Early stress-induced impaired microglial pruning of excitatory synapses on immature CRH-expressing neurons provokes aberrant adult stress responses

Bolton, Jessica L.; Short, Annabel K.; Othy, Shivashankar; Kooiker, Cassandra L.; Shao, Manlin; Gunn, Benjamin G.; Beck, Jaclyn; Bai, Xinglong; Law, Stephanie M.; Savage, Julie C.; Lambert, Jeremy J.; Belelli, Delia; Tremblay, Marie‐Ève; Cahalan, Michael D.; Baram, Tallie Z.

doi:10.1016/j.celrep.2022.110600

Cited by 82 publications

(82 citation statements)

References 107 publications

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“…This is in line with the increased phagocytosis of bacterial particles observed in mice exposed to maternal separation (13), even though this was at a much younger age. Our data, taken together with the reported findings by Delpech et al ( 13) and Bolton et al (88), suggest that ELS effects of phagocytosis, rather than being generalized, are more complex, dependent e.g. on specific substrates and possible eat-me signals.…”

Section: Els Impacts On Microglial Phagocytosis Of Synaptosomessupporting

confidence: 83%

Section: Els Impacts On Microglial Phagocytosis Of Synaptosomessupporting

confidence: 64%

“…This suggests that ELS leads to an altered molecular signature in the developmental synapses in the hippocampus. Such reduction of the phagocytosis of ELS synapses, is in line with ELS-induced impaired pruning of excitatory synapses in the hypothalamus at P9 (88). These synaptic signatures could drive the lasting microglial (mal-) adaptations, as we found in our adult data, where the early-life condition of both synaptosomes and microglia contributed to reduced synaptic uptake, possibly ultimately contributing to the well-established ELS effects on hippocampal plasticity (40,89,90).…”

Section: Discussionsupporting

confidence: 52%

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Early-life stress lastingly impacts microglial transcriptome and function under basal and immune-challenged conditions

Reemst

Kracht

Kotah

et al. 2022

Preprint

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Early-life stress (ELS) leads to increased vulnerability to psychiatric disorders including depression later in life. Neuroinflammatory processes have been implicated in ELS-induced negative health outcomes, but how ELS impacts microglia, the main tissue-resident macrophages of the central nervous system, is unknown. Here, we determined the effects of ELS induced by limited bedding and nesting material during the first week of life (postnatal days [P]2 - 9) on microglial i) morphology; ii) hippocampal gene expression; and iii) synaptosome phagocytic capacity in male pups (P9) and adult (P200) mice. The hippocampus of ELS-exposed adult mice displayed altered proportions of morphological subtypes of microglia, as well as microglial transcriptomic changes related to the tumor necrosis factor response and protein ubiquitination. ELS exposure leads to distinct gene expression profiles during microglial development from P9 to P200 and in response to an LPS challenge at P200. Functionally, synaptosomes from ELS-exposed mice were phagocytosed less by age-matched microglia. At P200, but not P9, ELS microglia showed reduced synaptosome phagocytic capacity when compared to CTRL microglia. Lastly, we confirmed the ELS-induced increased expression of the phagocytosis-related gene GAS6 that we observed in mice, in the dentate gyrus of individuals with a history of child abuse using in situ hybridization. These findings reveal persistent effects of ELS on microglial function and suggest that altered microglial phagocytic capacity is a key contributor to ELS-induced phenotypes.

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Section: Els Impacts On Microglial Phagocytosis Of Synaptosomessupporting

confidence: 83%

Section: Els Impacts On Microglial Phagocytosis Of Synaptosomessupporting

confidence: 64%

Section: Discussionsupporting

confidence: 52%

See 1 more Smart Citation

Early-life stress lastingly impacts microglial transcriptome and function under basal and immune-challenged conditions

Reemst

Kracht

Kotah

et al. 2022

Preprint

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“…In humans, unpredictable (high entropy) sequences of maternal sensory signals to the infant predict enduring adverse emotional outcomes, including poorer control of emotions and behaviors (effortful control) (13), an established predictor of mental vulnerabilities and risk of posttraumatic stress disorder later in life. Notably, in controlled mouse and rat studies, unpredictable sequences of dam behaviors directly led to aberrant emotional circuit maturation and consequent disrupted pleasure-like behaviors in the pups (11,12,14).…”

Section: Learning From Sensory and Memory Circuitsmentioning

confidence: 99%

“…For example, unpredictable sequences of mouse maternal care behaviors influence synaptic connectivity in key brain nodes that contribute to stress and other emotional circuits. Specifically, mice reared by dams displaying unpredictable sequences of care (but with the same amount of care overall) during the sensitive early postnatal period have augmented density of functional excitatory synapses on stress-sensitive and regulatory corticotropin-releasing hormone (CRH)-expressing hypothalamic neurons (14). This aberrant synaptic connectivity leads to disrupted behavioral and hormonal responses to acute and chronic stresses later in life.…”

Section: Learning From Sensory and Memory Circuitsmentioning

confidence: 99%

Principles of emotional brain circuit maturation

Birnie

Baram

2022

Science

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Chemogenetic modulation of astrocytes and microglia: State‐of‐the‐art and implications in neuroscience

Bossuyt

Herrewegen

Nestor

et al. 2023

Glia

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Insights into the role astrocytes and microglia play in normal and diseased brain functioning has expanded drastically over the last decade. Recently, chemogenetic tools have emerged as cutting-edge techniques, allowing targeted and spatiotemporal precise manipulation of a specific glial cell type. As a result, significant advances in astrocyte and microglial cell function have been made, showing how glial cells can intervene in central nervous system (CNS) functions such as cognition, reward and feeding behavior in addition to their established contribution in brain diseases, pain, and CNS inflammation. Here, we discuss the latest insights in glial functions in health and disease that have been made through the application of chemogenetics. We will focus on the manipulation of intracellular signaling pathways induced by activation of the designer receptors exclusively activated by designer drugs (DREADDs) in astrocytes and microglia. We will also elaborate on some of the potential pitfalls and the translational potential of the DREADD technology.

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Early stress-induced impaired microglial pruning of excitatory synapses on immature CRH-expressing neurons provokes aberrant adult stress responses

Cited by 82 publications

References 107 publications

Early-life stress lastingly impacts microglial transcriptome and function under basal and immune-challenged conditions

Early-life stress lastingly impacts microglial transcriptome and function under basal and immune-challenged conditions

Principles of emotional brain circuit maturation

Chemogenetic modulation of astrocytes and microglia: State‐of‐the‐art and implications in neuroscience

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