Biology subjects

Gill, G.

Publications and source records attributed to Gill, G..

4 recordsLinked to original sources

bioRxiv2024

Enhancer AAV toolbox for accessing and perturbing striatal cell types and circuits

We present an enhancer AAV toolbox for accessing and perturbing striatal cell types and circuits. Best-in-class vectors were curated for accessing major striatal neuron populations including medium spiny neurons (MSNs), direct and indirect pathway MSNs, as well as Sst-Chodl, Pvalb-Pthlh, and cholinergic interneurons. Specificity was evaluated by multiple modes of molecular validation, three different routes of virus delivery, and with diverse transgene cargos. Importantly, we provide detailed information necessary to achieve reliable cell type specific labeling under different experimental contexts. We demonstrate direct pathway circuit-selective optogenetic perturbation of behavior and multiplex labeling of striatal interneuron types for targeted analysis of cellular features. Lastly, we show conserved in vivo activity for exemplary MSN enhancers in rat and macaque. This collection of striatal enhancer AAVs offers greater versatility compared to available transgenic lines and can readily be applied for cell type and circuit studies in diverse mammalian species beyond the mouse model.

neuroscience↗

bioRxiv2023

The X-Linked Intellectual Disability gene, ZDHHC9, is important for oligodendrocyte maturation and myelin formation

Two percent of patients with X-linked intellectual disability (XLID) exhibit loss-of-function mutations in the enzyme, ZDHHC9. One of the main anatomical deficits observed in these patients is a decrease in corpus callosum volume and a concurrent disruption in white matter integrity. In this study, we demonstrate that deletion of Zdhhc9 in mice disrupts the balance of mature oligodendrocyte subtypes within the corpus callosum. While overall mature oligodendrocyte numbers are unchanged, there is a marked increase in MOL5/6 cells that are enriched in genes associated with cell adhesion and synapses, and a concomitant decrease in MOL2/3 cells that are enriched in genes associated with myelination. In line with this, we observed a decrease in the density of myelinated axons and disruptions in myelin compaction in the corpus callosum of Zdhhc9 knockout mice. RNA sequencing and proteomic analysis further unveiled a reduction in genes and proteins essential for lipid metabolism, cholesterol synthesis, and myelin compaction. These findings reveal a previously under-appreciated and fundamental role for ZDHHC9 and protein palmitoylation in regulating oligodendrocyte subtype determination and myelinogenesis, offering mechanistic insights into the deficits observed in white matter volume in patients with mutations in ZDHHC9.

neuroscience↗

bioRxiv2023

Induction of antiviral Interferon-Stimulated Genes (ISGs) by neuronal STING promotes the resolution of pain

Inflammation and pain are intertwined responses to injury, infection, or chronic diseases. While acute inflammation is essential in determining pain resolution and opioid analgesia, maladaptive processes occurring during resolution can lead to the transition to chronic pain. Here we found that inflammation activates the cytosolic DNA-sensing protein Stimulator of Interferon Genes (STING) in DRG nociceptors. Neuronal activation of STING promotes signaling through TANK-binding kinase 1 (TBK1) and triggers an interferon-beta (IFN{beta}) response that mediates pain resolution. Notably, we found that mice expressing a nociceptor-specific gain-of-function mutation in STING exhibited an IFN gene signature that reduced nociceptor excitability and inflammatory hyperalgesia through a KChIP1-Kv4.3 regulation. Our findings reveal a role of IFN-regulated genes (IRGs) and KChIP1 downstream of STING, in the resolution of inflammatory pain.

neuroscience↗

bioRxiv2021

Protracted yet coordinated differentiation of long-lived SARS-CoV-2-specific CD8+ T cells during COVID-19 convalescence

CD8+ T cells are important antiviral effectors that can potentiate long-lived immunity against COVID-19, but a detailed characterization of these cells has been hampered by technical challenges. We screened 21 well-characterized, longitudinally-sampled convalescent donors that recovered from mild COVID-19 against a collection of SARS-CoV-2 tetramers, and identified one participant with an immunodominant response against Nuc322-331, a peptide that is conserved in all the SARS-CoV-2 variants-of-concern reported to date. We conducted 38- parameter CyTOF phenotyping on tetramer-identified Nuc322-331-specific CD8+ T cells, and on CD4+ and CD8+ T cells recognizing the entire nucleocapsid and spike proteins from SARS- CoV-2, and took 32 serological measurements on longitudinal specimens from this participant. We discovered a coordination of the Nuc322-331-specific CD8+ T response with both the CD4+ T cell and antibody pillars of adaptive immunity. Nuc322-331-specific CD8+ T cells were predominantly central memory T cells, but continually evolved over a [~]6-month period of convalescence. We observed a slow and progressive decrease in the activation state and polyfunctionality of the Nuc322-331-specific CD8+ T cells, accompanied by an increase in their lymph-node homing and homeostatic proliferation potential. These results suggest that following a typical case of mild COVID-19, SARS-CoV-2-specific CD8+ T cells not only persist but continuously differentiate in a coordinated fashion well into convalescence, into a state characteristic of long-lived, self-renewing memory.

immunology↗