Brian Kalmbach
A5006854970- Neural dynamics and brain function
- Neuroscience and Neuropharmacology Research
- Single-cell and spatial transcriptomics
- Neuroscience and Neural Engineering
- Neuroinflammation and Neurodegeneration Mechanisms
- Cell Image Analysis Techniques
- Genetics and Neurodevelopmental Disorders
- Advanced Electron Microscopy Techniques and Applications
- Vestibular and auditory disorders
- Advanced Fluorescence Microscopy Techniques
- Autism Spectrum Disorder Research
- RNA Research and Splicing
- Neurogenesis and neuroplasticity mechanisms
- Receptor Mechanisms and Signaling
- Force Microscopy Techniques and Applications
- Memory and Neural Mechanisms
- Mitochondrial Function and Pathology
- Photoreceptor and optogenetics research
- CRISPR and Genetic Engineering
- Nanofabrication and Lithography Techniques
- Genetic Neurodegenerative Diseases
- Glaucoma and retinal disorders
- Hearing, Cochlea, Tinnitus, Genetics
- Ion channel regulation and function
- Alzheimer's disease research and treatments
Allen Institute
2018-2025
Allen Institute for Brain Science
2018-2024
University of Washington
2018-2024
Allen Institute for Neural Dynamics
2023
The University of Texas at Austin
2009-2023
Seattle University
2020
Boston Center for Memory
2010
Abstract The primary motor cortex (M1) is essential for voluntary fine-motor control and functionally conserved across mammals 1 . Here, using high-throughput transcriptomic epigenomic profiling of more than 450,000 single nuclei in humans, marmoset monkeys mice, we demonstrate a broadly cellular makeup this region, with similarities that mirror evolutionary distance are consistent between the transcriptome epigenome. core molecular identities neuronal non-neuronal cell types allow us to...
Here we report the generation of a multimodal cell census and atlas mammalian primary motor cortex as initial product BRAIN Initiative Cell Census Network (BICCN). This was achieved by coordinated large-scale analyses single-cell transcriptomes, chromatin accessibility, DNA methylomes, spatially resolved morphological electrophysiological properties cellular resolution input-output mapping, integrated through cross-modal computational analysis. Our results advance collective knowledge...
Abstract The neocortex is disproportionately expanded in human compared with mouse 1,2 , both its total volume relative to subcortical structures and the proportion occupied by supragranular layers composed of neurons that selectively make connections within other telencephalic structures. Single-cell transcriptomic analyses show an increased diversity glutamatergic neuron types pronounced gradients as a function cortical depth 3 . Here, probe functional anatomical correlates this diversity,...
Viral genetic tools that target specific brain cell types could transform basic neuroscience and targeted gene therapy. Here, we use comparative open chromatin analysis to identify thousands of human-neocortical-subclass-specific putative enhancers from across the genome control expression in adeno-associated virus (AAV) vectors. The cellular specificity reporter enhancer-AAVs is established by molecular profiling after systemic AAV delivery mouse. Over 30% produce subclass, including both...
Human cortex transcriptomic studies have revealed a hierarchical organization of γ-aminobutyric acid-producing (GABAergic) neurons from subclasses to high diversity more granular types. Rapid GABAergic neuron viral genetic labeling plus Patch-seq (patch-clamp electrophysiology single-cell RNA sequencing) sampling in human brain slices was used reliably target and analyze individual This characterization elucidated transitions between PVALB SST subclasses, morphological heterogeneity within...
Neocortical layer 1 (L1) is a site of convergence between pyramidal-neuron dendrites and feedback axons where local inhibitory signaling can profoundly shape cortical processing. Evolutionary expansion human neocortex marked by distinctive pyramidal neurons with extensive L1 branching, but whether interneurons are similarly diverse underexplored. Using Patch-seq recordings from neurosurgical tissue, we identified four transcriptomic subclasses mouse homologs, along distinct subtypes types...
Alzheimer's disease (AD) is the leading cause of dementia in older adults. Although AD progression characterized by stereotyped accumulation proteinopathies, affected cellular populations remain understudied. Here we use multiomics, spatial genomics and reference atlases from BRAIN Initiative to study middle temporal gyrus cell types 84 donors with varying pathologies. This cohort includes 33 male 51 female donors, an average age at time death 88 years. We used quantitative neuropathology...
Eyelid conditioning has proven useful for analysis of learning and computation in the cerebellum. Two variants, delay trace conditioning, differ only by relative timing training stimuli. Despite subtlety this difference, eyelid is prevented lesions cerebellum, hippocampus, or medial prefrontal cortex (mPFC), whereas cerebellar largely unaffected forebrain lesions. Here we test whether these lesion results can be explained two assertions: (1) Cerebellar requires temporal overlap between mossy...
The powerful suite of available genetic tools is driving tremendous progress in understanding mouse brain cell types and circuits. However, the degree conservation human remains largely unknown large part due to lack such healthy tissue preparations. To close this gap, we describe a robust stable adult neurosurgically-derived ex vivo acute cultured neocortical slice system optimized for rapid molecular-genetic manipulation. Surprisingly, slices exhibited exceptional viability, neuronal...
