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

Díaz-Castro, Blanca; Bernstein, Alexander M.; Coppola, Giovanni; Sofroniew, Michael V.; Khakh, Baljit S.

doi:10.1101/2020.12.27.424483

Cited by 4 publications

(6 citation statements)

References 61 publications

(103 reference statements)

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“…Akin to previous studies, results from the current study showed that RiboTag can be used as an effective method to isolate astrocyte-specific mRNAs for subsequent RNA-seq (Boisvert et al, 2018;Yu et al, 2021;Diaz-Castro et al, 2021), which can be used to elucidate cell-type specific transcriptional and translational changes. We hypothesized that cocaine-administering rats would display significant numbers of differentially expressed genes in comparison to saline at both withdrawal timepoints, day 1 and 45.…”

Section: Discussionsupporting

confidence: 57%

“…Following diffusion, microinjectors were removed slowly over 1-2 minutes. Plasmids for AAV manufacturing used were pZac2.1.GfaABC1D-Rpl22-HA (Diaz-Castro et al, 2019;Diaz-Castro et al, 2021;Yu et al, 2020). The plasmid was provided by Addgene and packaged into an AAV at the UNC Viral Vector Core.…”

Section: Animals and Surgical Proceduresmentioning

confidence: 99%

“…This method employs astrocyte-specific AAV5 GfaABC1D-Rpl22-HA to enable immunoprecipitation of HA-tagged ribosome-associated mRNAs from NAc astrocytes, thus providing insight into how NAc astrocyte gene expression is affected by a history of cocaine selfadministration and home cage abstinence and how cocaine-induced functional deficits in NAc astrocytes may promote cocaine-seeking behaviors. Several others (Boisvert et al, 2018;Yu et al, 2020;Diaz-Castro et al, 2021) have utilized this technique either with AAV or transgenic mice to examine astrocyte gene expression changes in diverse contexts, including development and aging, neuroinflammation, and pharmacological activation of astrocytes. In relation to cocaine, other previous studies have investigated the effects of cocaine on gene expression in varied brain regions including the ventral tegmental area, but these studies used bulk RNA-Seq (Walker et al, 2018;Campbell et al, 2021), which lacks ability to examine cell-specific gene expression.…”

Section: Introductionmentioning

confidence: 99%

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Investigating cocaine- and abstinence-induced effects on astrocyte gene expression in the nucleus accumbens

Franklin,

Testen,

Mieczkowski

et al. 2024

Preprint

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In recent years, astrocytes have been increasingly implicated in cellular mechanisms of substance use disorders (SUD). Astrocytes are structurally altered following exposure to drugs of abuse; specifically, astrocytes within the nucleus accumbens (NAc) exhibit significantly decreased surface area, volume, and synaptic colocalization after operant self-administration of cocaine and extinction or protracted abstinence (45 days). However, the mechanisms that elicit these morphological modifications are unknown. The current study aims to elucidate the molecular modifications that lead to observed astrocyte structural changes in rats across cocaine abstinence using astrocyte-specific RiboTag and RNA-seq, as an unbiased, comprehensive approach to identify genes whose transcription or translation change within NAc astrocytes following cocaine self- administration and extended abstinence. Using this method, our data reveal cellular processes including cholesterol biosynthesis that are altered specifically by cocaine self-administration and abstinence, suggesting that astrocyte involvement in these processes is changed in cocaine-abstinent rats. Overall, the results of this study provide insight into astrocyte functional adaptations that occur due to cocaine exposure or during cocaine withdrawal, which may pinpoint further mechanisms that contribute to cocaine-seeking behavior.

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Section: Discussionsupporting

confidence: 57%

Section: Animals and Surgical Proceduresmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Investigating cocaine- and abstinence-induced effects on astrocyte gene expression in the nucleus accumbens

Franklin,

Testen,

Mieczkowski

et al. 2024

Preprint

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“…We chose LPS to induce a physiological form of systemic inflammation. LPS produces robust and pervasive inflammation, including microglial and astrocytic activation within the CNS (Hoogland et al, 2015;Perez-Dominguez et al, 2019;Diaz-Castro et al, 2021). In particular, LPS was previously shown to cause the secretion of pro-inflammatory mediators and neuronal activation within the LPBN (Tkacs and Li, 1999;Zhang et al, 2003;Cheng et al, 2022).…”

Section: Failed To Induce Any Detectable Changes In Lpbn Glial Cellsmentioning

confidence: 99%

Differential activation of spinal and parabrachial glial cells in a neuropathic pain model

Mussetto

Møen

Trofimova

et al. 2023

Front. Cell. Neurosci.

