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21 pages, 3380 KiB

Open AccessArticle

Astrocyte L-Lactate Signaling in the ACC Regulates Visceral Pain Aversive Memory in Rats

by Zafar Iqbal, Shu Liu, Zhuogui Lei, Aruna Surendran Ramkrishnan, Mastura Akter and Ying Li

Cells 2023, 12(1), 26; https://doi.org/10.3390/cells12010026 - 21 Dec 2022

Cited by 10 | Viewed by 2966

Abstract

Pain involves both sensory and affective elements. An aspect of the affective dimension of pain is its sustained unpleasantness, characterized by emotional feelings. Pain results from interactions between memory, attentional, and affective brain circuitry, and it has attracted enormous interest in pain research. [...] Read more.

Pain involves both sensory and affective elements. An aspect of the affective dimension of pain is its sustained unpleasantness, characterized by emotional feelings. Pain results from interactions between memory, attentional, and affective brain circuitry, and it has attracted enormous interest in pain research. However, the brain targets and signaling mechanism involved in pain remain elusive. Using a conditioned place avoidance (CPA) paradigm, we show that colorectal distention (CRD magnitude ≤ 35 mmHg, a subthreshold for pain) paired with a distinct environment can cause significant aversion to a location associated with pain-related insults in rats. We show a substantial increase in the L-lactate concentration in the anterior cingulate cortex (ACC) following CPA training. Local exogenous infusion of lactate into the ACC enhances aversive memory and induces the expression of the memory-related plasticity genes pCREB, CREB, and Erk1/2. The pharmacological experiments revealed that the glycogen phosphorylation inhibitor 1,4-dideoxy-1,4-imino-D-arabinitol (DAB) impairs memory consolidation. Furthermore, short-term Gi pathway activation of ACC astrocytes before CPA training significantly decreases the lactate level and suppresses pain-related aversive learning. The effects were reversed by the local infusion of lactate into the ACC. Our study demonstrates that lactate is released from astrocytes in vivo following visceral pain-related aversive learning and memory retrieval and induces the expression of the plasticity-related immediate early genes CREB, pCREB, and Erk1/2 in the ACC. Chronic visceral pain is an important factor in the pathophysiology of irritable bowel syndrome (IBS). The current study provides evidence that astrocytic activity in the ACC is required for visceral pain-related aversive learning and memory. Full article

(This article belongs to the Special Issue Advance in Neuron-Glia Interaction: From Brain-Physiology To-Pathology)

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15 pages, 2650 KiB

Open AccessArticle

Transcriptome Analysis Unveils That Exosomes Derived from M1-Polarized Microglia Induce Ferroptosis of Neuronal Cells

by Sheng Gao, Shu Jia, Luyue Bai, Dongru Li and Chunyang Meng

Cells 2022, 11(24), 3956; https://doi.org/10.3390/cells11243956 - 7 Dec 2022

Cited by 8 | Viewed by 2333

Abstract

Microglia play a vital role in neurodegenerative diseases. However, the effects of microglia-derived exosomes on neuronal cells are poorly understood. This study aimed to explore the role of M1-polarized microglia exosomes in neuronal cells by transcriptome analysis. Exosomes isolated from resting M0-phenotype BV2 [...] Read more.

Microglia play a vital role in neurodegenerative diseases. However, the effects of microglia-derived exosomes on neuronal cells are poorly understood. This study aimed to explore the role of M1-polarized microglia exosomes in neuronal cells by transcriptome analysis. Exosomes isolated from resting M0-phenotype BV2 (M0-BV2) microglia and M1-polarized BV2 (M1-BV2) microglia were analyzed using high-throughput sequencing of the transcriptome. Differentially expressed genes (DEGs) between the two types of exosomes were identified by analyzing the sequencing data. The biological functions and pathways regulated by the identified DEGs were then identified using bioinformatics analyses. Finally, we evaluated the effects of exosomes on neuronal cells by coculturing M0-BV2 and M1-BV2 exosomes with primary neuronal cells. Enrichment analyses revealed that DEGs were significantly enriched in the ferroptosis pathway (p = 0.0137). M0-BV2 exosomes had no distinct effects on ferroptosis in neuronal cells, whereas M1-BV2 exosomes significantly reduced ferroptosis suppressor proteins (GPX4, SLC7A11, and FTH1) and elevated the levels of intracellular and mitochondrial ferrous iron and lipid peroxidation in neuronal cells. Polarized M1-BV2 microglia exosomes can induce ferroptosis in neuronal cells, thereby aggravating neuronal damage. Taken together, these findings enhance knowledge of the pathogenesis of neurological disorders and suggest potential therapeutic targets against neurodegenerative diseases. Full article

