Context-Specific Striatal Astrocyte Molecular Responses Are Phenotypically Exploitable

Yu, Xinzhu; Nagai, Jun; Martí-Solano, Maria; Soto, Joselyn S.; Coppola, Giovanni; Babu, M. Madan; Khakh, Baljit S.

doi:10.1016/j.neuron.2020.09.021

Cited by 87 publications

(94 citation statements)

References 83 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Broadly, these data demonstrate that astrocytes from different brain areas show diverse responses to the same stimulus and underscore the necessity of drawing conclusions based on evaluations of defined brain areas, rather than mixing between brain regions. These data add support to the emerging view that astrocytes are separable between brain areas and respond in a contextspecific manner (Chai et al, 2017;Haim and Rowitch, 2017;Khakh and Deneen, 2019;Yu et al, 2020).…”

Section: Impact Of Neuroinflammation On Pfc and Vcx Astrocyte Transcrsupporting

confidence: 80%

“…This is potentially an important question with relevance to regional susceptibility of CNS regions to specific diseases. Furthermore, this result underscores the need for considerable caution when analyzing gene expression data that are available in various resources and published studies: the impact of regional variation (Haim and Rowitch, 2017;Khakh and Deneen, 2019), context-specific responses (Yu et al, 2020), and of variable responses to the same stimulus that is dependent on the brain region, as shown here, need to be thoughtfully accounted for in order to make meaningful conclusions. To what extent these region specific responses are due to cell autonomous mechanisms or to the variability of response of surrounding cells needs further exploration.…”

Section: Discussionmentioning

confidence: 71%

“…As the main integrator of the decision making circuits of the limbic system, the PFC becomes dysfunctional in both psychiatric and dementia-related disorders and when symptoms such as anhedonia are observed (Russo and Nestler, 2013;Elahi and Miller, 2017;Dafsari and Jessen, 2020;Haber et al, 2020). Astrocyte specific and whole tissue RNA-seq was performed during the development and recovery of anhedonia with the goal of identifying molecular changes within astrocytes in an unbiased way (Srinivasan et al, 2016;Chai et al, 2017;Yu et al, 2018;Yu et al, 2020). In addition, we compared astrocyte gene expression data from PFC to that from visual cortex (VCX) to evaluate how neuroinflammation affected astrocyte regional transcriptional identity.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Molecular and functional properties of PFC astrocytes during neuroinflammation-induced anhedonia

Díaz-Castro

Bernstein

Coppola

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

Astrocytes are widely implicated in CNS diseases, but their contributions to disease related phenotypes remain incompletely explored. Anhedonia accompanies several neurological and psychiatric diseases, including major depressive disorder (MDD) and Alzheimer’s disease (AD), both of which are associated with neuroinflammation. In order to explore how neuroinflammation affects astrocytes, we assessed medial prefrontal cortex (PFC) and visual cortex (VCX) astrocytic gene expression using a neuroinflammation mouse model that displayed anhedonia as a phenotype. In this model, anhedonia was reversed by the fast acting antidepressant ketamine. Astrocyte specific gene expression alterations included those related to immune cell signaling, intracellular Ca2+ signaling, cholesterol biosynthesis, and metabolic pathways. Such changes peaked when anhedonia was greatest, and reversed to normal when anhedonia subsided. However, region-specific molecular identities between PFC and VCX astrocytes were maintained throughout, implying that astrocyte identities do not converge during neuroinflammation. We also mapped anhedonia-related astrocyte and bulk tissue gene expression changes onto published PFC single cell RNA sequencing data, and compared them to MDD and AD post-mortem human tissue samples to identify shared mechanisms. Finally, we assessed how neuroinflammation affected mPFC neuronal properties and detected no alterations at a time point when there was strong astrocyte reactivity. Our data show that neuroinflammation can cause significant and reversible changes in astrocyte gene expression and mouse behaviour without obvious neurotoxicity or loss of essential homeostatic functions. Furthermore, gene expression signatures accompanying neuroinflammation reveal pathways shared with MDD and AD, which display neuroinflammation as a comorbidity in humans.Significance statementAstrocytes are widely implicated in brain diseases, but their contributions to disease-related phenotypes remain incompletely explored. To make inroads into this problem, we assessed medial prefrontal cortex (PFC) and visual cortex (VCX) astrocyte gene expression using a peripherally induced neuroinflammation mouse model that produced anhedonia – a phenotype associated with several brain disorders. Neuroinflammation caused reversible changes in mouse behaviour and astrocyte-specific gene expression changes, some of which were related to human post mortem data for major depressive disorder (MDD) and Alzheimer’s disease (AD), but without any clear evidence of neurotoxicity in PFC of mice. The astrocyte molecular alterations accompanying neuroinflammation-induced anhedonia will be informative to explore diverse brain disorders and the effects of neuroinflammation on the CNS more broadly.

show abstract

Section: Impact Of Neuroinflammation On Pfc and Vcx Astrocyte Transcrsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 71%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Molecular and functional properties of PFC astrocytes during neuroinflammation-induced anhedonia

