Biology subjects

Dorman, L. C.

Publications and source records attributed to Dorman, L. C..

7 recordsLinked to original sources

bioRxiv2026

A multimodal perturbation atlas defines the phenotypic resolution of cellular morphology.

Modeling cellular behavior requires measurements that capture how cells evolve across time, environments, and interventions. Microscopy is uniquely suited to this goal: it is non-destructive and can be applied to living cells in their native context. Yet its phenotypic resolving power remains incompletely characterized relative to molecular assays. Here, we present a multimodal perturbation atlas of 1,000 pooled CRISPR knockouts in A549 cells, profiled by fluorescence microscopy (42 live, 13 fixed markers), label-free quantitative phase imaging of the same live cells (at single timepoints), and single-cell RNA sequencing (scRNA-seq). We develop deep learning frameworks to interpret the rich cell-biological signatures in these ~65M single-cell profiles. At matched reagent cost, phase imaging exceeds the phenotypic resolution of both fluorescence imaging and scRNA-seq, and more reliably recovers higher-order pathway organization. These results establish intrinsic morphology as a high-precision readout of cellular state, and lay a foundation for live-cell profiling of phenotypic trajectories.

systems biology↗

bioRxiv2024

Type 1 lymphocytes and interferon-γ accumulate in the thalamus and restrict seizure susceptibility after traumatic brain injury

Chronic neural circuit hyperexcitability frequently emerges after brain injury, but endogenous mechanisms constraining runaway activity remain poorly understood. Here, we reveal that the adaptive immune system acts as a homeostatic brake on network excitability following traumatic brain injury (TBI). In mice, cortical trauma triggered a delayed infiltration of interferon-{gamma} (IFN{gamma})-producing type 1 lymphocytes into the sensory thalamus. Rather than driving pathology, IFN{gamma} signaling directly in neurons restricted thalamocortical network hyperexcitability. This protective axis was tonically regulated; depleting CD4 T cells de-repressed local non-CD4 type 1 lymphocytes, elevating IFN{gamma} signaling and protecting from seizures. A single dose of exogenous IFN{gamma} abolished hypersynchronous circuit bursting and rescued injury-induced seizure incidence, severity, and mortality, establishing a therapeutic framework for safeguarding circuit stability after brain injury.

immunology↗

bioRxiv2023

Group 2 innate lymphoid cells promote inhibitory synapse development and social behavior

The innate immune system plays essential roles in brain synaptic development, and immune dysregulation is implicated in neurodevelopmental diseases. Here we show that a subset of innate lymphocytes (group 2 innate lymphoid cells, ILC2s) is required for cortical inhibitory synapse maturation and adult social behavior. ILC2s expanded in the developing meninges and produced a surge of their canonical cytokine Interleukin-13 (IL-13) between postnatal days 5-15. Loss of ILC2s decreased cortical inhibitory synapse numbers in the postnatal period where as ILC2 transplant was sufficient to increase inhibitory synapse numbers. Deletion of the IL-4/IL-13 receptor (Il4ra) from inhibitory neurons phenocopied the reduction inhibitory synapses. Both ILC2 deficient and neuronal Il4ra deficient animals had similar and selective impairments in adult social behavior. These data define a type 2 immune circuit in early life that shapes adult brain function. One sentence summaryType 2 innate lymphoid cells and Interleukin-13 promote inhibitory synapse development.

neuroscience↗

bioRxiv2023

Single-cell and spatial multi-omics identify innate and stromal modules targeted by anti-integrin therapy in ulcerative colitis.

Ulcerative colitis (UC) is driven by immune and stromal subsets, culminating in epithelial injury. Vedolizumab (VDZ) is an anti-integrin antibody that is effective for treating UC. VDZ is known to inhibit lymphocyte trafficking to the intestine, but its broader effects on other cell subsets are less defined. To identify the inflammatory cells that contribute to colitis and are affected by VDZ, we performed single-cell transcriptomic and proteomic analyses of peripheral blood and colonic biopsies in healthy controls and patients with UC on VDZ or other therapies. Here we show that VDZ treatment is associated with alterations in circulating and tissue mononuclear phagocyte (MNP) subsets, along with modest shifts in lymphocytes. Spatial multi-omics of formalin-fixed biopsies demonstrates trends towards increased abundance and proximity of MNP and fibroblast subsets in active colitis. Spatial transcriptomics of archived specimens pre-treatment identifies epithelial-, MNP-, and fibroblast-enriched genes related to VDZ responsiveness, highlighting important roles for these subsets in UC.

