Biology subjects

McCoy, E. S.

Publications and source records attributed to McCoy, E. S..

4 recordsLinked to original sources

bioRxiv2026

Perturbation of genes linked to common schizophrenia risk variants identifies cilia programs

Schizophrenia (SCZ) is a common psychiatric disorder characterized by psychosis, emotional withdrawal, and cognitive deficits. Most SCZ risk variants reside in non-coding regions of the genome and are thought to influence disease risk by modulating gene regulation. However, the target genes, biological pathways, and cell types through which these variants exert their effects remain poorly understood. To address this gap, we employed in vivo CRISPR droplet sequencing (CROP-seq) in the postnatal mouse neocortex. We perturbed 12 SCZ risk genes previously linked to functionally validated risk variants, followed by single-cell RNA sequencing. We identified 3,031 differentially expressed genes (DEGs) that recapitulate transcriptional alterations observed in postmortem SCZ brains. Integrative analysis using DEG clustering, factor analysis, and gene regulatory network inference uncovered convergent gene programs with distinct biological functions and cell type specificity. Notably, ciliary transcriptional programs consistently emerged across analytical frameworks. The primary cilium is a neurocircuit modulating signaling organelle in neurons and glia that remains understudied in SCZ. Perturbation of key contributors to the ciliary transcriptional programs led to significant alterations in ciliary structure, suggesting that SCZ genetic risk factors may influence how brain cells sense and transduce extracellular signals through synapse-independent mechanisms. Together, this study provides the first in vivo characterization of the functional consequence of common variant architecture in SCZ and implicates ciliary dysfunction as a convergent downstream mechanism.

neuroscience↗

bioRxiv2022

The open field assay is influenced by room temperature and by drugs that affect core body temperature

The open field assay is used to study anxiety-related traits and anxiolytic drugs in rodents. This assay entails measuring locomotor activity and time spent in the center of a chamber that is maintained at ambient room temperature. However, the ambient temperature in most laboratories varies daily and seasonally and can differ substantially between buildings. Here, we sought to evaluate how varying ambient temperature and core body temperature (CBT) affected open field locomotor activity and center time of wild-type (WT) and Trpm8 knock-out (Trpm8-/-) mice. TRPM8 is an ion channel that detects cool temperatures and is activated by cooling agents, including icilin and menthol. We found that the cooling agent icilin increased CBT and profoundly reduced distance traveled and center time of WT mice relative to vehicle controls. Likewise, cooling the ambient temperature to 4{degrees}C reduced distance traveled and center time of WT mice relative to Trpm8-/- mice. Conversely, the TRPM8 antagonist (M8-B) reduced CBT and increased distance traveled and center time of WT mice when tested at 4{degrees}C. Predictably, the TRPM8 antagonist (M8-B) had no effect on CBT or open field behavior of Trpm8-/- mice. The anxiolytic diazepam reduced CBT in both WT and Trpm8-/- mice. When tested at 4{degrees}C, diazepam increased distance traveled and center time in WT mice but did not alter open field behavior of Trpm8-/- mice. Our study shows that environmental temperature and drugs that affect CBT can influence locomotor behavior and center time in the open field assay, highlighting temperature (ambient and core) as sources of environmental and physiologic variability in this commonly used behavioral assay.

neuroscience↗

bioRxiv2022

Development and validation of PainFace, a software platform that simplifies and standardizes mouse grimace analyses

Facial grimaces are now commonly used to quantify spontaneous pain in mice and other mammalian species, but scoring remains subjective and relies on humans with very different levels of proficiency. Here, we developed a Mouse Grimace Scale (MGS) for black-coated (C57BL/6) mice consisting of four facial action units (orbitals, nose, ears, whiskers). We used this scale to generate ground truth data from over 70,000 images of black mice in different settings. With this large data set, we developed a deep neural network and cloud-based software platform called PainFace (http://painface.net) that accurately scores facial grimaces of black mice on a 0-8 scale. PainFace generates over two orders of magnitude more MGS data than humans can realistically achieve, and at superhuman speed. By analyzing the frequency distribution of grimace scores, we found that mice spent >7x more time in a high grimace state following laparotomy surgery relative to sham surgery controls. The analgesic carprofen reduced the amount of time animals spent in this high grimace state after surgery. Specific facial action unit score combinations were overrepresented following laparotomy surgery, suggesting that characteristic facial expressions are associated with a high grimace state. We performed validation experiments in two labs located in different countries to demonstrate reproducibility of the PainFace platform. To further enhance rigor and reproducibility, we will invite pain researchers to beta test PainFace and then incorporate their feedback into the software and manuscript prior to peer review. While this study is focused on mice, PainFace was designed to simplify, standardize, and scale up grimace analyses with many other mammalian species, including humans.

neuroscience↗

bioRxiv2017

Single-cell transcriptomic catalog of mouse cortical development

We generated a single-cell transcriptomic catalog of the developing mouse cerebral cortex that includes numerous classes of neurons, progenitors, and glia, their proliferation, migration, and activation states, and their relatedness within and across timepoints. Cell expression profiles stratified neurological disease-associated genes into distinct subtypes. Complex neurodevelopmental processes can be reconstructed with single-cell transcriptomics data, permitting a deeper understanding of cortical development and the cellular origins of brain diseases.

neuroscience↗