Biology subjects

Majewska, A. K.

Publications and source records attributed to Majewska, A. K..

6 recordsLinked to original sources

bioRxiv2026

Disrupted maternal care alters neural-microglia interactions in the primate paralaminar (PL) nucleus of the amygdala.

Prolonged postnatal maturation of the primate amygdala is thought to be driven, at least partially, by continued neural maturation within the paralaminar nucleus (PL). At birth, the PL is densely populated with post-mitotic glutamatergic neurons that gradually mature throughout postnatal life. This active process is likely supported by microglia, which promotes synaptic maturation. Our previous work showed that early life stress associated with maternal separation alters microglia development across the infant to adolescent transition. Here, we examined whether these morphologic microglial changes are associated with alterations in the numbers of pre-synaptic terminals (SYN1+ puncta), post-synaptic terminals (PSD95+ puncta), and putative excitatory contacts (SYN1-PSD95 colocalization), and whether these synaptic elements are engulfed by phagocytic microglia. In maternally reared animals, SYN1+ puncta, PSD95+ puncta, and putative synaptic contacts decreased, while microglial (IBA1+) volume, CD68+ content, and engulfment of synaptic elements increased, between infancy and adolescence. These findings suggest greater pruning of all synaptic elements by adolescence. Maternal separation altered this trajectory, resulting in increased phagocytic activity and engulfment of synaptic elements in infancy, but not in adolescence. Maternal separation also resulted in a 50% reduction in mature PL neurons by adolescence, suggesting maturational failure, cell loss, or both by adolescence. These findings demonstrate that early life stress disrupts normative synaptic pruning and microglia-synapse interactions in the developing primate PL. Increased synaptic engulfment in infants with disrupted care is associated with premature, aberrant pruning, and highlights a potential cellular mechanism through which early environmental insults could change PL neural development by adolescence. Significance StatementThe paralaminar nucleus (PL) of the amygdala is an important substrate for the delayed post-natal development of the amygdala in human and nonhuman primates. Gradually maturing glutamatergic neurons in this region, and the microglia that support them, are exposed to life events which may shape their development. We recently found that maternal separation in infants produces aberrant hyper-ramified microglia in the PL beginning in infancy and persisting into adolescence. Examining neuron-microglial interactions in the same cohort, we now find Increased phagocytic engulfment of synaptic elements by microglia after maternal separation in infancy only, with a reduction in PL mature neurons that is apparent by adolescence. Together these data suggest a mechanism for altered PL maturation, instigated by disrupted maternal care.

neuroscience↗

bioRxiv2025

Sex, not estrous cycle stage, drives differences in the microglial transcriptome in the 5xFAD mouse model of amyloidosis

Alzheimers disease (AD) presents with a sex bias where women are at higher risk and exhibit worse cognitive decline and brain atrophy compared to men. Microglia play a significant role in the pathogenesis and progression of AD and have been shown to be sexually differentiated in health and disease. Whether microglia contribute to the sex differences in AD remains to be elucidated. Herein, we characterize the sex differences in amyloid-beta (A{beta}) plaque pathology and microglia-plaque interaction using the 5xFAD mouse model of amyloidosis and further elucidate the microglial transcriptomic changes that occur in males and females. In females we concentrate on two hormonally distinct stages of the rodent estrous cycle: proestrus and diestrus. Our results indicate that A{beta} plaque morphology is sexually distinct with females having greater plaque volume and lower plaque sphericity compared to males. Microglia also interact with plaques in a sexually distinct manner with females phagocytosing A{beta} to a greater extent compared to males. Furthermore, we found that female microglia are not overtly different at the proestrus or diestrus stages. However, we found stark sex differences between female and male microglia transcriptomes in the 5xFAD brains, where female 5xFAD microglia were enriched in genes involved in glycolytic metabolism, antigen presentation, disease-associated microglia and microglia neurodegenerative phenotype (DAM/MGnD), and interferon signaling compared to male 5xFAD microglia.

neuroscience↗

bioRxiv2024

The effects of P2Y12 loss on microglial gene expression, dynamics, and injury response in the cerebellum and cerebral cortex.

Despite the emerging consensus that microglia are critical to physiological and pathological brain function, it is unclear how microglial roles and their underlying mechanisms differ between brain regions. Microglia throughout the brain express common markers, such as the purinergic receptor P2Y12, that delineate them from peripheral macrophages. P2Y12 is a critical sensor of injury but also contributes to the sensing of neuronal activity and remodeling of synapses, with microglial loss of P2Y12 resulting in behavioral deficits. P2Y12 has largely been studied in cortical microglia, despite the fact that a growing body of evidence suggests that microglia exhibit a high degree of regional specialization. Cerebellar microglia, in particular, exhibit transcriptional, epigenetic, and functional profiles that set them apart from their better studied cortical and hippocampal counterparts. Here, we demonstrate that P2Y12 deficiency does not alter the morphology, distribution, or dynamics of microglia in the cerebellum. In fact, loss of P2Y12 does little to disturb the distinct transcriptomic profiles of cortical and cerebellar microglia. However, unlike in cortex, P2Y12 is not required for a full microglial response to focal injury, suggesting that cerebellar and cortical microglia use different cues to respond to injury. Finally, we show that P2Y12 deficiency impairs cerebellar learning in a delay eyeblink conditioning task, a common test of cerebellar plasticity and circuit function. Our findings suggest not only region-specific roles of microglial P2Y12 signaling in the focal injury response, but also indicate a conserved role for P2Y12 in microglial modulation of plasticity across regions.

