Biology subjects

Ghazisaeidi, S.

Publications and source records attributed to Ghazisaeidi, S..

4 recordsLinked to original sources

bioRxiv2026

Spatial dynamics of cellular and molecular plasticity in the maternal and postpartum mouse brain

Pregnancy is a critical window for neuroplasticity and maternal mental health, yet our understanding of the molecular and cellular changes underlying this adaptation remains incomplete. Here we profile the female mouse brain in nulliparous, late-pregnant and postpartum states with three single-cell spatial technologies (Slide-tags, MERFISH and Xenium). Together these assays resolve 1.5 million cells in one coronal plane spanning the cortex, striatum, lateral septum and preoptic area. Pregnancy is associated with changes in gene expression in most cell types, beyond the circuits previously established to govern maternal behavior. These changes resolve into three programs that are reproducible across platforms: synaptic pathways increase in neurons as growth and plasticity pathways decrease; immune and angiogenic pathways increase in glia and vascular cells; and cholesterol synthesis decreases as uptake increases across both neurons and glia. Finally, mapping human depression genetics onto these data, we find risk genes concentrated almost entirely in neurons, and this concentration changes with reproductive state in the preoptic area, basal forebrain and ventral striatum. These results place the neurons carrying depression risk among the circuits remodeled during pregnancy, providing a possible cellular substrate for peripartum vulnerability.

genomics↗

bioRxiv2025

Meningeal macrophages mask incision pain sensitization in male rats

IntroductionMeninges surrounding the brain and spinal cord house a variety of immune cell types including macrophages that express the CD206 mannose receptor. Here, we investigated whether CD206+ macrophages in the meninges play a role in regulating nociception and pain hypersensitivity. MethodsWe selectively depleted CD206+ macrophages in the meninges around the lumbar spinal cord by intrathecal administration of anti-CD206 coupled to saporin, and determined the effects of CD206+ macrophage depletion on responses in naive rats and in those that had received a skin incision to the upper hindlimb. In addition, we used RNAseq to investigate transcriptional changes in lumbar meninges and dorsal root ganglia. Experiments were done in both male and female rats. ResultsDepleting CD206+ meningeal macrophages did not alter basal responses in naive animals of either sex. By contrast depleting these cells after skin injury induced mechanical hypersensitivity in male rats, without changes in thermal sensitivity but had no effect in females. In male rats with skin incision injury, we found that the mechanical hypersensitivity induced by depleting CD206+ meningeal macrophages was reversed by administering the NMDAR antagonist, APV. In addition, the hypersensitivity was reversed by an enhancer of KCC2 function, CLP290. Unexpectedly, skin incision caused significant transcriptional changes in the meninges, but only in male rats. ConclusionsTaken together, our results indicate that while CD206+ meningeal macrophages do not regulate basal nociception in naive rats, after skin incision injury, these cells mask mechanical hypersensitivity in male rats only. Thus, we conclude that in a sex-dependent manner CD206+ meningeal macrophages prevent the spread of pain hypersensitivity after a minor injury. Importantly, the skin incision we used was comparable to that used in sham controls in numerous rodent studies of neuropathic pain. Our findings have, therefore, potentially broad implications for re-interpreting results from previous neuropathic pain research.

neuroscience↗

bioRxiv2022

Regulation of neuropathic pain by microglial Orai1 channels

Microglia are important mediators of neuroinflammation that underlies neuropathic pain. However, the molecular checkpoints controlling microglial reactivity are not well-understood. We investigated the role of Orai1 channels for microglia-mediated neuroinflammation following nerve injury and find that deletion of Orai1 in microglia attenuates Ca2+ signaling and the production of inflammatory cytokines by proalgesic agonists. Conditional deletion of Orai1 attenuated microglia proliferation in the dorsal horn, spinal cytokines levels, and potentiation of excitatory neurotransmission following peripheral nerve injury. These cellular effects were accompanied by mitigation of pain hyperalgesia in Orai1 knockout mice. A small-molecule Orai1 inhibitor, CM4620, similarly mitigated allodynia in male mice. Surprisingly, these protective effects were not seen in female mice, revealing striking sexual dimorphism in Orai1 regulation of microglial reactivity and hyperalgesia. These findings indicate that Orai1 channels are key regulators of the sexually dimorphic role of microglia for the neuroinflammation that underlies neuropathic pain.

neuroscience↗

bioRxiv2022

Conserved transcriptional programming across sex and species after peripheral nerve injury predicts treatments for neuropathic pain

Chronic pain is a devastating problem affecting 1 in 5 individuals around the globe, with neuropathic pain the most debilitating and poorly treated type of chronic pain. Advances in transcriptomics and data mining have contributed to cataloging diverse cellular pathways and transcriptomic alterations in response to peripheral nerve injury but have focused on phenomenology and classifying transcriptomic responses. Here, with the goal of identifying new types of pain-relieving agents, we compared transcriptional reprogramming changes in the dorsal spinal cord after peripheral nerve injury cross-sex and cross-species and imputed commonalities, as well as differences in cellular pathways and gene regulation. We identified 93 transcripts in the dorsal horn that were increased by peripheral nerve injury in male and female mice and rats. Following gene ontology and transcription factor analyses, we constructed a pain interactome for the proteins encoded by the differentially expressed genes, discovering new, conserved signaling nodes. We interrogated the interactome with the Drug-Gene database to predict FDA-approved medications that may modulate key nodes within the network. The top hit from the analysis was fostamatinib, the molecular target of which is the non-receptor tyrosine kinase Syk, which our analysis had identified as a key node in the interactome. We found that intrathecally administrating the active metabolite of fostamatinib, R406, significantly reversed pain hypersensitivity in both sexes. Thus, we have identified and shown the efficacy of an agent that could not have been previously predicted to have analgesic properties. One sentence summaryUnbiased approach to predicting safe therapies for neuropathic pain

neuroscience↗