Biology subjects

Ceasrine, A. M.

Publications and source records attributed to Ceasrine, A. M..

6 recordsLinked to original sources

bioRxiv2024

Neuron Derived Cytokine Interleukin-34 Controls Developmental Microglia Function

Neuron-microglia interactions dictate the development of neuronal circuits in the brain. However, the factors that regulate these processes across development are largely unknown. Here, we find that IL34, a neuron-derived cytokine, is upregulated in early development and maintains neuroprotective, mature microglia in the anterior cingulate cortex (ACC) of mice. We show that IL34 is upregulated in the second week of postnatal life and is expressed primarily in excitatory neurons. Excitatory-neuron specific knock-out of IL34 reduced microglia number and TMEM119 expression and increased aberrant microglial phagocytosis of excitatory thalamocortical synapses in the ACC. Acute, low dose blocking of IL34 at postnatal day 15 similarly decreased TMEM119 and inappropriately increased microglial phagocytosis of synapses. Viral overexpression of IL34 induced TMEM119 expression and prevented appropriate microglial phagocytosis of synapses. These findings establish IL34 as a key regulator of neuron-microglia crosstalk in postnatal brain development, controlling both microglial maturation and synapse engulfment.

neuroscience↗

bioRxiv2023

Hofbauer cells and fetal brain microglia share transcriptional profiles and responses to maternal diet-induced obesity

Maternal immune activation is associated with adverse offspring neurodevelopmental outcomes, many mediated by in utero microglial programming. As microglia remain inaccessible throughout development, identification of noninvasive biomarkers reflecting fetal brain microglial programming could permit screening and intervention. We used lineage tracing to demonstrate the shared ontogeny between fetal brain macrophages (microglia) and fetal placental macrophages (Hofbauer cells) in a mouse model of maternal diet-induced obesity, and single-cell RNA-seq to demonstrate shared transcriptional programs. Comparison with human datasets demonstrated conservation of placental resident macrophage signatures between mice and humans. Single-cell RNA-seq identified common alterations in fetal microglial and Hofbauer cell gene expression induced by maternal obesity, as well as sex differences in these alterations. We propose that Hofbauer cells, which are easily accessible at birth, provide novel insights into fetal brain microglial programs, and may facilitate the early identification of offspring vulnerable to neurodevelopmental disorders in the setting of maternal exposures.

developmental biology↗

bioRxiv2022

Gonadal Hormones Impart Male-Biased Behavioral Vulnerabilities to Immune Activation via Microglial Mitochondrial Function

There is a strong male bias in the prevalence of many neurodevelopmental disorders such as autism spectrum disorder. However, the mechanisms underlying this sex bias remain elusive. Infection during the perinatal period is associated with an increased risk of neurodevelopmental disorder development. Here, we used a mouse model of early-life immune activation that reliably induces deficits in social behaviors only in males. We demonstrate that male-biased alterations in social behavior are dependent upon microglial immune signaling and are coupled to alterations in mitochondrial morphology, gene expression, and function specifically within microglia, the innate immune cells of the brain. Additionally, we show that this behavioral and microglial mitochondrial vulnerability to early-life immune activation is programmed by the male-typical perinatal gonadal hormone surge. These findings demonstrate that social behavior in males over the lifespan are regulated by microglia-specific mechanisms that are shaped by events that occur in early development.

neuroscience↗

bioRxiv2021

Single cell profiling of Hofbauer cells and fetal brain microglia reveals shared programs and functions

Maternal immune activation is associated with adverse offspring neurodevelopmental outcomes, many of which are mediated by in utero microglial programming. Microglia remain inaccessible at birth and throughout development, thus identification of noninvasive biomarkers that can reflect fetal brain microglial programming may permit screening and intervention during critical developmental windows. Here we used lineage tracing to demonstrate the shared ontogeny between fetal brain macrophages (microglia) and fetal placental macrophages (Hofbauer cells). Single-cell RNA sequencing of murine fetal brain and placental macrophages demonstrated shared transcriptional programs. Comparison with human datasets demonstrated that placental resident macrophage signatures are highly conserved between mice and humans. Single-cell RNA-seq identified sex differences in fetal microglial and Hofbauer cell programs, and robust differences between placenta-associated maternal macrophage/monocyte (PAMM) populations in the context of a male versus a female fetus. We propose that Hofbauer cells, which are easily accessible at birth, provide novel insights into fetal brain microglial programs, potentially facilitating the early identification of offspring most vulnerable to neurodevelopmental disorders.

developmental biology↗

bioRxiv2021

Maternal diet disrupts the placenta-brain axis in a sex-specific manner

High maternal weight is associated with a number of detrimental outcomes in offspring, including increased susceptibility to neurological disorders such as anxiety, depression, and communicative disorders (e.g. autism spectrum disorders)1-8. Despite widespread acknowledgement of sex-biases in the prevalence, incidence, and age of onset of these disorders, few studies have investigated potential sex-biased mechanisms underlying disorder susceptibility. Here, we use a mouse model to demonstrate how maternal high-fat diet, one contributor to overweight, causes endotoxin accumulation in fetal tissue, and subsequent perinatal inflammation influences sex-specific behavioral outcomes in offspring. In male high-fat diet offspring, increased macrophage toll like receptor 4 signaling results in excess phagocytosis of serotonin neurons in the developing dorsal raphe nucleus, decreasing serotonin bioavailability in the fetal and adult brain. Bulk sequencing from a large cohort of matched first trimester human fetal brain, placenta, and maternal decidua samples reveals sex-specific transcriptome-wide changes in placenta and brain tissue in response to maternal triglyceride accumulation (a proxy for dietary fat content). Further, we find that fetal brain serotonin levels decrease as maternal dietary fat intake increases in males only. These findings uncover a microglia-dependent mechanism through which maternal diet may impact offspring susceptibility for neuropsychiatric disorder development in a sex-specific manner.

neuroscience↗

bioRxiv2018

Tamoxifen improves glucose tolerance in a delivery, sex, and strain-dependent manner in mice

Tamoxifen, a selective estrogen receptor modulator, is widely used in mouse models to temporally control gene expression but is also known to affect body composition. Here, we report that tamoxifen has significant and sustained effects on glucose tolerance, independent of effects on insulin sensitivity, in mice. Intraperitoneal, but not oral, tamoxifen delivery improved glucose tolerance in three inbred mouse strains. The extent and persistence of tamoxifen-induced effects were sex- and strain-dependent. These findings highlight the need to revise commonly used tamoxifen-based protocols for gene manipulation in mice by including longer chase periods following injection, oral delivery, and the use of tamoxifen-treated littermate controls.

physiology↗