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Introduction
Publications
Publications (106)
Genomic DNA (gDNA) undergoes structural interconversion between single- and double-stranded states during transcription, DNA repair and replication, which is critical for cellular homeostasis. We describe “CHEX-seq” which identifies the single-stranded DNA (ssDNA) in situ in individual cells. CHEX-seq uses 3’-terminal blocked, light-activatable pro...
Cognitive impairment is a common symptom following mild traumatic brain injury (mTBI or concussion) and can persist for years in some individuals. Hippocampal slice preparations following closed-head, rotational acceleration injury in swine have previously demonstrated reduced axonal function and hippocampal circuitry disruption. However, electroph...
Closed-head traumatic brain injury (TBI) is induced by rapid motion of the head, resulting in diffuse strain fields throughout the brain. The injury mechanism(s), loading thresholds, and neuroanatomical distribution of affected cells remain poorly understood, especially in the gyrencephalic brain. We utilized a porcine model to explore the relation...
Brain organoids are self-organizing, three-dimensional tissues derived from pluripotent stem cells that recapitulate many aspects of the cellular diversity and architectural features of the developing brain. Recently, there has been growing interest in using human brain organoid transplantation in animal models as a means of addressing the limitati...
We argue that the study of single-cell subcellular organelle omics is needed to understand and regulate cell function. This requires and is being enabled by new technology development.
Brain organoids created from human pluripotent stem cells represent a promising approach for brain repair. They acquire many structural features of the brain and raise the possibility of patient-matched repair. Whether these entities can integrate with host brain networks in the context of the injured adult mammalian brain is not well established....
Functional restoration following major peripheral nerve injury (PNI) is challenging, given slow axon growth rates and eventual regenerative pathway degradation in the absence of axons. We are developing tissue-engineered nerve grafts (TENGs) to simultaneously “bridge” missing nerve segments and “babysit” regenerative capacity by providing living ax...
Cognitive impairment is a common symptom following mild traumatic brain injury (mTBI or concussion) and can persist for years in some individuals. While the underlying mechanisms driving these impairments remain unknown, structural changes in the hippocampus post-mTBI have been reported in human patients, as well as electrophysiological changes in...
Soft bioelectronic interfaces for mapping and modulating excitable networks at high resolution and at large scale can enable paradigm-shifting diagnostics, monitoring, and treatment strategies. Yet, current technologies largely rely on materials and fabrication schemes that are expensive, do not scale, and critically limit the maximum attainable re...
Over 2.8 million people experience mild traumatic brain injury (TBI) in the United States each year, which may lead to long-term neurological dysfunction. The mechanical forces that are caused by TBI propagate through the brain to produce diffuse axonal injury (DAI) and trigger secondary neuroinflammatory cascades. The cascades may persist from acu...
IMPACT: This study will provide the essential characterization of intrinsic neural activity in human brain organoids, both at the single cell and network levels, to harness for translational purposes. OBJECTIVES/GOALS: Brain organoids are 3D, stem cell-derived neural tissues that recapitulate neurodevelopment. However, to levy their full translatio...
Soft bioelectronic interfaces for mapping and modulating excitable networks at high resolution and at large scale can enable paradigm-shifting diagnostics, monitoring, and treatment strategies. Yet, current technologies largely rely on materials and fabrication schemes that are expensive, do not scale, and critically limit the maximum attainable re...
For implantable neural interfaces, functional/clinical outcomes are challenged by limitations in specificity and stability of inorganic microelectrodes. A biological intermediary between microelectrical devices and the brain may improve specificity and longevity through (i) natural synaptic integration with deep neural circuitry, (ii) accessibility...
Parkinson’s disease (PD) is the second most common progressive neurodegenerative disease, affecting 1–2% of people over 65. The classic motor symptoms of PD result from selective degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc), resulting in a loss of their long axonal projections to the striatum. Current treatment...