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The clinical burden faced by chronic pain patients is compounded by affective comorbidities, such as depression and anxiety disorders. Emerging evidence suggests that reactive glial cells in the spinal cord dorsal horn play a key role in the chronification of pain, while supraspinal glia are important for psychological aspects of chronic pain. The lateral parabrachial nucleus (LPBN) in the brainstem is a key node in the ascending pain system, and is crucial for the emotional dimension of pain. Yet, whether astrocytes and microglia in the LPBN are activated during chronic pain is unknown. Here, we evaluated the occurrence of glial activation in the LPBN of male Sprague–Dawley rats 1, 4, and 7 weeks after inducing a chronic constriction injury (CCI) of the sciatic nerve, a prevalent neuropathic pain model. CCI animals developed mechanical and thermal hypersensitivity that persisted for at least 4 weeks, and was mostly reversed after 7 weeks. Using immunohistochemical staining and confocal imaging, we found that CCI caused a strong increase in the expression of the astrocytic marker GFAP and the microglial marker Iba1 in the ipsilateral spinal dorsal horn, with peak expression observed 1 week post-injury. Moreover, morphology analysis revealed changes in microglial phenotype, indicative of microglia activation. In contrast, CCI did not induce any detectable changes in either astrocytes or microglia in the LPBN, at any time point. Thus, our results indicate that while neuropathic pain induces a robust glial reaction in the spinal dorsal horn, it fails to activate glial cells in the LPBN.

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“…Despite the clear evidence that glial cells of peripheral somatosensory system, including dorsal root ganglion (DRG) and spinal cord, play a pivotal role in sensory perception, processing as well as motor behavior, their cellular and functional heterogeneity remain unclear. Recently, emerging evidence has revealed cellular and molecular heterogeneity in specific glial cells of the CNS using single-cell (scRNA-seq) or single-nucleus RNA sequencing (snRNA-seq) [3,[9][10][11][12]. Using scRNA-seq, Hasel et al identified 10 astrocyte subclusters in the mouse brain and characterized the heterogeneous responses of different astrocyte subsets to inflammation [12].…”

Section: Introductionmentioning

confidence: 99%

Single-nucleus transcriptomic analysis reveals divergence of glial cells in peripheral somatosensory system between human and mouse

Zhang

Wei

Liu

et al. 2022

Preprint

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Glial cells play a crucial role in regulating physiological and pathological functions, such as sensation, infections, acute injuries, and chronic neurodegenerative disorders. Glial cells include astrocytes, microglia, and oligodendrocytes in the central nervous system (CNS) and satellite glial cells (SGCs) in the peripheral nervous system (PNS). Despite the understanding of glial subtypes and functional heterogeneity in animal models achieved by single-cell or single-nucleus RNA sequencing, no research has investigated the transcriptomic profiles of glial cells in the human PNS and spinal cord. Here, we used high-throughput single-nucleus RNA sequencing to map the cellular and molecular heterogeneity of SGCs in the human dorsal root ganglion (DRG) and astrocytes, microglia, and oligodendrocytes in the human spinal cord. To explore the conservation and divergence across species, we compared these human findings with those from mice. Additionally, the expression profiles of risk genes of common DRG and spinal cord diseases in glial cells were compared between humans and mice. As a result, little SGCs heterogeneity was found in both human and mouse DRG. In the human spinal cord, astrocytes, microglia, and oligodendrocytes were respectively divided into six distinct transcriptomic subclusters. In the mouse spinal cord, astrocytes, microglia, and oligodendrocytes were divided into six, five, and six distinct transcriptomic subclusters, respectively. The comparative results revealed substantial heterogeneity in all glial cells between humans and mice. Notably, we also identified transcriptomic heterogeneity in several classical genes and risk genes for neurological disorders across humans and mice. Together, the present data comprehensively profiled glial cell heterogeneity and provides a powerful resource for investigating the cellular basis of glial-related physiological and pathological conditions in peripheral somatosensory system.

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

Cited by 4 publications

References 61 publications

Investigating cocaine- and abstinence-induced effects on astrocyte gene expression in the nucleus accumbens

Investigating cocaine- and abstinence-induced effects on astrocyte gene expression in the nucleus accumbens

Differential activation of spinal and parabrachial glial cells in a neuropathic pain model

Single-nucleus transcriptomic analysis reveals divergence of glial cells in peripheral somatosensory system between human and mouse

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