Depression is a common mental illness, affecting more than 300 million people worldwide. Decades of investigation have yielded symptomatic therapies for this disabling condition but have not led to a ...consensus about its pathogenesis. There are data to support several different theories of causation, including the monoamine hypothesis, hypothalamic-pituitary-adrenal axis changes, inflammation and immune system alterations, abnormalities of neurogenesis and a conducive environmental milieu. Research in these areas and others has greatly advanced the current understanding of depression; however, there are other, less widely known theories of pathogenesis. Oligodendrocyte lineage cells, including oligodendrocyte progenitor cells and mature oligodendrocytes, have numerous important functions, which include forming myelin sheaths that enwrap central nervous system axons, supporting axons metabolically, and mediating certain forms of neuroplasticity. These specialized glial cells have been implicated in psychiatric disorders such as depression. In this review, we summarize recent findings that shed light on how oligodendrocyte lineage cells might participate in the pathogenesis of depression, and we discuss new approaches for targeting these cells as a novel strategy to treat depression.
NG2 glia, also known as oligodendrocyte precursor cells (OPCs), play an important role in proliferation and give rise to myelinating oligodendrocytes during early brain development. In contrast to ...other glial cell types, the most intriguing aspect of NG2 glia is their ability to directly sense synaptic inputs from neurons. However, whether this synaptic interaction is bidirectional or unidirectional, or its physiological relevance has not yet been clarified. Here, we report that NG2 glia form synaptic complexes with hippocampal interneurons and that selective photostimulation of NG2 glia (expressing channelrhodopsin-2) functionally drives GABA release and enhances inhibitory synaptic transmission onto proximal interneurons in a microcircuit. The mechanism involves GAD67 biosynthesis and VAMP-2 containing vesicular exocytosis. Further, behavioral assays demonstrate that NG2 glia photoactivation triggers anxiety-like behavior in vivo and contributes to chronic social defeat stress.
Pericytes are one of the main components of the neurovascular unit. They play a critical role in regulating blood flow, blood–brain barrier permeability, neuroinflammation, and neuronal activity. In ...the central nervous system (CNS), pericytes are classified into three subtypes, that is, ensheathing, mesh, and thin‐strand pericytes, based on their distinct morphologies and region‐specific distributions. However, whether these three types of pericytes exhibit heterogeneity or homogeneity with regard to membrane properties has been understudied to date. Here, we combined bulk RNA sequencing analysis with electrophysiological methods to demonstrate that the three subtypes of pericytes share similar electrical membrane properties in the CNS, suggesting a homogenous population of neurovascular pericytes in the brain. Furthermore, we identified an inwardly rectifying potassium channel subtype Kir4.1 functionally expressed in pericytes. Electrophysiological patch clamp recordings indicate that Kir4.1 channel currents in pericytes represent a small portion of the K+ macroscopic currents in physiological conditions. However, a significant augmentation of Kir4.1 currents in pericytes was induced when the extracellular K+ was elevated to pathological levels, suggesting pericytes Kir4.1 channels might play an important role as K+ sensors and contribute to K+ homeostasis in local neurovascular networks in pathology.
MAIN POINTS
Three types of pericytes share similar intrinsic membrane properties in the brain.
Kir4.1 channels are homogeneously expressed in pericytes.
Pericyte Kir4.1 channels play a crucial role as K+ sensors in local neurovascular networks.
Huntington's disease (HD) is characterized by striatal medium spiny neuron (MSN) dysfunction, but the underlying mechanisms remain unclear. We explored roles for astrocytes, in which mutant ...huntingtin is expressed in HD patients and mouse models. We found that symptom onset in R6/2 and Q175 HD mouse models was not associated with classical astrogliosis, but was associated with decreased Kir4.1 K(+) channel functional expression, leading to elevated in vivo striatal extracellular K(+), which increased MSN excitability in vitro. Viral delivery of Kir4.1 channels to striatal astrocytes restored Kir4.1 function, normalized extracellular K(+), ameliorated aspects of MSN dysfunction, prolonged survival and attenuated some motor phenotypes in R6/2 mice. These findings indicate that components of altered MSN excitability in HD may be caused by heretofore unknown disturbances of astrocyte-mediated K(+) homeostasis, revealing astrocytes and Kir4.1 channels as therapeutic targets.
The spatiotemporal activities of astrocyte Ca2+ signaling in mature neuronal circuits remain unclear. We used genetically encoded Ca2+ and glutamate indicators as well as pharmacogenetic and ...electrical control of neurotransmitter release to explore astrocyte activity in the hippocampal mossy fiber pathway. Our data revealed numerous localized, spontaneous Ca2+ signals in astrocyte branches and territories, but these were not driven by neuronal activity or glutamate. Moreover, evoked astrocyte Ca2+ signaling changed linearly with the number of mossy fiber action potentials. Under these settings, astrocyte responses were global, suppressed by neurotransmitter clearance, and mediated by glutamate and GABA. Thus, astrocyte engagement in the fully developed mossy fiber pathway was slow and territorial, contrary to that frequently proposed for astrocytes within microcircuits. We show that astrocyte Ca2+ signaling functionally segregates large volumes of neuropil and that these transients are not suited for responding to, or regulating, single synapses in the mossy fiber pathway.