(This article belongs to the Special Issue Advance in Neuron-Glia Interaction: From Brain-Physiology To-Pathology)

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25 pages, 6276 KiB

Open AccessArticle

by Constance Vennin, Charlotte Hewel, Hristo Todorov, Marlon Wendelmuth, Konstantin Radyushkin, André Heimbach, Illia Horenko, Sarah Ayash, Marianne B. Müller, Susann Schweiger, Susanne Gerber and Beat Lutz

Cells 2022, 11(21), 3405; https://doi.org/10.3390/cells11213405 - 27 Oct 2022

Cited by 5 | Viewed by 3064

Abstract

Upon chronic stress, a fraction of individuals shows stress resilience, which can prevent long-term mental dysfunction. The underlying molecular mechanisms are complex and have not yet been fully understood. In this study, we performed a data-driven behavioural stratification together with single-cell transcriptomics of [...] Read more.

Upon chronic stress, a fraction of individuals shows stress resilience, which can prevent long-term mental dysfunction. The underlying molecular mechanisms are complex and have not yet been fully understood. In this study, we performed a data-driven behavioural stratification together with single-cell transcriptomics of the hippocampus in a mouse model of chronic social defeat stress. Our work revealed that in a sub-group exhibiting molecular responses upon chronic stress, the dorsal hippocampus is particularly involved in neuroimmune responses, angiogenesis, myelination, and neurogenesis, thereby enabling brain restoration and homeostasis after chronic stress. Based on these molecular insights, we applied rapamycin after the stress as a proof-of-concept pharmacological intervention and were able to substantially increase stress resilience. Our findings serve as a data resource and can open new avenues for further understanding of molecular processes underlying stress response and for targeted interventions supporting resilience. Full article

(This article belongs to the Special Issue Advance in Neuron-Glia Interaction: From Brain-Physiology To-Pathology)

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22 pages, 5021 KiB

Open AccessArticle

Diverging Effects of Adolescent Ethanol Exposure on Tripartite Synaptic Development across Prefrontal Cortex Subregions

by Christopher Douglas Walker, Hannah Gray Sexton, Jentre Hyde, Brittani Greene and Mary-Louise Risher

Cells 2022, 11(19), 3111; https://doi.org/10.3390/cells11193111 - 2 Oct 2022

Cited by 7 | Viewed by 2918

Abstract

Adolescence is a developmental period that encompasses, but is not limited to, puberty and continues into early adulthood. During this period, maturation and refinement are observed across brain regions such as the prefrontal cortex (PFC), which is critical for cognitive function. Adolescence is [...] Read more.

Adolescence is a developmental period that encompasses, but is not limited to, puberty and continues into early adulthood. During this period, maturation and refinement are observed across brain regions such as the prefrontal cortex (PFC), which is critical for cognitive function. Adolescence is also a time when excessive alcohol consumption in the form of binge drinking peaks, increasing the risk of long-term cognitive deficits and the risk of developing an alcohol use disorder later in life. Animal models have revealed that adolescent ethanol (EtOH) exposure results in protracted disruption of neuronal function and performance on PFC-dependent tasks that require higher-order decision-making. However, the role of astrocytes in EtOH-induced disruption of prefrontal cortex-dependent function has yet to be elucidated. Astrocytes have complex morphologies with an extensive network of peripheral astrocyte processes (PAPs) that ensheathe pre- and postsynaptic terminals to form the ‘tripartite synapse.’ At the tripartite synapse, astrocytes play several critical roles, including synaptic maintenance, dendritic spine maturation, and neurotransmitter clearance through proximity-dependent interactions. Here, we investigate the effects of adolescent binge EtOH exposure on astrocyte morphology, PAP-synaptic proximity, synaptic stabilization proteins, and dendritic spine morphology in subregions of the PFC that are important in the emergence of higher cognitive function. We found that adolescent binge EtOH exposure resulted in subregion specific changes in astrocyte morphology and astrocyte-neuronal interactions. While this did not correspond to a loss of astrocytes, synapses, or dendritic spines, there was a corresponding region-specific and EtOH-dependent shift in dendritic spine phenotype. Lastly, we found that changes in astrocyte-neuronal interactions were not a consequence of changes in the expression of key synaptic structural proteins neurexin, neuroligin 1, or neuroligin 3. These data demonstrate that adolescent EtOH exposure results in enduring effects on neuron-glia interactions that persist into adulthood in a subregion-specific PFC manner, suggesting selective vulnerability. Further work is necessary to understand the functional and behavioral implications. Full article

