Millions of cancer survivors experience a persistent neurological syndrome that includes deficits in memory, attention, information processing, and mental health. Cancer therapy-related cognitive ...impairment can cause mild to severe disruptions to quality of life for these cancer survivors. Understanding the cellular and molecular underpinnings of this disorder will facilitate new therapeutic strategies aimed at ameliorating these long-lasting impairments. Accumulating evidence suggests that a range of cancer therapies induce persistent activation of the brain’s resident immune cells, microglia. Cancer therapy-induced microglial activation disrupts numerous mechanisms of neuroplasticity, and emerging findings suggest that this impairment in plasticity is central to cancer therapy-related cognitive impairment. This review explores reactive microglial dysregulation of neural circuit structure and function following cancer therapy.
Cancer survivors frequently exhibit persistent disruptions in cognitive function, including deficits in memory, attention, speed of information processing, and mental health.Studies in both human cancer survivors and preclinical rodent models of chemotherapy and radiation exposure indicate dysregulation of neural plasticity mechanisms underlying cancer therapy-related cognitive impairment.Both cranial irradiation and systemic chemotherapy treatment have been shown to induce a reactive state in microglia.Activated microglia are associated with deficits in neural precursor cell population maintenance and neurogenesis, in synaptic structure and function, and in myelin plasticity.
Active neurons exert a mitogenic effect on normal neural precursor and oligodendroglial precursor cells, the putative cellular origins of high-grade glioma (HGG). By using optogenetic control of ...cortical neuronal activity in a patient-derived pediatric glioblastoma xenograft model, we demonstrate that active neurons similarly promote HGG proliferation and growth in vivo. Conditioned medium from optogenetically stimulated cortical slices promoted proliferation of pediatric and adult patient-derived HGG cultures, indicating secretion of activity-regulated mitogen(s). The synaptic protein neuroligin-3 (NLGN3) was identified as the leading candidate mitogen, and soluble NLGN3 was sufficient and necessary to promote robust HGG cell proliferation. NLGN3 induced PI3K-mTOR pathway activity and feedforward expression of NLGN3 in glioma cells. NLGN3 expression levels in human HGG negatively correlated with patient overall survival. These findings indicate the important role of active neurons in the brain tumor microenvironment and identify secreted NLGN3 as an unexpected mechanism promoting neuronal activity-regulated cancer growth.
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•Neuronal activity promotes high-grade glioma (HGG) proliferation and growth•Neuroligin-3 is an activity-regulated secreted glioma mitogen•Neuroligin-3 induces PI3K-mTOR signaling in HGG cells•Neuroligin-3 expression is inversely correlated with survival in human HGG
Neuronal activity promotes the growth of malignant glioma through activity-regulated secretion of the synaptic protein neuroligin-3, which acts as a mitogen, recruiting the PI3K-mTOR pathway to induce glioma cell proliferation.
Myelin plasticity in the central nervous system Purger, David; Gibson, Erin M.; Monje, Michelle
Neuropharmacology,
November 2016, 2016-Nov, 2016-11-00, 20161101, Letnik:
110, Številka:
Pt B
Journal Article
Recenzirano
Myelin sheaths, specialized segments of oligodendrocyte (OL) plasma membranes in the central nervous system (CNS), facilitate fast, saltatory conduction of action potentials down axons. Changes to ...the fine structure of myelin in a neural circuit, including sheath thickness and internode length (length of myelin segments between nodes of Ranvier), are expected to affect conduction velocity of action potentials. Myelination of the mammalian CNS occurs in a stereotyped, progressive pattern and continues well into adulthood in humans. Recent evidence from zebrafish, rodents, non-human primates, and humans suggests that myelination may be sensitive to experiences during development and adulthood, and that varying levels of neuronal activity may underlie these experience-dependent changes in myelin and myelin-forming cells. Several cellular, molecular, and epigenetic mechanisms have been investigated as contributors to myelin plasticity. A deeper understanding of myelin plasticity and its underlying mechanisms may provide insights into diseases involving myelin damage or dysregulation.
This article is part of the Special Issue entitled ‘Oligodendrocytes in Health and Disease’.
•Experience influences myelin microstructure in some parts of the central nervous system.•Neuronal activity modulates oligodendrocyte precursor cell proliferation and differentiation, and myelin sheath thickness.•Activity-regulated oligodendrogenesis plays a role in some forms of learning.•Adaptive changes in myelin represent a dimension along which experience modulates brain structure and function.
Activity-dependent myelination is thought to contribute to adaptive neurological function. However, the mechanisms by which activity regulates myelination and the extent to which myelin plasticity ...contributes to non-motor cognitive functions remain incompletely understood. Using a mouse model of chemotherapy-related cognitive impairment (CRCI), we recently demonstrated that methotrexate (MTX) chemotherapy induces complex glial dysfunction for which microglial activation is central. Here, we demonstrate that remote MTX exposure blocks activity-regulated myelination. MTX decreases cortical Bdnf expression, which is restored by microglial depletion. Bdnf-TrkB signaling is a required component of activity-dependent myelination. Oligodendrocyte precursor cell (OPC)-specific TrkB deletion in chemotherapy-naive mice results in impaired cognitive behavioral performance. A small-molecule TrkB agonist rescues both myelination and cognitive impairment after MTX chemotherapy. This rescue after MTX depends on intact TrkB expression in OPCs. Taken together, these findings demonstrate a molecular mechanism required for adaptive myelination that is aberrant in CRCI due to microglial activation.
