architecture. The pathologic tau forms aggregates inside the neurons and ultimately forms the neurofibrillary tangles. Intracellular and extracellular accumulation of different tau isoforms, including dimers, oligomers, paired helical filaments and tangles, lead to a highly heterogenous group of diseases named “Tauopathies”. About twenty-six different types of tauopathy diseases have been identified that have different clinical phenotypes or pathophysiological characteristics. Although all these diseases are identified by tau aggregation, they are distinguishable based on the specific tau isoforms, the affected cell types and the brain regions. The neuropathological and phenotypical heterogeneity of these diseases impose significant challenges for discovering new diagnostic and therapeutic strategies. Here, we review the recent literature on tau protein and the pathophysiological mechanisms of tauopathies. This article mainly focuses on physiologic and pathologic tau and aims to summarize the upstream and downstream events and discuss the current diagnostic approaches and therapeutic strategies. Full article

(This article belongs to the Special Issue New Era in Neuroscience)

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21 pages, 3438 KiB

Open AccessEditor’s ChoiceReview

Wide-Field Calcium Imaging of Neuronal Network Dynamics In Vivo

by Angela K. Nietz, Laurentiu S. Popa, Martha L. Streng, Russell E. Carter, Suhasa B. Kodandaramaiah and Timothy J. Ebner

Biology 2022, 11(11), 1601; https://doi.org/10.3390/biology11111601 - 01 Nov 2022

Cited by 12 | Viewed by 6462

Abstract

A central tenet of neuroscience is that sensory, motor, and cognitive behaviors are generated by the communications and interactions among neurons, distributed within and across anatomically and functionally distinct brain regions. Therefore, to decipher how the brain plans, learns, and executes behaviors requires [...] Read more.

A central tenet of neuroscience is that sensory, motor, and cognitive behaviors are generated by the communications and interactions among neurons, distributed within and across anatomically and functionally distinct brain regions. Therefore, to decipher how the brain plans, learns, and executes behaviors requires characterizing neuronal activity at multiple spatial and temporal scales. This includes simultaneously recording neuronal dynamics at the mesoscale level to understand the interactions among brain regions during different behavioral and brain states. Wide-field Ca²⁺ imaging, which uses single photon excitation and improved genetically encoded Ca²⁺ indicators, allows for simultaneous recordings of large brain areas and is proving to be a powerful tool to study neuronal activity at the mesoscopic scale in behaving animals. This review details the techniques used for wide-field Ca²⁺ imaging and the various approaches employed for the analyses of the rich neuronal-behavioral data sets obtained. Also discussed is how wide-field Ca²⁺ imaging is providing novel insights into both normal and altered neural processing in disease. Finally, we examine the limitations of the approach and new developments in wide-field Ca²⁺ imaging that are bringing new capabilities to this important technique for investigating large-scale neuronal dynamics. Full article

(This article belongs to the Special Issue New Era in Neuroscience)

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Other

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23 pages, 2830 KiB

Open AccessSystematic Review

The Effects of Vagus Nerve Stimulation on Animal Models of Stroke-Induced Injury: A Systematic Review

by Mohammad Yusuf Hasan, Rosfaiizah Siran and Mohd Kaisan Mahadi

Biology 2023, 12(4), 555; https://doi.org/10.3390/biology12040555 - 05 Apr 2023

Cited by 1 | Viewed by 1859

Abstract

Ischemic stroke is one of the leading causes of death worldwide, and poses a great burden to society and the healthcare system. There have been many recent advances in the treatment of ischemic stroke, which usually results from the interruption of blood flow [...] Read more.

Ischemic stroke is one of the leading causes of death worldwide, and poses a great burden to society and the healthcare system. There have been many recent advances in the treatment of ischemic stroke, which usually results from the interruption of blood flow to a particular part of the brain. Current treatments for ischemic stroke mainly focus on revascularization or reperfusion of cerebral blood flow to the infarcted tissue. Nevertheless, reperfusion injury may exacerbate ischemic injury in patients with stroke. In recent decades, vagus nerve stimulation (VNS) has emerged as an optimistic therapeutic intervention. Accumulating evidence has demonstrated that VNS is a promising treatment for ischemic stroke in various rat models through improved neural function, cognition, and neuronal deficit scores. We thoroughly examined previous evidence from stroke-induced animal studies using VNS as an intervention until June 2022. We concluded that VNS yields stroke treatment potential by improving neurological deficit score, infarct volume, forelimb strength, inflammation, apoptosis, and angiogenesis. This review also discusses potential molecular mechanisms underlying VNS-mediated neuroprotection. This review could help researchers conduct additional translational research on patients with stroke. Full article

(This article belongs to the Special Issue New Era in Neuroscience)

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