Biology subjects

Hostetler, R. E.

Publications and source records attributed to Hostetler, R. E..

3 recordsLinked to original sources

bioRxiv2025

Annotation Comparison Explorer (ACE): connecting brain cell types across studies of health and Alzheimer's Disease

BackgroundSingle-cell multiomic technologies have allowed unprecedented access to gene profiles of individual cells across species and organ systems, including the brain. The Allen Institute has created foundational atlases characterizing mammalian cell types in the adult mouse brain and the neocortex of humans with and without Alzheimers disease (AD). However, proliferation of public cell type classifications (or taxonomies) by us and others creates a challenge for knowledge integration. ResultsHere, we introduce Annotation Comparison Explorer (ACE), a web application for comparing cell type assignments and other cell-based annotations (e.g., donor demographics, anatomic locations, quality control metrics). ACE can filter cells and includes an interactive set of visualization tools, plot and data downloads, and statistics for comparing two or more taxonomy annotations alongside collected knowledge (e.g., cell type aliases, marker genes, abundance changes in disease). In this study we describe ACE functionality and present the following three ACE use cases. First, we demonstrate how a user can assign labels from the Seattle Alzheimers Disease Brain Cell Atlas (SEA-AD) taxonomy to their own cells and compare these mappings to user-defined cell type assignments and other cell metadata, using a previous cell type classification from the Allen Institute and two independent studies of different brain diseases as inputs. Second, we extend this approach for comparison of ten published human AD studies previously reprocessed through a common data analysis pipeline, and identify congruent cell type abundance changes in AD, including a decrease in certain somatostatin interneurons. Finally, ACE includes translation tables between different mouse and human brain cell type taxonomies on Allen Brain Map, from initial studies in neocortex to more recent studies spanning the whole brain, along with a human immune cell atlas focused on peripheral blood mononuclear cells. These use cases represent three of many possible applications for ACE. ConclusionsACE combines standard and custom visualizations into a user-friendly, open-source web tool for exploring categorical and numeric relationships and translating cell type classifications and knowledge across studies. ACE can be freely and publicly accessed at https://sea-ad.shinyapps.io/ACEapp/.

neuroscience↗

bioRxiv2023

Genetically Defined Subtypes of Layer 5 Somatostatin-Containing Cortical Interneurons

Inhibitory interneurons play a crucial role in proper development and function of the mammalian cerebral cortex. Of the different inhibitory subclasses, dendritic-targeting, somatostatin-containing (SOM) interneurons may be the most diverse. Earlier studies used transgenic mouse lines to identify and characterize subtypes of SOM interneurons by morphological, electrophysiological and neurochemical properties. More recently, large-scale studies classified SOM interneurons into 13 morpho-electro-transcriptomic (MET) types. It remains unclear, however, how these various classification schemes relate to each other, and experimental access to MET types has been limited by the scarcity of type-specific mouse driver lines. To begin to address these issues we crossed Flp and Cre driver mouse lines and a dual-color combinatorial reporter, allowing experimental access to genetically defined SOM subsets. Brains from adult mice of both sexes were retrogradely dye-labeled from the pial surface to identify layer 1-projecting neurons, and immunostained against several marker proteins, allowing correlation of genetic label, axonal target and marker protein expression in the same neurons. Using whole-cell recordings ex-vivo, we compared electrophysiological properties between intersectional and transgenic SOM subsets. We identified two layer 1-targeting intersectional subsets with non-overlapping marker protein expression and electrophysiological properties which, together with a previously characterized layer 4-targeting subtype, account for about half of all layer 5 SOM cells and >40% of all SOM cells, and appear to map onto 5 of the 13 MET types. Genetic access to these subtypes will allow researchers to determine their synaptic inputs and outputs and uncover their roles in cortical computations and animal behavior. SIGNIFICANCE STATEMENTInhibitory neurons are critically important for proper development and function of the cerebral cortex. Although a minority population, they are highly diverse, which poses a major challenge to investigating their contributions to cortical computations and animal and human behavior. As a step towards understanding this diversity we crossed genetically modified mouse lines to allow detailed examination of genetically-defined groups of the most diverse inhibitory subtype, somatostatin-containing interneurons. We identified and characterized three somatostatin subtypes in the deep cortical layers with distinct combinations of anatomical, neurochemical and electrophysiological properties. Future studies could now use these genetic tools to examine how these different subtypes are integrated into the cortical circuit and what roles they play during sensory, cognitive or motor behavior.

neuroscience↗

bioRxiv2022

Ultrafast (>400 Hz) network oscillations induced in thalamorecipient cortical layers by optogenetic activation of thalamocortical axons

Oscillations of extracellular voltage, reflecting synchronous rhythmic activity in large populations of neurons, are a ubiquitous feature in the mammalian brain and are thought to subserve critical, if not fully understood cognitive functions. Oscillations at different frequency bands are hallmarks of specific brain or behavioral states. At the higher end of the scale, ultrafast (400-600 Hz) oscillations in the somatosensory cortex, in response to peripheral stimulation, were observed in human and a handful of animal studies; however, their synaptic basis and functional significance remain largely unexplored. Here we report that brief optogenetic activation of thalamocortical axons ex-vivo elicited precisely reproducible, ~410 Hz local field potential wavelets ("ripplets") in middle layers of mouse somatosensory (barrel) cortex. Fast-spiking (FS) inhibitory interneurons were exquisitely synchronized with each other and fired spike bursts in anti-phase with ripplets, while excitatory neurons fired only 1-2 spikes per stimulus. Both subtypes received shared excitatory inputs at ripplet frequency, and bursts in layer 5 FS cells required intact connection with layer 4, suggesting that layer 4 excitatory cells were driving FS bursts in both layers. Ripplets may be a ubiquitous cortical response to exceptionally salient sensory stimuli, and could provide increased bandwidth for encoding and transmitting sensory information. Lastly, optogenetically-induced ripplets are a uniquely accessible model system for studying synaptic mechanisms of fast and ultrafast oscillations.

neuroscience↗