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•Methotrexate (MTX) causes a microglia-dependent reduction in Bdnf expression•Activity-regulated myelination requires Bdnf-TrkB signaling and fails after MTX•Conditional, inducible TrkB loss in OPCs impairs cognitive behavioral performance•TrkB agonism rescues cognitive performance after MTX only if OPCs express TrkB
Methotrexate chemotherapy results in a microglial-dependent reduction of Bdnf expression and loss of activity-regulated myelination, which requires Bdnf to TrkB signaling. OPC-specific loss of TrkB results in cognitive impairment. Stimulating OPC TrkB signaling restores myelination and rescues cognition after MTX.
Sheehan and Nadarajah et al.1 identified that Bmal1 loss from astrocytes induces the expression of BAG3, a macroautophagy chaperone enriched in Alzheimer’s disease patients and in disease-associated ...astrocytes, enhancing the phagocytosis of misfolded proteins and preventing tau and alpha-synuclein pathologies.
Sheehan and Nadarajah et al. identified that Bmal1 loss from astrocytes induces the expression of BAG3, a macroautophagy chaperone enriched in Alzheimer’s disease patients and in disease-associated astrocytes, enhancing the phagocytosis of misfolded proteins and preventing tau and alpha-synuclein pathologies.
Myelination of the central nervous system requires the generation of functionally mature oligodendrocytes from oligodendrocyte precursor cells (OPCs). Electrically active neurons may influence OPC ...function and selectively instruct myelination of an active neural circuit. In this work, we use optogenetic stimulation of the premotor cortex in awake, behaving mice to demonstrate that neuronal activity elicits a mitogenic response of neural progenitor cells and OPCs, promotes oligodendrogenesis, and increases myelination within the deep layers of the premotor cortex and subcortical white matter. We further show that this neuronal activity-regulated oligodendrogenesis and myelination is associated with improved motor function of the corresponding limb. Oligodendrogenesis and myelination appear necessary for the observed functional improvement, as epigenetic blockade of oligodendrocyte differentiation and myelin changes prevents the activity-regulated behavioral improvement.
PURPOSE OF REVIEWModern innovations in cancer therapy have dramatically increased the number of cancer survivors. An unfortunately frequent side-effect of cancer treatment is enduring neurological ...impairment. Persistent deficits in attention, concentration, memory, and speed of information processing afflict a substantial fraction of cancer survivors following completion of these life-saving therapies. Here, we highlight chemotherapy-related cognitive impairment (CRCI) and discuss the current understanding of mechanisms underlying CRCI.
RECENT FINDINGSNew studies emphasize the deleterious impact of chemotherapeutic agents on glial–glial and neuron–glial interactions that shape the form, function and plasticity of the central nervous system. An emerging theme in cancer therapy-related cognitive impairment is therapy-induced microglial activation and consequent dysfunction of both neural precursor cells and mature neural cell types. Recent work has highlighted the complexity of dysregulated intercellular interactions involving oligodendrocyte lineage cells, microglia, astrocytes, and neurons following exposure to traditional cancer therapies such as methotrexate. This new understanding of the mechanistic underpinnings of CRCI has elucidated potential therapeutic interventions, including colony-stimulating factor 1 receptor inhibition, TrkB agonism, and aerobic exercise.
SUMMARYTraditional cancer therapies induce lasting alterations to multiple neural cell types. Therapy-induced microglial activation is a critical component of the cause of CRCI, contributing to dysregulation of numerous processes of neural plasticity. Therapeutic targeting of microglial activation or the consequent dysregulation of neural plasticity mechanisms are emerging.
The molecular mechanisms that maintain circadian rhythms in mammalian as well as non-mammalian systems are well documented in neuronal populations but comparatively understudied in glia. Glia are ...highly dynamic in form and function, and the circadian clock provides broad dynamic ranges for the maintenance of this homeostasis, thus glia are key to understanding the role of circadian biology in brain function. Here, we highlight the implications of the molecular circadian clock on the homeodynamic nature of glia, underscoring the current gap in understanding the role of the circadian system in oligodendroglia lineage cells and subsequent myelination. Through this perspective, we will focus on the intersection of circadian and glial biology and how it interfaces with global circadian rhythm maintenance associated with normative and aberrant brain function.
Circadian disruptions through frequent transmeridian travel, rotating shift work, and poor sleep hygiene are associated with an array of physical and mental health maladies, including marked deficits ...in human cognitive function. Despite anecdotal and correlational reports suggesting a negative impact of circadian disruptions on brain function, this possibility has not been experimentally examined.
In the present study, we investigated whether experimental 'jet lag' (i.e., phase advances of the light:dark cycle) negatively impacts learning and memory and whether any deficits observed are associated with reductions in hippocampal cell proliferation and neurogenesis. Because insults to circadian timing alter circulating glucocorticoid and sex steroid concentrations, both of which influence neurogenesis and learning/memory, we assessed the contribution of these endocrine factors to any observed alterations. Circadian disruption resulted in pronounced deficits in learning and memory paralleled by marked reductions in hippocampal cell proliferation and neurogenesis. Significantly, deficits in hippocampal-dependent learning and memory were not only seen during the period of the circadian disruption, but also persisted well after the cessation of jet lag, suggesting long-lasting negative consequences on brain function.
Together, these findings support the view that circadian disruptions suppress hippocampal neurogenesis via a glucocorticoid-independent mechanism, imposing pronounced and persistent impairments on learning and memory.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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