neuroscience↗

bioRxiv2024

Microglia morphology in the developing primate amygdala and effects of early life stress

A unique pool of immature glutamatergic neurons in the primate amygdala, known as the paralaminar nucleus (PL), are maturing between infancy and adolescence. The PL is a potential substrate for the steep growth curve of amygdala volume during this developmental period. A microglial component is also embedded among the PL neurons, and likely supports local neuronal maturation and emerging synaptogenesis. Microglia may alter neuronal growth following environmental perturbations such as stress. Using multiple measures, we first found that microglia in the infant primate PL had relatively large somas, and a small arbor size. In contrast, microglia in the adolescent PL had a smaller soma, and a larger dendritic arbor. We then examined microglial morphology in the PL after a novel maternal separation protocol, to examine the effects of early life stress. After maternal separation, the microglia had increased soma size, arbor size and complexity. Surprisingly, strong effects were seen not only in the infant PL, but also in the adolescent PL from subjects who had experienced the separation many years earlier. We conclude that under maternal-rearing conditions, PL microglia morphology tracks PL neuronal growth, progressing to a more mature phenotype by adolescence. Maternal separation has long-lasting effects on microglia, altering their normal developmental trajectory, and resulting in a hyper-ramified phenotype that persists for years. We speculate that these changes have consequences for neuronal development in young primates. Significance StatementThe paralaminar (PL) nucleus of the amygdala is an important source of plasticity, due to its unique repository of immature glutamatergic neurons. PL immature neurons mature between birth and adolescence. This process is likely supported by synaptogenesis, which requires microglia. Between infancy and adolescence in macaques, PL microglia became more dense, and shifted to a ramified phenotype, consistent with increased synaptic pruning functions. Early life stress in the form of maternal separation, however, blunted this normal trajectory, leading to persistent parainflammatory microglial morphologies. We speculate that early life stress may alter PL neuronal maturation and synapse formation through microglia.

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bioRxiv2023

Noradrenergic signaling controls Alzheimer's disease pathology via activation of microglial β2 adrenergic receptors

In Alzheimers disease (AD) pathophysiology, plaque and tangle accumulation trigger an inflammatory response that mounts positive feed-back loops between inflammation and protein aggregation, aggravating neurite damage and neuronal death. One of the earliest brain regions to undergo neurodegeneration is the locus coeruleus (LC), the predominant site of norepinephrine (NE) production in the central nervous system (CNS). In animal models of AD, dampening the impact of noradrenergic signaling pathways, either through administration of beta blockers or pharmacological ablation of the LC, heightened neuroinflammation through increased levels of pro-inflammatory mediators. Since microglia are the resident immune cells of the CNS, it is reasonable to postulate that they are responsible for translating the loss of NE tone into exacerbated disease pathology. Recent findings from our lab demonstrated that noradrenergic signaling inhibits microglia dynamics via {beta}2 adrenergic receptors ({beta}2ARs), suggesting a potential anti-inflammatory role for microglial {beta}2AR signaling. Thus, we hypothesize that microglial {beta}2 adrenergic signaling is progressively impaired during AD progression, which leads to the chronic immune vigilant state of microglia that worsens disease pathology. First, we characterized changes in microglial {beta}2AR signaling as a function of amyloid pathology. We found that LC neurons and their projections degenerate early and progressively in the 5xFAD mouse model of AD; accompanied by mild decrease in the levels of norepinephrine and its metabolite normetanephrine. Interestingly, while 5xFAD microglia, especially plaque-associated microglia, significant downregulated {beta}2AR gene expression early in amyloid pathology, they did not lose their responsiveness to {beta}2AR stimulation. Most importantly, we demonstrated that specific microglial {beta}2AR deletion worsened disease pathology while chronic {beta}2AR stimulation resulted in attenuation of amyloid pathology and associated neuritic damage, suggesting microglial {beta}2AR might be used as potential therapeutic target to modify AD pathology.

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bioRxiv2019

Noradrenergic signaling in wakeful states inhibits microglial surveillance and synaptic plasticity in the mouse visual cortex.

Microglia are the innate immune cells of the brain with roles in neuroimmunology and synaptic plasticity. Microglial processes continuously survey the brain parenchyma interacting with synaptic elements and maintaining tissue homeostasis. However, the mechanisms that control surveillance and its role in synaptic plasticity are poorly understood. Microglial dynamics in vivo have been primarily studied in anesthetized animals, where slow-wave neural activity resembles sleep-like states. We report that microglial surveillance and injury response in awake animals are reduced compared to when animals are anesthetized, suggesting that arousal state profoundly modulates microglial roles in the physiological brain. Stimulating {beta}2-adrenergic receptors recapitulated these observations and also disrupted experience-dependent plasticity only when intact {beta}2-adrenergic receptors were present in microglia specifically. These results indicate that microglial roles in surveillance and synaptic plasticity in the healthy brain are modulated by noradrenergic fluctuations between arousal states and raises new considerations for sleep/wake disruption in neurodevelopment and neuropathology.

neuroscience↗