Díaz-Castro

Bernstein

Coppola

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…There is now a variety of evidence showing that astrocytes help shape circuit functions and behavior (Nedergaard, 1994; Parpura et al, 1994; Halassa et al, 2009; Robel et al, 2015; Papouin et al, 2017; Dowling and Allen, 2018; Mu et al, 2019; Nagai et al, 2019; Huang et al, 2020). Various groups have demonstrated that altering intracellular astrocyte signaling in vivo can induce abnormal behavior or correct phenotypic behavior in disease models (Chen et al, 2016; Ma et al, 2016; Ng et al, 2016; Kelley et al, 2018; Yu et al, 2018; Ung et al, 2020; Yu et al, 2020; Nagai et al, 2021). Beyond these roles in synapse development and function, astrocytes provide metabolic support to neurons (Walz and Mukerji, 1988; Pellerin and Magistretti, 1994; Lebon et al, 2002; Itoh et al, 2003), maintain extracellular potassium levels (Kuffler et al, 1966; Olsen and Sontheimer, 2008; Kelley et al, 2018), participate in recycling neurotransmitters (Rothstein et al, 1996), regulate blood flow (Mulligan and MacVicar, 2004; Takano et al, 2006; Attwell et al, 2010), and maintain the integrity of the blood-brain barrier (Abbott et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

“…Astrocytes undergoing reactive astrogliosis in response to a challenge can display stark morphological changes, including hypertrophy and retraction of processes, in addition to a plethora of intracellular alterations (Sofroniew, 2020). Reactivity is observed in many neurological disorders including traumatic brain injury, stroke, epilepsy, and neurodegenerative diseases, and there appears to be disease-specific aspects to this response (Beach et al, 1989; Panickar and Norenberg, 2005; Binder and Steinhauser, 2006; Burda et al, 2016; Liddelow et al, 2017; Yu et al, 2020). This raises the question, what characterizes human astrocyte reactivity, and how does this profile differ in response to varying stimuli?…”

Section: Introductionmentioning

confidence: 99%

Human Astrocytes Exhibit Tumor Microenvironment-, Age-, and Sex-Related Transcriptomic Signatures

Mc¹,

Haney²,

Caneda³

et al. 2021

Preprint

View full text Add to dashboard Cite

Astrocytes are dynamic cells with important roles in brain function and neurological disease. There are notable species differences between human astrocytes and commonly used animal models. However, changes of the molecular attributes of human astrocytes across disease states, sex, and age are largely unknown, which is a barrier in understanding human astrocyte biology and its potential involvement in neurological diseases. To better understand the properties of human astrocytes, we acutely purified astrocytes from the cerebral cortices of over 40 humans across various ages, sexes, and disease states. We performed RNA sequencing to generate transcriptomic profiles of these astrocytes and identified genes associated with these biological variables. Here, we identified a robust transcriptomic signature of human astrocytes in the tumor-surrounding microenvironment, including upregulation of proliferation processes, along with downregulation of genes involved in ionic homeostasis and synaptic function, suggesting involvement of peri-tumor astrocytes in tumor-associated neural circuit dysfunction. In aging, we also found downregulation of synaptic regulators and upregulation of markers of astrocyte reactivity, while in maturation we identified changes in ionic transport with implications for calcium signaling. In addition, we identified some of the first transcriptomic evidence of sexual dimorphism in human cortical astrocytes, which has implications for observed sex differences across many neurological disorders. Overall, genes involved in synaptic function exhibited dynamic changes in multiple conditions. This data provides powerful new insights into human astrocyte biology in several biologically relevant states, that will aid in generating novel testable hypotheses about homeostatic and reactive astrocytes in humans.

show abstract

A perspective on astrocyte regulation of neural circuit function and animal behavior

Hirrlinger

Nimmerjahn

2022

Glia

View full text Add to dashboard Cite

Studies over the past two decades have demonstrated that astrocytes are tightly associated with neurons and play pivotal roles in neural circuit development, operation, and adaptation in health and disease. Nevertheless, precisely how astrocytes integrate diverse neuronal signals, modulate neural circuit structure and function at multiple temporal and spatial scales, and influence animal behavior or disease through aberrant excitation and molecular output remains unclear. This Perspective discusses how new and state‐of‐the‐art approaches, including fluorescence indicators, opto‐ and chemogenetic actuators, genetic targeting tools, quantitative behavioral assays, and computational methods, might help resolve these longstanding questions. It also addresses complicating factors in interpreting astrocytes' role in neural circuit regulation and animal behavior, such as their heterogeneity, metabolism, and inter‐glial communication. Research on these questions should provide a deeper mechanistic understanding of astrocyte‐neuron assemblies' role in neural circuit function, complex behaviors, and disease.

show abstract

Context-Specific Striatal Astrocyte Molecular Responses Are Phenotypically Exploitable

Cited by 87 publications

References 83 publications

Molecular and functional properties of PFC astrocytes during neuroinflammation-induced anhedonia

Molecular and functional properties of PFC astrocytes during neuroinflammation-induced anhedonia

Human Astrocytes Exhibit Tumor Microenvironment-, Age-, and Sex-Related Transcriptomic Signatures

A perspective on astrocyte regulation of neural circuit function and animal behavior

Contact Info

Product

Resources

About