(This article belongs to the Special Issue Advance in Neuron-Glia Interaction: From Brain-Physiology To-Pathology)

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Review

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31 pages, 2187 KiB

Open AccessReview

The Role of Oxytocin in Abnormal Brain Development: Effect on Glial Cells and Neuroinflammation

by Marit Knoop, Marie-Laure Possovre, Alice Jacquens, Alexandre Charlet, Olivier Baud and Pascal Darbon

Cells 2022, 11(23), 3899; https://doi.org/10.3390/cells11233899 - 2 Dec 2022

Cited by 13 | Viewed by 5180

Abstract

The neonatal period is critical for brain development and determinant for long-term brain trajectory. Yet, this time concurs with a sensitivity and risk for numerous brain injuries following perinatal complications such as preterm birth. Brain injury in premature infants leads to a complex [...] Read more.

The neonatal period is critical for brain development and determinant for long-term brain trajectory. Yet, this time concurs with a sensitivity and risk for numerous brain injuries following perinatal complications such as preterm birth. Brain injury in premature infants leads to a complex amalgam of primary destructive diseases and secondary maturational and trophic disturbances and, as a consequence, to long-term neurocognitive and behavioral problems. Neuroinflammation is an important common factor in these complications, which contributes to the adverse effects on brain development. Mediating this inflammatory response forms a key therapeutic target in protecting the vulnerable developing brain when complications arise. The neuropeptide oxytocin (OT) plays an important role in the perinatal period, and its importance for lactation and social bonding in early life are well-recognized. Yet, novel functions of OT for the developing brain are increasingly emerging. In particular, OT seems able to modulate glial activity in neuroinflammatory states, but the exact mechanisms underlying this connection are largely unknown. The current review provides an overview of the oxytocinergic system and its early life development across rodent and human. Moreover, we cover the most up-to-date understanding of the role of OT in neonatal brain development and the potential neuroprotective effects it holds when adverse neural events arise in association with neuroinflammation. A detailed assessment of the underlying mechanisms between OT treatment and astrocyte and microglia reactivity is given, as well as a focus on the amygdala, a brain region of crucial importance for socio-emotional behavior, particularly in infants born preterm. Full article

(This article belongs to the Special Issue Advance in Neuron-Glia Interaction: From Brain-Physiology To-Pathology)

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27 pages, 8751 KiB

Open AccessReview

Region-Specific Characteristics of Astrocytes and Microglia: A Possible Involvement in Aging and Diseases

by Jae Lee, Sung Wook Kim and Kyong-Tai Kim

Cells 2022, 11(12), 1902; https://doi.org/10.3390/cells11121902 - 12 Jun 2022

Cited by 14 | Viewed by 5061

Abstract

Although different regions of the brain are dedicated to specific functions, the intra- and inter-regional heterogeneity of astrocytes and microglia in these regions has not yet been fully understood. Recently, an advancement in various technologies, such as single-cell RNA sequencing, has allowed for [...] Read more.

Although different regions of the brain are dedicated to specific functions, the intra- and inter-regional heterogeneity of astrocytes and microglia in these regions has not yet been fully understood. Recently, an advancement in various technologies, such as single-cell RNA sequencing, has allowed for the discovery of astrocytes and microglia with distinct molecular fingerprints and varying functions in the brain. In addition, the regional heterogeneity of astrocytes and microglia exhibits different functions in several situations, such as aging and neurodegenerative diseases. Therefore, investigating the region-specific astrocytes and microglia is important in understanding the overall function of the brain. In this review, we summarize up-to-date research on various intra- and inter-regional heterogeneities of astrocytes and microglia, and provide information on how they can be applied to aging and neurodegenerative diseases. Full article

(This article belongs to the Special Issue Advance in Neuron-Glia Interaction: From Brain-Physiology To-Pathology)

