How do glia sculpt neural circuits and how does dysregulation of glia contribute to disease? Glia make up more than half of the cells in the human brain, but we are just beginning to understand the complex and multifactorial role glia play in health and disease. Glia are decidedly dynamic in form and function. Understanding the mechanisms underlying the dynamic nature of glia is imperative to developing novel therapeutic strategies for diseases of the nervous system that involve aberrant gliogenesis.
The Gibson Lab, starting in early 2020 in the Department of Psychiatry and Behavioral Sciences and the Stanford Center for Sleep Sciences and Medicine, studies the cellular and molecular mechanisms modulating glia. One molecular mechanism that affords cells a dynamical nature is the circadian clock. While much is known about how the circadian clock influences neurons and peripheral cells throughout the body, little is known about how this core molecular mechanism regulates glia. We study how the circadian clock system regulates glial function to better understand diseases of the nervous system in which both circadian/sleep and glial dysfunction are prominent, such as autism, multiple sclerosis, and chemotherapy-related cognitive impairment.
?What cellular processes in glia are regulated by the circadian system?
?What is the function of the circadian clock system during myelination?
?How does the circadian clock machinery influence myelin-forming cell structure and function?
?How does disruption in the circadian clock affect diseases of dysregulated myelination?
?How do circadian disruptions mediated by environmental changes (i.e. jet lag, shift work, light at night) affect brain form and function in health and disease?
Emerging mechanistic underpinnings and therapeutic targets for chemotherapy-related cognitive impairment.
Current opinion in oncology
PURPOSE OF REVIEW: Modern 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 FINDINGS: New 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.SUMMARY: Traditional 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.
View details for DOI 10.1097/CCO.0000000000000578
View details for PubMedID 31449084
Loss of Adaptive Myelination Contributes to Methotrexate Chemotherapy-Related Cognitive Impairment.
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.
View details for DOI 10.1016/j.neuron.2019.04.032
View details for PubMedID 31122677
- How to tackle the childcare-conference conundrum PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2018; 115 (12): 2845?49
Bad wrap: Myelin and myelin plasticity in health and disease
2018; 78 (2): 123?35
Human central nervous system myelin development extends well into the fourth decade of life, and this protracted period underscores the potential for experience to modulate myelination. The concept of myelin plasticity implies adaptability in myelin structure and function in response to experiences during development and beyond. Mounting evidence supports this concept of neuronal activity-regulated changes in myelin-forming cells, including oligodendrocyte precursor cell proliferation, oligodendrogenesis and modulation of myelin microstructure. In healthy individuals, myelin plasticity in associative white matter structures of the brain is implicated in learning and motor function in both rodents and humans. Activity-dependent changes in myelin-forming cells may influence the function of neural networks that depend on the convergence of numerous neural signals on both a temporal and spatial scale. However, dysregulation of myelin plasticity can disadvantageously alter myelin microstructure and result in aberrant circuit function or contribute to pathological cell proliferation. Emerging roles for myelin plasticity in normal neurological function and in disease are discussed. © 2017 Wiley Periodicals, Inc. Develop Neurobiol 78: 123-135, 2018.
View details for PubMedID 28986960
View details for PubMedCentralID PMC5788316
Methotrexate Chemotherapy Induces Persistent Tri-glial Dysregulation that Underlies Chemotherapy-Related Cognitive Impairment.
Chemotherapy results in a frequent yet poorly understood syndrome of long-term neurological deficits. Neural precursor cell dysfunction and white matter dysfunction are thought to contribute to this debilitating syndrome. Here, we demonstrate persistent depletion of oligodendrocyte lineage cells in humans who received chemotherapy. Developing a mouse model of methotrexate chemotherapy-induced neurological dysfunction, we find a similar depletion of white matter OPCs, increased but incomplete OPC differentiation, and a persistent deficit in myelination. OPCs from chemotherapy-naive mice similarly exhibit increased differentiation when transplanted into the microenvironment of previously methotrexate-exposed brains, indicating an underlying microenvironmental perturbation. Methotrexate results in persistent activation of microglia and subsequent astrocyte activation that is dependent on inflammatory microglia. Microglial depletion normalizes oligodendroglial lineage dynamics, myelin microstructure, and cognitive behavior after methotrexate chemotherapy. These findings indicate that methotrexate chemotherapy exposure is associated with persistent tri-glial dysregulation and identify inflammatory microglia as a therapeutic target to abrogate chemotherapy-related cognitive impairment.
View details for PubMedID 30528430
Myelin plasticity in the central nervous system.
2016; 110: 563-573
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'.
View details for DOI 10.1016/j.neuropharm.2015.08.001
View details for PubMedID 26282119
Neuronal Activity Promotes Glioma Growth through Neuroligin-3 Secretion
2015; 161 (4): 803-816
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.
