Biology subjects

Plemel, J. R.

Publications and source records attributed to Plemel, J. R..

5 recordsLinked to original sources

bioRxiv2026

Spinal microglia are dispensable for the development of opioid-induced hyperalgesia

Adverse side effects of chronic opioid use, including analgesic tolerance, opioid-induced hyperalgesia, and addiction, are serious clinical challenges for pain management and opioid deprescribing. Microglia have been implicated in the development of these adverse effects, but the extent to which opioids alter microglia and the mechanisms behind opioid effects on microglia are poorly understood. We performed morphological and single-cell transcriptomic analysis on spinal microglia from opioid-withdrawn and saline-treated mice, and found that while morphological changes recapitulated prior reports, transcriptomic changes in these cells were modest. Furthermore, peripherally, but not centrally, restricted opioid administration was sufficient to induce both hyperalgesia and microglial morphological changes in mice. Finally, complete loss of microglia in Csf1r{Delta}{Delta}FIRE mice did not prevent the development of opioid-induced hyperalgesia, analgesic tolerance, and somatic withdrawal symptoms. These data argue against any microglial involvement in the development of these phenomena.

neuroscience↗

bioRxiv2025

Modulation of repopulating microglia in multiple sclerosis models with implications for neuroprotection

Microglia play a critical role in central nervous system (CNS) pathologies including multiple sclerosis (MS), and their modulation offers therapeutic potential especially during progressive disease courses. Using cell culture and experimental autoimmune encephalomyelitis (EAE) models, we investigated microglial dynamics during depletion and repopulation (MGrepo) and their modulation using siponimod (sipo), an established CNS penetrating MS medication. Repopulating microglia exhibited a transient reactive state (CD86, MHC-II, Il1b, Tnf). Sipo modulated microglia populations, increasing CD163+, CD206+, and CX3CR1+ while reducing CD86+MHC-II+ cells accompanied by a reduction of neuronal damage. Proteomic spinal cord analysis revealed protein expression alterations by MGrepo and sipo linked to inflammation, myelination, and neuronal structural organization, supported by RNA sequencing of the spinal cord. The neuroinflammation attenuating role of sipo could be linked to cell maintenance and myelin formation associated processes. These findings highlight the capacity of pharmacological interventions to modulate microglia, offering new insights into therapeutic strategies targeting microglial activity in neuroinflammatory diseases.

neuroscience↗

bioRxiv2024

Senescent-like microglia limit remyelination through the senescence associated secretory phenotype

The capacity to regenerate myelin in the central nervous system (CNS) diminishes with age. This decline is particularly evident in multiple sclerosis (MS), which has been suggested to exhibit features of accelerated biological aging. Whether cellular senescence, a hallmark of aging, contributes to remyelination impairment remains unknown. Here, we show that senescent cells (SCs) accumulate within demyelinated lesions after injury, and their elimination enhances remyelination in young mice but not in aged mice. In young mice, we observed the upregulation of senescence-associated transcripts primarily in microglia after demyelination, followed by their reduction during remyelination. However, in aged mice, senescence-associated factors persisted within lesions, correlating with inefficient remyelination. We found that SC elimination enhanced remyelination in young mice but was ineffective in aged mice. Proteomic analysis of senescence-associated secretory phenotype (SASP) revealed elevated levels of CCL11/Eotaxin-1 in lesions, which was found to inhibit efficient oligodendrocyte maturation. These results suggest therapeutic targeting of SASP components, such as CCL11, may improve remyelination in aging and MS.

neuroscience↗

bioRxiv2023

Alzheimer's disease associated isoforms of human CD33 distinctively modulate microglial cell responses in 5XFAD mice

Microglia play diverse pathophysiological roles in Alzheimers disease (AD), with genetic susceptibility factors skewing microglial cell function to influence AD risk. CD33 is an immunomodulatory receptor associated with AD susceptibility through a single nucleotide polymorphism that modulates mRNA splicing, skewing protein expression from a long protein isoform (CD33M) to a short isoform (CD33m). Understanding how human CD33 isoforms differentially impact microglial cell function in vivo has been challenging due to functional divergence of CD33 between mice and humans. We address this challenge by studying transgenic mice expressing either of the human CD33 isoforms crossed with the 5XFAD mouse model of amyloidosis and find that human CD33 isoforms have opposing effects on the response of microglia to amyloid-{beta} (A{beta}) deposition. Mice expressing CD33M have increased A{beta} levels, mo7re diffuse plaques, fewer disease-associated microglia, and more dystrophic neurites compared to control 5XFAD mice. Conversely, CD33m promotes plaque compaction and microglia-plaque contacts, and minimizes neuritic plaque pathology, highlighting an AD protective role for this isoform. Protective phenotypes driven by CD33m are detected at an earlier timepoint compared to the more aggressive pathology in CD33M mice that appears at a later timepoint, suggesting that CD33m has a more prominent impact on microglia cell function at earlier stages of disease progression. In addition to divergent roles in modulating phagocytosis, scRNAseq and proteomics analyses demonstrate that CD33m+ microglia upregulate nestin, an intermediate filament involved in cell migration, at plaque contact sites. Overall, our work provides new functional insights into how CD33, as a top genetic susceptibility factor for AD, modulates microglial cell function.

neuroscience↗

bioRxiv2022

Social isolation produces a brain-region specific expansion of microglia structure and reorganization of neural activity

Social isolation is a profound form of psychological stress that impacts the mental health of a large proportion of society. Other experimental models of stress and injury have demonstrated microglia activation and alterations in neural activity. Microglia and neural activity undergo coordinated changes under physiological and pathological states. However, the effect of social isolation on microglia and neural activity has not been thoroughly investigated. Here we show that the dorsal medial hypothalamus and hippocampal CA2 region of male mice undergo an increased microglia volume and branching following social isolation, whereas females exhibit this increase in the hypothalamus only. The prefrontal cortex, central amygdala, nucleus accumbens shell, and visual cortex did not exhibit changes in microglia structure in either male or female mice. The home cage resting level of neural activity, as measured by the immediate early gene c-fos, was reduced in CA2 and the prefrontal cortex of female but not male mice following isolation. However, the co-variation in neural activity across brain regions was abolished in male but not female isolated mice. These data show that different brain regions undergo independent and dissociable changes in microglia structure and network activity following social isolation which may account for changes in cognition and behavior associated with this form of psychological stress.

neuroscience↗