Work hard, play hard: how sexually differentiated microglia work to shape social play and reproductive behavior

Sullivan, Olivia; Ciernia, Annie Vogel

doi:10.3389/fnbeh.2022.989011

Cited by 11 publications

(13 citation statements)

References 98 publications

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“…Last, it may be of note that sex hormones have been found to influence microglia morphology and function [ 120 ], and thus are an important consideration when assessing sex differences in immune responses. However, in the context of female stress responses, results from our previous work [ 49 ] showed that CUS significantly increased estrous cycle length with some rats showing a total loss of cycling, effects that began early in the CUS paradigm.…”

Section: Discussionmentioning

confidence: 99%

Nrf2 activation rescues stress-induced depression-like behaviour and inflammatory responses in male but not female rats

McCallum,

Thériault,

Manduca

et al. 2024

Biol Sex Differ

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Background Major depressive disorder (MDD) is a recurring affective disorder that is two times more prevalent in females than males. Evidence supports immune system dysfunction as a major contributing factor to MDD, notably in a sexually dimorphic manner. Nuclear factor erythroid 2-related factor 2 (Nrf2), a regulator of antioxidant signalling during inflammation, is dysregulated in many chronic inflammatory disorders; however, its role in depression and the associated sex differences have yet to be explored. Here, we investigated the sex-specific antidepressant and immunomodulatory effects of the potent Nrf2 activator dimethyl fumarate (DMF), as well as the associated gene expression profiles. Methods Male and female rats were treated with vehicle or DMF (25 mg/kg) whilst subjected to 8 weeks of chronic unpredictable stress. The effect of DMF treatment on stress-induced depression- and anxiety-like behaviours, as well as deficits in recognition and spatial learning and memory were then assessed. Sex differences in hippocampal (HIP) microglial activation and gene expression response were also evaluated. Results DMF treatment during stress exposure had antidepressant effects in male but not female rats, with no anxiolytic effects in either sex. Recognition learning and memory and spatial learning and memory were impaired in chronically stressed males and females, respectively, and DMF treatment rescued these deficits. DMF treatment also prevented stress-induced HIP microglial activation in males. Conversely, females displayed no HIP microglial activation associated with stress exposure. Last, chronic stress elicited sex-specific alterations in HIP gene expression, many of which were normalized in animals treated with DMF. Of note, most of the differentially expressed genes in males normalized by DMF were related to antioxidant, inflammatory or immune responses. Conclusions Collectively, these findings support a greater role of immune processes in males than females in a rodent model of depression. This suggests that pharmacotherapies that target Nrf2 have the potential to be an effective sex-specific treatment for depression.

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Section: Discussionmentioning

confidence: 99%

Nrf2 activation rescues stress-induced depression-like behaviour and inflammatory responses in male but not female rats

McCallum,

Thériault,

Manduca

et al. 2024

Biol Sex Differ

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“…While our dataset was too underpowered to quantify sex differences in morphology, our tool could be used to explore known sex differences in microglia in various contexts such as early brain development. (Sullivan & Ciernia, 2022)…”

Section: Discussionmentioning

confidence: 99%

Development of a high-throughput pipeline to characterize microglia morphological states at a single-cell resolution

Kim,

Pavlidis,

Ciernia

2023

Preprint

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As rapid responders to their environments, microglia engage in functions that are mirrored by their cellular morphology. Microglia are classically thought to exhibit a ramified morphology under homeostatic conditions which switches to an ameboid form during inflammatory conditions. However, microglia display a wide spectrum of morphologies outside of this dichotomy, including rod-like, ramified, ameboid, and hypertrophic states, which have been observed across brain regions, neurodevelopmental timepoints, and various pathological contexts. We used dimensionality reduction and clustering approaches to consider contributions of multiple morphology measures together to define a spectrum of microglial morphological states. Using ImageJ tools, we first developed a semi-automated approach to characterize 27 morphology features from hundreds to thousands of individual microglial cells in a brain subregion-specific manner. Within this pool of morphology measures, we defined distinct sets of highly correlated features that describe different aspects of morphology, including branch length, branching complexity, territory span, and cell circularity. When considered together, these sets of features drove different morphological clusters. Furthermore, our analysis toolset captured morphological states similarly and robustly when applied to independent datasets and using different immunofluorescent markers for microglia. We have compiled our morphology analysis pipeline into an accessible, easy to use, and fully open-source ImageJ macro and R package that the neuroscience community can expand upon and directly apply to their own analyses. Outcomes from this work will supply the field with new tools to systematically evaluate the heterogeneity of microglia morphological states across various experimental models and research questions.

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“…Autocrine feedback loops are often utilized by immune cells to self-regulate state, but whether C1q could be acting in this manner is unknown and will be investigated in future studies. In parallel, the critical role of sex differences in microglia has become increasingly recognized (Lynch, 2022; Sullivan & Ciernia, 2022). The novel organelle phenotyping approach established here provides the field with a vital tool that enables investigation of autocrine mechanisms and sex differences in microglia.…”

Section: Discussionmentioning

confidence: 99%

Organelle phenotyping and multi-dimensional microscopy identify C1q as a novel regulator of microglial function

Sakthivel,

Scipioni,

Karam

et al. 2023

Preprint

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Microglia, the immune cells of the central nervous system (CNS), are incredibly dynamic and heterogenous cells. While single cell RNA sequencing has become the conventional methodology for evaluating microglial state, transcriptomics do not provide insight into functional changes. Here, we propose a novel organelle phenotyping approach where we treat live human induced pluripotent stem cell-derived microglia (iMGL) with organelle dyes (mitochondria, lipids, lysosomes) and acquire data by live-cell spectral microscopy. Dimensionality reduction techniques and unbiased cluster identification allow for recognition of microglial subpopulations based in organelle function. We validate this methodology using lipopolysaccharide (LPS) and IL-10 treatment to polarize iMGL to an inflammatory” and “anti-inflammatory state, respectively, and then apply it to identify a novel regulator of iMGL function, complement protein C1q. C1q is traditionally known as the initiator of the complement cascade, but here we use organelle phenotyping to identify a role for C1q in regulating iMGL fatty acid storage and mitochondria membrane potential. Follow up evaluation of microglia with more traditional read outs of activation state confirm that C1q drives an increase in microglia pro-inflammatory cytokine production and migration, while suppressing microglial proliferation. These data together validate the use of a novel organelle phenotyping approach and enable better mechanism investigation of molecular regulators of microglial state, such as C1q.

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Work hard, play hard: how sexually differentiated microglia work to shape social play and reproductive behavior

Cited by 11 publications

References 98 publications

Nrf2 activation rescues stress-induced depression-like behaviour and inflammatory responses in male but not female rats

Nrf2 activation rescues stress-induced depression-like behaviour and inflammatory responses in male but not female rats

Development of a high-throughput pipeline to characterize microglia morphological states at a single-cell resolution

Organelle phenotyping and multi-dimensional microscopy identify C1q as a novel regulator of microglial function

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