View details for DOI 10.1016/j.cell.2015.04.012
View details for PubMedID 25913192
Neuronal Activity Promotes Oligodendrogenesis and Adaptive Myelination in the Mammalian Brain
2014; 344 (6183): 487-?
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.
View details for DOI 10.1126/science.1252304
View details for Web of Science ID 000335157700034
View details for PubMedCentralID PMC4096908
Effect of cancer therapy on neural stem cells: implications for cognitive function
CURRENT OPINION IN ONCOLOGY
2012; 24 (6): 672-678
Modern cancer therapies have allowed for a dramatic increase in the survival rates in both children and adults. However, a frequent and unfortunate side-effect of cancer therapy is a long-term decline in neurocognitive function. Specifically, cranial radiation therapy markedly alters memory processes, while chemotherapeutic agents are correlated with deficits in attention, concentration, and speed of information processing. Here, we describe the putative cellular etiologies of cancer treatment-induced cognitive decline, with an emphasis on the role of neural stem and precursor cell dysfunction.New studies highlight the lasting effects of chemotherapy on memory, executive function, attention, and speed of information processing up to 20 years following chemotherapy. Cognitive decrements are associated with decreased white-matter integrity as well as alterations in stem cell function in humans and rodent models of cancer therapy. Genetic polymorphisms may underlie differential sensitivity of certain individuals to the neurological consequences of chemotherapy. Increasing data support the concept that disruption of normal neural stem and precursor cell function is an important causative factor for the cognitive deficits that result from cancer therapy in both children and adults.Further studies are needed to elucidate the role of chemotherapy on cell-intrinsic processes and cellular microenvironments. Further, the effects of the new generation of targeted molecular therapies on neural stem and progenitor cell function remains largely untested. Understanding the mechanisms behind cancer therapy-induced damage to neural stem and precursor cell populations will elucidate neuroprotective and cell replacement strategies aimed at preserving cognition after cancer therapy.
View details for DOI 10.1097/CCO.0b013e3283571a8e
View details for Web of Science ID 000310361500011
View details for PubMedID 22913969
Experimental 'Jet Lag' Inhibits Adult Neurogenesis and Produces Long-Term Cognitive Deficits in Female Hamsters
2010; 5 (12): e15267
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.
View details for DOI 10.1371/journal.pone.0015267
View details for Web of Science ID 000284821300019
View details for PubMedID 21152025
View details for PubMedCentralID PMC2995744
Proximate mechanisms driving circadian control of neuroendocrine function: Lessons from the young and old
OXFORD UNIV PRESS INC. 2009: 519?37
Circadian rhythms impact a variety of behavioral and physiological functions contributing to longevity and successful reproduction. In their natural environments, individuals of a species are faced with a multitude of challenges and the coordination of internal processes and behavior with external pressures has been hypothesized to be an important target of natural selection. Several lines of evidence from cyanobacteria, Drosophila, and plants provide strong support for an important role of the circadian clock in survival and reproductive success. Similarly in mammals, disruptions in circadian function markedly impact reproduction and lifespan. The present review discusses research outlining the proximate and ultimate mechanisms responsible for the central and peripheral control of the reproductive axis. Because precise temporal coordination of the endocrine system is particularly crucial for reproduction by females, the present overview focuses on the role of circadian timing in this sex.
View details for DOI 10.1093/icb/icp041
View details for Web of Science ID 000271946500005
View details for PubMedID 21665838
Aging in the circadian system: Considerations for health, disease prevention and longevity
PERGAMON-ELSEVIER SCIENCE LTD. 2009: 51?56
The circadian system orchestrates internal physiology on a daily schedule to promote optimal health and maximize disease prevention. Chronic disruptions in circadian function are associated with an increase in a variety of disease states including, heart disease, ulcers and diabetes. With advanced age, the genes regulating circadian function at the cellular level become disorganized and the ability of the brain clock to entrain to local time diminishes. As a result, aged individuals exhibit a loss of temporal coordination among bodily systems, leading to deficits in homeostasis and sub-optimal functioning. Such disruptions in the circadian system appear to accelerate the aging process and contribute to senescence, with some systems being more vulnerable than others. This review explores aging-associated changes in circadian function and examines evidence linking such alterations to adverse health consequences in late life and promotion of the aging process.