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16 pages, 7942 KiB

Open AccessReview

Regional Development of Glioblastoma: The Anatomical Conundrum of Cancer Biology and Its Surgical Implication

by Ciro De Luca, Assunta Virtuoso, Michele Papa, Francesco Certo, Giuseppe Maria Vincenzo Barbagallo and Roberto Altieri

Cells 2022, 11(8), 1349; https://doi.org/10.3390/cells11081349 - 15 Apr 2022

Cited by 12 | Viewed by 3023

Abstract

Glioblastoma (GBM) are among the most common malignant central nervous system (CNS) cancers, they are relatively rare. This evidence suggests that the CNS microenvironment is naturally equipped to control proliferative cells, although, rarely, failure of this system can lead to cancer development. Moreover, [...] Read more.

Glioblastoma (GBM) are among the most common malignant central nervous system (CNS) cancers, they are relatively rare. This evidence suggests that the CNS microenvironment is naturally equipped to control proliferative cells, although, rarely, failure of this system can lead to cancer development. Moreover, the adult CNS is innately non-permissive to glioma cell invasion. Thus, glioma etiology remains largely unknown. In this review, we analyze the anatomical and biological basis of gliomagenesis considering neural stem cells, the spatiotemporal diversity of astrocytes, microglia, neurons and glutamate transporters, extracellular matrix and the peritumoral environment. The precise understanding of subpopulations constituting GBM, particularly astrocytes, is not limited to glioma stem cells (GSC) and could help in the understanding of tumor pathophysiology. The anatomical fingerprint is essential for non-invasive assessment of patients’ prognosis and correct surgical/radiotherapy planning. Full article

(This article belongs to the Special Issue Advance in Neuron-Glia Interaction: From Brain-Physiology To-Pathology)

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Other

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17 pages, 13752 KiB

Open AccessEssay

Involvement of DAAO Overexpression in Delayed Hippocampal Neuronal Death

by Hao Liu, Jun-Tao Zhang, Chen-Ye Mou, Yue Hao and Wei Cui

Cells 2022, 11(22), 3689; https://doi.org/10.3390/cells11223689 - 21 Nov 2022

Cited by 3 | Viewed by 2180

Abstract

Background: D-amino acid oxidase (DAAO) is a flavoenzyme that specifically catalyzes the deamination of many neutral and basic D-amino acids. This study aims to explore the pathological increment of hippocampal DAAO and its potential relationship with delayed hippocampal neuronal death. Methods: Ischemia–reperfusion was [...] Read more.

Background: D-amino acid oxidase (DAAO) is a flavoenzyme that specifically catalyzes the deamination of many neutral and basic D-amino acids. This study aims to explore the pathological increment of hippocampal DAAO and its potential relationship with delayed hippocampal neuronal death. Methods: Ischemia–reperfusion was induced in mice through middle cerebral artery occlusion (MCAO). Neurological deficit scores and hippocampal neuronal death were assessed in MCAO mice. Immunofluorescent staining was applied to identify activated astrocytes and evaluate DAAO expression. TUNEL and Nissl staining were utilized to identify cell apoptosis of hippocampal neurons. Results: Hippocampal astrocytic DAAO was strikingly increased following ischemic stroke, with the greatest increase on day 5 after surgery, followed by the manifestation of neurobehavioral deficits. Astrocytic DAAO was found to be mainly expressed in the hippocampal CA2 region and linked with subsequent specific neural apoptosis. Thus, it is supposed that the activation of astrocytic DAAO in ischemic stroke might contribute to neuronal death. An intravenous, twice-daily administration of 4H-furo[3,2-b]pyrrole-5-carboxylic acid (SUN, 10 mg/kg) markedly relieved behavioral status and delayed hippocampal neuronal death by 38.0% and 41.5%, respectively, compared to the model group treated with saline. In transfected primary astrocytes, DAAO overexpression inhibits cell activity, induces cytotoxicity, and promotes hippocampal neuronal death at least partly by enhancing H₂O₂ levels with subsequent activation of TRP calcium channels in neurons. Conclusions: Our findings suggest that increased hippocampal DAAO is causally associated with the development of delayed neuronal death after MCAO onset via astrocyte–neuron interactions. Hence, targeting DAAO is a promising therapeutic strategy for the management of neurological disorders. Full article

(This article belongs to the Special Issue Advance in Neuron-Glia Interaction: From Brain-Physiology To-Pathology)

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