•Astrocyte branches/territories were studied using optical and pharmacogenetic tools•Spontaneous astrocyte Ca2+ signals were not due to action potentials or glutamate•Evoked astrocyte Ca2+ signals were slow, territorial and triggered by spike trains•Astrocyte Ca2+ signaling was tightly gated by neurotransmitter clearance
Haustein et al. use optical and genetic methods to explore the rules under which astrocytes are engaged in a model neuronal circuit. The findings show that astrocytes listen to synapses during bursts of action potentials in mossy fiber axons.
This paper presents the results of a study that explored undergraduate students’ perceptions of cognitive, social, and teaching presences in online business courses and their relationship to ...students’ course satisfaction in addition to demographic variables. Student engagement has proven to be one of the main reasons for student retention and satisfaction in online courses and the Community of Inquiry (CoI) framework by Garrison, Anderson, and Archer promised to provide clear structure to identify student engagement. A total of 223 business undergraduate students participated in the online survey adapted from the CoI survey (Garrison et al.,
The Internet and Higher Education, 2
(2–3), 87–105,
2000
) with additional demographic variables. Results indicated that teaching presence and cognitive presence of the CoI framework has a significant impact on the course rate of online undergraduate business courses confirmed by the Structural Equation Modeling (SEM). A moderation effect of gender on the relationship between age and course rate was also found.
The discovery of intracellular Ca2+ signals within astrocytes has changed our view of how these ubiquitous cells contribute to brain function. Classically thought merely to serve supportive ...functions, astrocytes are increasingly thought to respond to, and regulate, neurons. The use of organic Ca2+ indicator dyes such as Fluo-4 and Fura-2 has proved instrumental in the study of astrocyte physiology. However, progress has recently been accelerated by the use of cytosolic and membrane targeted genetically encoded calcium indicators (GECIs). Herein, we review these recent findings, discuss why studying astrocyte Ca2+ signals is important to understand brain function, and summarize work that led to the discovery of TRPA1 channel-mediated near-membrane Ca2+ signals in astrocytes and their indirect neuromodulatory roles at inhibitory synapses in the CA1 stratum radiatum region of the hippocampus. We suggest that the use of membrane-targeted and cytosolic GECIs holds great promise to explore the diversity of Ca2+ signals within single astrocytes and also to study diversity of function for astrocytes in different parts of the brain.
Noxious stimulus and painful experience in early life can induce cognitive deficits and abnormal pain sensitivity. As a major component of the outer membrane of gram-negative bacteria, ...lipopolysaccharide (LPS) injection mimics clinical symptoms of bacterial infections. Spinal microglial activation and the production of pro-inflammatory cytokines have been implicated in the pathogenesis of LPS-induced hyperalgesia in neonatal rats. Dexmedetomidine (DEX) possesses potent anti-neuroinflammatory and neuroprotective properties through the inhibition of microglial activation and microglial polarization toward pro-inflammatory (M1) phenotype and has been widely used in pediatric clinical practice. However, little is known about the effects of DEX on LPS-induced spinal inflammation and hyperalgesia in neonates. Here, we investigated whether systemic LPS exposure has persistent effects on spinal inflammation and hyperalgesia in neonatal rats and explored the protective role of DEX in adverse effects caused by LPS injection. Systemic LPS injections induced acute mechanical hyperalgesia, increased levels of pro-inflammatory cytokines in serum, and short-term increased expressions of pro-inflammatory cytokines and M1 microglial markers in the spinal cord of neonatal rats. Pretreatment with DEX significantly decreased inflammation and alleviated mechanical hyperalgesia induced by LPS. The inhibition of M1 microglial polarization and microglial pro-inflammatory cytokines expression in the spinal cord may implicate its neuroprotective effect, which highlights a new therapeutic target in the treatment of infection-induced hyperalgesia in neonates and preterm infants.
Oligodendrocytes have robust regenerative ability and are key players in remyelination during physiological and pathophysiological states. However, the mechanisms of brain microenvironmental cue in ...regulation of the differentiation of oligodendrocytes still needs to be further investigated.
We demonstrated that myelin-associated glycoprotein (MAG) was a novel receptor for angiopoietin-like protein 2 (ANGPTL2). The binding of ANGPTL2 to MAG efficiently promoted the differentiation of oligodendrocytes in vitro, as evaluated in an HCN cell line. Angptl2-null mice had a markedly impaired myelination capacity in the early stage of oligodendrocyte development. These mice had notably decreased remyelination capacities and enhanced motor disability in a cuprizone-induced demyelinating mouse model, which was similar to the Mag-null mice. The loss of remyelination ability in Angptl2-null/Mag-null mice was similar to the Angptl2-WT/Mag-null mice, which indicated that the ANGPTL2-mediated oligodendrocyte differentiation effect depended on the MAG receptor. ANGPTL2 bound MAG to enhance its phosphorylation level and recruit Fyn kinase, which increased Fyn phosphorylation levels, followed by the transactivation of myelin regulatory factor (MYRF).
Our study demonstrated an unexpected cross-talk between the environmental protein (ANGPTL2) and its surface receptor (MAG) in the regulation of oligodendrocyte differentiation, which may benefit the treatment of many demyelination disorders, including multiple sclerosis.
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