Biology subjects

Gwinn, R.

Publications and source records attributed to Gwinn, R..

5 recordsLinked to original sources

bioRxiv2023

Morpho-electric and computational properties of three types of human hippocampal CA1 pyramidal neurons

Hippocampal pyramidal neuron activity underlies episodic memory and spatial navigation. Although extensively studied in rodents, extremely little is known about human hippocampal pyramidal neurons, even though human hippocampus underwent strong evolutionary reorganization and shows lower theta rhythm frequencies. To test whether biophysical and computational properties of human CA1 pyramidal neurons can explain observed rhythms, we map the morpho-electric and computational properties of individual CA1 pyramidal neurons in human, non-pathological hippocampal slices from neurosurgery. Human CA1 pyramidal neurons have extensive dendrites and resonate at 2.9 Hz, optimally tuned to human theta frequencies. Morphological and biophysical properties reveal three cell types with distinct dendrite bifurcations and physiology. Data-driven biophysical models show that human CA1 pyramidal neurons use i) computationally independent dendritic compartments, ii) preferential routing of electrical activity towards soma or dendritic tree and iii) non-linear input-output transformations. Across cell types, morpho-electric properties consistently increase computational richness in human CA1 pyramidal neurons. TeaserHuman CA1 pyramidal neurons have large and intricate morphologies, which translates to complex computational properties.

neuroscience↗

bioRxiv2022

Inter-individual variation in human cortical cell type abundance and expression

Single cell transcriptomic studies have identified a conserved set of neocortical cell types from small post-mortem cohorts. We extend these efforts by assessing cell type variation across 75 adult individuals undergoing epilepsy and tumor surgeries. Nearly all nuclei map to one of 125 robust cell types identified in middle temporal gyrus, but with varied abundances and gene expression signatures across donors, particularly in deep layer glutamatergic neurons. A minority of variance is explainable by known factors including donor identity and small contributions from age, sex, ancestry, and disease state. Genomic variation was significantly associated with variable expression of 150-250 genes for most cell types. Thus, human individuals display a highly consistent cellular makeup, but with significant variation reflecting donor characteristics, disease condition, and genetic regulation. One-Sentence SummaryInter-individual variation in human cortex is greatest for deep layer excitatory neurons and largely unexplainable by known factors.

neuroscience↗

bioRxiv2020

Signature morpho-electric, transcriptomic, and dendritic properties of extratelencephalic-projecting human layer 5 neocortical pyramidal neurons

In the neocortex, subcerebral axonal projections originate largely from layer 5 (L5) extratelencephalic-projecting (ET) neurons. The highly distinctive morpho-electric properties of these neurons have mainly been described in rodents, where ET neurons can be labeled by retrograde tracers or transgenic lines. Similar labeling strategies are not possible in the human neocortex, rendering the translational relevance of findings in rodents unclear. We leveraged the recent discovery of a transcriptomically-defined L5 ET neuron type to study the properties of human L5 ET neurons in neocortical brain slices derived from neurosurgeries. Patch-seq recordings, where transcriptome, physiology and morphology are assayed from the same cell, revealed many conserved morpho-electric properties of human and rodent L5 ET neurons. Divergent properties were also apparent but were often smaller than differences between cell types within these two species. These data suggest a conserved function of L5 ET neurons in the neocortical hierarchy, but also highlight marked phenotypic divergence possibly related to functional specialization of human neocortex.

neuroscience↗

bioRxiv2020

Multi-modal characterization and simulation of human epileptic circuitry

Temporal lobe epilepsy is the fourth most common neurological disorder with about 40% of patients not responding to pharmacological treatment. Increased cellular loss in the hippocampus is linked to disease severity and pathological phenotypes such as heightened seizure propensity. While the hippocampus is the target of therapeutic interventions such as temporal lobe resection, the impact of the disease at the cellular level remains unclear in humans. Here we show that properties of hippocampal granule cells change with disease progression as measured in living, resected hippocampal tissue excised from epilepsy patients. We show that granule cells increase excitability and shorten response latency while also enlarging in cellular volume, surface area and spine density. Single-cell RNA sequencing combined with simulations ascribe the observed electrophysiological changes to gradual modification in three key ion channel conductances: BK, Cav2.2 and Kir2.1. In a bio-realistic computational network model, we show that the changes related to disease progression bring the circuit into a more excitable state. In turn, we observe that by reversing these changes in the three key conductances produces a less excitable, "early disease-like" state. These results provide mechanistic understanding of epilepsy in humans and will inform future therapies such as viral gene delivery to reverse the course of the disorder.

neuroscience↗

bioRxiv2017

SmartScope2: Simultaneous Imaging and Reconstruction of Neuronal Morphology

Quantitative analysis of neuronal morphology is critical in cell type classification and for deciphering how structure gives rise to function in the brain. Most current approaches to imaging and tracing neuronal 3D morphology are data intensive. We introduce SmartScope2, the first open source, automated neuron reconstruction machine integrating online image analysis with automated multiphoton imaging. SmartScope2 takes advantage of a neurons sparse morphology to improve imaging speed and reduce image data stored, transferred and analyzed. We show that SmartScope2 is able to produce the complex 3D morphology of human and mouse cortical neurons with six-fold reduction in image data requirements and three times the imaging speed compared to conventional methods.

bioinformatics↗