immunology↗

bioRxiv2021

Interleukin-33 coordinates a microglial phagocytic response and limits corticothalamic excitability and seizure susceptibility

Microglia are key remodelers of neuronal synapses during brain development, but the mechanisms that regulate this process and its ultimate impact on neural circuit function are not well defined. We previously identified the IL-1 family cytokine Interleukin-33 (IL-33) as a novel mediator of microglial synapse remodeling. Here we define the phagocytic program induced in microglia in response to IL-33. We find that IL-33 markedly alters the microglial enhancer landscape and exposes AP-1 transcription factor sites that promote target gene expression. We identify the scavenger receptor MARCO and the pattern recognition receptor TLR2 as downstream mediators of IL-33 dependent synapse engulfment. Conditional deletion of IL-33 in the CNS or its receptor on microglia results in increased numbers of excitatory synapses in the corticothalamic circuit and spontaneous epileptiform activity as well as increased seizure susceptibility by early adulthood. These findings define novel mechanisms through which IL-33 coordinates experience-dependent synaptic refinement to restrict hyperexcitability in the developing brain.

neuroscience↗

bioRxiv2021

In situ and transcriptomic identification of synapse-associated microglia in the developing zebrafish brain

Microglia are brain resident macrophages that play vital roles in central nervous system (CNS) development, homeostasis, and pathology. Microglia both remodel synapses and engulf apoptotic cell corpses during development, but whether unique molecular programs regulate these distinct phagocytic functions is unknown. Here we identify a molecularly distinct synapse-associated microglial subset in the zebrafish (Danio rerio). We found that ramified microglia populated synapse-rich regions of the midbrain and hindbrain between 7 and 28 days post fertilization. In contrast, microglia in the optic tectum were ameboid and clustered around neurogenic zones. Using single-cell mRNA sequencing combined with metadata from regional bulk sequencing, we identified synapse-associated microglia (SAMs) that were highly enriched in the hindbrain, expressed known synapse modulating genes as well as novel candidates, and engulfed synaptic proteins. In contrast, neurogenic-associated microglia (NAMs) were enriched in optic tectum, had active cathepsin activity, and preferentially engulfed neuronal corpses. These data yielded a functionally annotated atlas of zebrafish microglia (https://www.annamolofskylab.org/microglia-sequencing). Furthermore, they reveal that molecularly distinct phagocytic programs mediate synaptic remodeling and cell engulfment, and establish zebrafish hindbrain as a model circuit for investigating microglial-synapse interactions.

neuroscience↗

bioRxiv2021

A type I interferon response defines a conserved microglial state required for effective phagocytosis

Microglia are brain resident phagocytes that can engulf synaptic components and extracellular matrix as well as whole neurons. However, whether there are unique molecular mechanisms that regulate these distinct phagocytic states is unknown. Here we define a molecularly distinct microglial subset whose function is to engulf neurons in the developing brain. We transcriptomically identified a cluster of Type I interferon (IFN-I) responsive microglia that expanded 20-fold in the postnatal day 5 somatosensory cortex after partial whisker deprivation, a stressor that accelerates neural circuit remodeling. In situ, IFN-I responsive microglia were highly phagocytic and actively engulfed whole neurons. Conditional deletion of IFN-I signaling (Ifnar1fl/fl) in microglia but not neurons resulted in dysmorphic microglia with stalled phagocytosis and an accumulation of neurons with double strand DNA breaks, a marker of cell stress. Conversely, exogenous IFN-I was sufficient to drive neuronal engulfment by microglia and restrict the accumulation of damaged neurons. IFN-I deficient mice had excess excitatory neurons in the developing somatosensory cortex as well as tactile hypersensitivity to whisker stimulation. These data define a molecular mechanism through which microglia engulf neurons during a critical window of brain development. More broadly, they reveal key homeostatic roles of a canonical antiviral signaling pathway in brain development.

neuroscience↗