Biology subjects

Lee, S. A.

Publications and source records attributed to Lee, S. A..

24 records · Page 2Linked to original sources

bioRxiv2019

Nascent RNA sequencing of peripheral blood leukocytes reveal gene expression diversity

Nascent RNA sequencing is a powerful method to measure transcription with high resolution, sensitivity, and directional information, which gives distinctive information about transcription from other methods such as chromatin immunoprecipitation or mRNA sequencing. We present an integrated package of nascent RNA-seq methods - ultrafast Precision Run On (uPRO) combined with computational procedures to discover cell type specific enhancers, promoters, and transcription factor networks. uPRO is composed of adaptor ligation and reverse transcription reactions, which is reduced to a one-day procedure and makes nascent RNA-seq more feasible and flexible for a widespread use. We generated genome-wide profiles of nascent transcription in human blood derived cell lines and clinical samples of ~1 ml of untreated whole blood. We integrated these data into deep learning and hierarchical network analysis to detect enhancers, promoters, and co-expression networks to define cell-type specific transcription programs. We found conservation of position but variation of expression in cell type specific enhancers and transcription start sites. Transcription factors (TFs) such as TCF-3 and OCT1 were pivotally associated with TF-enhancer-gene networks across cell types. Intriguingly, we also discovered that TFs related to cell stress and inflammation - such as SRF, ATF, CHOP, and NF-kB - are associated with inter-individual variation of leukocyte transcription in whole blood. Our integration of experimental and computational nascent RNA methods will provide an efficient strategy to identify specific transcriptional programs, both in cell-type and patient/disease-associated, with minimal sample requirements.

molecular biology↗

bioRxiv2019

Vector Trace cells in the Subiculum of the Hippocampal formation

Successfully navigating in physical or semantic space requires a neural representation of allocentric (map-based) vectors to boundaries, objects, and goals. Cognitive processes such as path-planning and imagination entail recall of vector representations, but evidence of neuron-level memory for allocentric vectors has been lacking. Here we describe a novel neuron type (Vector Trace cell, VTC) whose firing generates a new vector field when a cue is encountered, and also a trace version of that field for hours after cue removal. VTCs are concentrated in subiculum distal to CA1. Compared to non-trace cells, VTCs fire at further distances from cues, and exhibit earlier-going shifts in preferred theta phase in response to newly introduced cues, demonstrating a theta-linked neural substrate for memory encoding. VTCs suggest a vector-based model of computing spatial relationships between an agent and multiple spatial objects, or between different objects, freed from the constraints of direct perception of those objects.

neuroscience↗

bioRxiv2019

The development of spatiotemporal organization of episodic memory in children and its disruption in Williams Syndrome

Recent theories of episodic memory propose that the hippocampus provides the spatiotemporal framework for episodic memories. If this is true, does the development of episodic memory depend on the binding of space and time? And does this rely, at least partly, on normal hippocampal function? We investigated the development of episodic memory in children 2-8 years of age (Study 1) and its impairment in Williams Syndrome (Study 2) by implementing a nonverbal object-placement task that dissociates the what, where, and when components of episodic memory. Our results indicate that the binding of space and time in memory emerges first in development around the age of 3 and is impaired in Williams Syndrome. Space-time binding both preceded and predicted success in full episodic memory (what+where+when), and associating objects to spatial location seemed to mediate this developmental process. Importantly, these effects were not explained by improvements in object or location memory.

neuroscience↗

bioRxiv2018

Boundaries in Spatial Cognition: How They Look is More Important than What They Do

Large walls and other typical boundaries strongly influence neural activity related to navigation and the representations of spatial layouts. They are also major aids to reliable navigation behavior in young children and non-human animals. Is this because they are physical boundaries (barriers to movement), or because they present certain visual features, such as visually extended 3D surfaces? Here, these two factors were dissociated by using immersive virtual reality and real boundaries. Eighty adults recalled target locations in one of four environments: plywood, where a virtual wall coincided with a large piece of real plywood; pass through, where the virtual wall coincided with empty space and participants could pass through it; pass over, where the virtual wall was projected downward to be visible underneath a transparent floor; and cones, where the walls were replaced with traffic cones. One condition had features that were boundaries and looked like boundaries (plywood); two had features that were not boundaries but looked like boundaries (pass over/through); and one had features that were not boundaries and did not look like boundaries (cones). The precision and bias of responses changed only as a function of looking like a boundary. This suggests that variations in spatial coding are more closely linked to the visual properties of environmental layouts than to whether they contain physical boundaries (barriers to movement).

animal behavior and cognition↗

bioRxiv2017

Electrophysiological signatures of spatial boundaries in the human subiculum

Environmental boundaries play a crucial role in spatial navigation and memory across a wide range of distantly-related species. In rodents, boundary representations have been identified at the single-cell level in the subiculum and entorhinal cortex of the hippocampal formation. While studies of hippocampal function and spatial behavior suggest that similar representations might exist in humans, boundary-related neural activity has not been identified electrophysiologically in humans until now. Here we present direct intracranial recordings from the hippocampal formation of surgical epilepsy patients while they performed a virtual spatial navigation task. Our results suggest that encoding target locations near boundaries elicited stronger theta oscillations than for target locations near the center of the environment and that this difference cannot be explained by variables such as trial length, speed, or movement. These findings provide the first direct evidence of boundary-dependent neural activity localized in humans to the subiculum, the homologue of the hippocampal subregion in which most rodent boundary cells are found.\n\nSignificance StatementSpatial computations using environmental boundaries are an integral part of the brains spatial mapping system. In rodents, border/boundary cells in the subiculum and entorhinal cortex reveal boundary coding at the single-neuron level. Although there is good reason to believe that such representations also exist in humans, the evidence has thus far been limited to fMRI studies that broadly implicate the hippocampus in boundary-based navigation. By combining intracranial recordings with high-resolution imaging of hippocampal subregions we identified, for the first time in humans, a neural marker of boundary representation in the subiculum.

neuroscience↗

bioRxiv2017

The medial temporal lobe organizes memory across time and space: Causal evidence from brain stimulation

The medial temporal lobe (MTL) is widely implicated in supporting episodic memory and navigation, but its precise functional role in organizing memory across time and space remains elusive. Here we examine the specific cognitive processes implemented by MTL structures (hippocampus and entorhinal cortex) to organize memory by using electrical brain stimulation, leveraging its ability to establish causal links between brain regions and features of behavior. We studied neurosurgical patients who performed spatial-navigation and verbal-episodic memory tasks while brain stimulation was applied in various regions during learning. During the verbal memory task, stimulation in the MTL disrupted the temporal organization of encoded memories such that items learned with stimulation tended to be recalled in a more randomized order. During the spatial task, MTL stimulation impaired subjects abilities to remember items using view-independent (allocentric) navigation strategies. These stimulation effects were specific to the MTL. Our findings thus provide the first causal demonstration in humans of the specific memory processes that are performed by the MTL to encode when and where events occurred.\n\nSignificance StatementNumerous studies have implicated the medial temporal lobe (MTL) in encoding spatial and temporal memories, but they have not been able to causally demonstrate the nature of the cognitive processes by which this occurs in real-time. Electrical brain stimulation is able to demonstrate causal links between a brain region and a given function with high temporal precision. By examining behavior in a memory task as subjects received MTL stimulation, we provide the first causal evidence demonstrating the role of the MTL in organizing the spatial and temporal aspects of episodic memory.

neuroscience↗