Abstract von Economo neurons (VENs) are bipolar, spindle-shaped restricted to layer 5 of human frontoinsula and anterior cingulate cortex that appear be selectively vulnerable neuropsychiatric neurodegenerative diseases, although little is known about other VEN cellular phenotypes. Single nucleus RNA-sequencing identifies a transcriptomically-defined cell cluster contained VENs, but also fork cells subset pyramidal neurons. Cross-species alignment this with well-annotated mouse...
Abstract The primary motor cortex (M1) is essential for voluntary fine control and functionally conserved across mammals. Using high-throughput transcriptomic epigenomic profiling of over 450,000 single nuclei in human, marmoset monkey, mouse, we demonstrate a broadly cellular makeup this region, whose similarity mirrors evolutionary distance consistent between the transcriptome epigenome. core molecular identity neuronal non-neuronal types allowed generation cross-species consensus cell...
Alzheimer's disease (AD) is the most common cause of dementia in older adults. Neuropathological and imaging studies have demonstrated a progressive stereotyped accumulation protein aggregates, but underlying molecular cellular mechanisms driving AD progression vulnerable cell populations affected by remain coarsely understood. The current study harnesses single spatial genomics tools knowledge from BRAIN Initiative Cell Census Network to understand impact on middle temporal gyrus types. We...
Abstract Alzheimer’s disease (AD) is the most common cause of dementia in older adults. Neuropathological and imaging studies have demonstrated a progressive stereotyped accumulation protein aggregates, but underlying molecular cellular mechanisms driving AD progression vulnerable cell populations affected by remain coarsely understood. The current study harnesses single spatial genomics tools knowledge from BRAIN Initiative Cell Census Network to understand impact on middle temporal gyrus...
The mammalian cortex is comprised of cells classified into types according to shared properties. Defining the contribution each cell type processes guided by essential for understanding its function in health and disease. We used transcriptomic epigenomic cortical taxonomies from mouse human define marker genes putative enhancers created a large toolkit transgenic lines enhancer AAVs selective targeting populations. report evaluation fifteen new driver lines, two reporter >800 different...
Hippocampal pyramidal neuron activity underlies episodic memory and spatial navigation. Although extensively studied in rodents, extremely little is known about human hippocampal neurons, even though the hippocampus underwent strong evolutionary reorganization shows lower theta rhythm frequencies. To test whether biophysical properties of Cornu Amonis subfield 1 (CA1) neurons can explain observed rhythms, we map morpho-electric individual CA1 human, non-pathological slices from neurosurgery....
We have addressed the source and nature of persistent neural activity that bridges stimulus-free gap between conditioned stimulus (CS) unconditioned (US) during trace eyelid conditioning. Previous work has demonstrated this is necessary for conditioning: CS-elicited in mossy fiber inputs to cerebellum does not extend into interval, which precludes cerebellar learning mediates response expression. In behaving rabbits we used vivo recordings from a region medial prefrontal cortex (mPFC)...
Abstract Fragile X syndrome (FXS) is caused by transcriptional silencing of the fmr1 gene resulting in loss fragile mental retardation protein (FMRP) expression. FXS patients display several behavioral phenotypes associated with prefrontal cortex (PFC) dysfunction. Voltage-gated ion channels, some which are regulated FMRP, heavily influence PFC neuron function. Although there evidence for brain region-specific alterations to function a single type channel FXS, it unclear whether subtypes...
The Patch-seq approach is a powerful variation of the patch-clamp technique that allows for combined electrophysiological, morphological, and transcriptomic characterization individual neurons. To generate datasets at scale, we identified refined key factors contribute to efficient collection high-quality data. We developed electrophysiology software with analysis functions specifically designed automate acquisition online quality control. recognized importance extracting nucleus success...
Rodent studies have demonstrated that synaptic dynamics from excitatory to inhibitory neuron types are often dependent on the target cell type. However, these cell-specific properties not been well investigated in human cortex, where there major technical challenges reliably obtaining healthy tissue, conducting multiple patch-clamp recordings types, and identifying those types. Here, we take advantage of newly developed methods for neurosurgical tissue analysis with recordings,
Abstract Trace eyeblink conditioning is useful for studying the interaction of multiple brain areas in learning and memory. The goal current work was to determine whether trace could be established a mouse model absence elicited startle responses circuitry that supports this learning. We show here mice can acquire conditioned (tCRs) devoid while head-restrained permitted freely run on wheel. Most (75%) learn with interval 250 ms. Because tCRs were not contaminated startle-associated...
The neocortex is disproportionately expanded in human compared to mouse, both its total volume relative subcortical structures and the proportion occupied by supragranular layers that selectively make connections within cortex other telencephalic structures. Single-cell transcriptomic analyses of mouse show an increased diversity glutamatergic neuron types pronounced gradients as a function cortical depth. To probe functional anatomical correlates this diversity, we describe robust Patch-seq...