View details for DOI 10.1016/j.exger.2008.05.007
View details for Web of Science ID 000262623800009
View details for PubMedID 18579326
View details for PubMedCentralID PMC2636858
Age-related declines in exploratory behavior and markers of hippocampal plasticity are attenuated by prenatal choline supplementation in rats
2008; 1237: 110-123
Supplemental choline in the maternal diet produces a lasting enhancement in memory in offspring that resists age-related decline and is accompanied by neuroanatomical, neurophysiological and neurochemical changes in the hippocampus. The present study was designed to examine: 1) if prenatal choline supplementation alters behaviors that contribute to risk or resilience in cognitive aging, and 2) whether, at old age (25 months), prenatally choline-supplemented rats show evidence of preserved hippocampal plasticity. A longitudinal design was used to look at exploration of an open field, with and without objects, at 1 and 24 months of age in male and female rats whose mothers were fed a diet supplemented with choline (SUP; 5 mg/kg choline chloride) or not supplemented (CON; 1.1 mg/kg choline chloride) on embryonic days 12-17. Aging caused a significant decline in open field exploration that was more pronounced in males but interest in novel objects was maintained in both sexes. Prenatal choline supplementation attenuated, but did not prevent age-related decline in exploration in males and increased object exploration in young females. Following behavioral assessment, rats were euthanized to assess markers of hippocampal plasticity. Aged SUP males and females had more newly proliferated cells in the hippocampal dentate gyrus and protein levels of vascular endothelial growth factor (VEGF) and neurotrophin-3 (NT-3) were significantly elevated in female SUP rats in comparison to all other groups. Taken together, these findings provide the first evidence that prenatal choline supplementation causes changes in exploratory behaviors over the lifespan and preserves some features of hippocampal plasticity that can be seen even at 2 years of age.
View details for DOI 10.1016/j.brainres.2008.08.049
View details for Web of Science ID 000260815600013
View details for PubMedID 18786518
View details for PubMedCentralID PMC2677022
Alterations in RFamide-related peptide expression are coordinated with the preovulatory luteinizing hormone surge
2008; 149 (10): 4958?69
The preovulatory LH surge is triggered when the circadian pacemaker, the bilateral suprachiasmatic nucleus (SCN), stimulates the GnRH system in the presence of high estrogen concentrations (positive feedback). Importantly, during the remainder of the estrous cycle, estradiol inhibits LH release via negative feedback. We have recently documented the presence of a novel mammalian RFamide-related peptide (RFRP), a putative gonadotropin-inhibitory hormone (GnIH), that presumably acts upstream of GnRH to modulate the negative feedback effects of estrogen. The present series of studies used female Syrian hamsters to examine the possibility that, in addition to driving the LH surge positively, the SCN concomitantly coordinates the removal of steroid-mediated RFRP inhibition of the gonadotropic axis to permit the surge. We found that the SCN forms close appositions with RFRP cells, suggesting the possibility for direct temporal control of RFRP activity. During the time of the LH surge, immediate-early gene expression is reduced in RFRP cells, and this temporal regulation is estrogen dependent. To determine whether projections from the SCN regulate the timed reduction in activation of the RFRP system, we exploited the phenomenon of splitting. In split animals in which the SCN are active in antiphase, activation of the RFRP system is asymmetrical. Importantly, this asymmetry is opposite to the state of the GnRH system. Together, these findings point to novel circadian control of the RFRP system and potential participation in the circuitry controlling ovulatory function.
View details for DOI 10.1210/en.2008-0316
View details for Web of Science ID 000259400300021
View details for PubMedID 18566114
View details for PubMedCentralID PMC2582915
Prenatal choline availability modulates hippocampal neurogenesis and neurogenic responses to enriching experiences in adult female rats
EUROPEAN JOURNAL OF NEUROSCIENCE
2007; 25 (8): 2473-2482
Increased dietary intake of choline early in life improves performance of adult rats on memory tasks and prevents their age-related memory decline. Because neurogenesis in the adult hippocampus also declines with age, we investigated whether prenatal choline availability affects hippocampal neurogenesis in adult Sprague-Dawley rats and modifies their neurogenic response to environmental stimulation. On embryonic days (ED) 12-17, pregnant rats ate a choline-supplemented (SUP-5 g/kg), choline sufficient (SFF-1.1 g/kg), or choline-free (DEF) semisynthetic diet. Adult offspring either remained in standard housing or were given 21 daily visits to explore a maze. On the last ten exploration days, all rats received daily injections of 5-bromo-2-deoxyuridine (BrdU, 100 mg/kg). The number of BrdU+ cells was significantly greater in the dentate gyrus in SUP rats compared to SFF or DEF rats. While maze experience increased the number of BrdU+ cells in SFF rats to the level seen in the SUP rats, this enriching experience did not alter cell proliferation in DEF rats. Similar patterns of cell proliferation were obtained with immunohistochemical staining for neuronal marker doublecortin, confirming that diet and exploration affected hippocampal neurogenesis. Moreover, hippocampal levels of the brain-derived neurotrophic factor (BDNF) were increased in SUP rats as compared to SFF and DEF animals. We conclude that prenatal choline intake has enduring effects on adult hippocampal neurogenesis, possibly via up-regulation of BDNF levels, and suggest that these alterations of neurogenesis may contribute to the mechanism of life-long changes in cognitive function governed by the availability of choline during gestation.
View details for DOI 10.1111/j.1460-9568.2007.05505.x
View details for Web of Science ID 000245742300020
View details for PubMedID 17445242
View details for PubMedCentralID PMC2435208