Over 2.8 million people experience mild traumatic brain injury (TBI) in the United States each year, which may lead to long-term neurological dysfunction. The mechanical forces that occur due to TBI propagate through the brain to produce diffuse axonal injury (DAI) and trigger secondary neuroinflammatory cascades. The cascades may persist from acut...
While hippocampal-dependent learning and memory are particularly vulnerable to traumatic brain injury (TBI), the functional status of individual hippocampal neurons and their interactions with oscillations are unknown following injury. Using the most common rodent TBI model and laminar recordings in CA1, we found a significant reduction in oscillat...
Background:
Millions of Americans experience residual deficits from traumatic peripheral nerve injury (PNI). Despite advancements in surgical technique, repair typically results in poor functional outcomes due to prolonged periods of denervation resulting from long regenerative distances coupled with slow rates of axonal regeneration. Novel surgic...
Traumatic brain injury (TBI) remains a prominent public health concern despite several decades of attempts to develop therapies for the associated neurological and cognitive deficits. Effective models of this condition are imperative for better defining its pathophysiology and testing therapeutics. Human brain organoids are stem cell-derived neural...
Human brain organoids provide unique platforms for modeling development and diseases by recapitulating the architecture of the embryonic brain. However, current organoid methods are limited by interior hypoxia and cell death due to insufficient surface diffusion, preventing generation of architecture resembling late developmental stages. Here, we r...
Abstract Background Each year in the USA, over 2.4 million people experience mild traumatic brain injury (TBI), which can induce long-term neurological deficits. The dentate gyrus of the hippocampus is notably susceptible to damage following TBI, as hilar mossy cell changes in particular may contribute to post-TBI dysfunction. Moreover, microglial...
Recent demonstrations of human brain organoid transplantation in rodents have accentuated ethical concerns associated with these entities, especially as they relate to potential "humanization" of host animals. Consideration of established scientific principles can help define the realistic range of expected outcomes in such transplantation studies....
Assays examining the open-chromatin landscape in single cells require isolation of the nucleus, resulting in the loss of spatial/microenvironment information. Here we describe CHEX-seq ( CH romatin EX posed) for identifying single-stranded open-chromatin DNA regions in paraformaldehyde-fixed single cells. CHEX-seq uses light-activated DNA probes th...
Decoding laminar information across deep brain structures and cortical regions is necessary in order to understand the neuronal ensembles that represent cognition and memory. Large animal models are essential for translational research due to their gyrencephalic neuroanatomy and significant white matter composition. A lack of long-length probes wit...
Multi-unit activity recorded with multichannel silicon probes designed for large animal electrophysiology. Recording profiles of multichannel silicon probes are displayed for NN32/EDGE80 and CAMB64/EDGE silicon probes. (A) Representative traces recorded from a single electrode site on NN32/EDGE80 silicon probe that was located in the pyramidal CA1...
Internal reference on multichannel silicon probes reduces artifacts during chronic and acute recordings. (A) All multichannel silicon probes used in the study were custom-designed to have a top electrode site substituted for a low-impedance reference site (site area = 4,200 μm2) placed 1–2 mm above the most-proximal probe site. Schematic diagram of...
Approximately 20 million Americans currently experience residual deficits from traumatic peripheral nerve injury. Despite recent advancements in surgical technique, peripheral nerve repair typically results in poor functional outcomes due to prolonged periods of denervation resulting from long regenerative distances coupled with relatively slow rat...
Within the neural engineering field, next-generation implantable neuroelectronic interfaces are being developed using biologically-inspired and/or biologically-derived materials to improve upon the stability and functional lifetime of current interfaces. These technologies use biomaterials, bioactive molecules, living cells, or some combination of...
Impact statement:
Axon regeneration is negligible in the adult mammalian brain, and thus, white matter damage often leads to permanent neurological deficits. A novel approach for axon repair is the generation of axon tracts in the laboratory setting followed by transplantation of these constructs. This article details a human substrate for this re...
Diffuse axonal injury (DAI) is an important consequence of traumatic brain injury (TBI). At the moment of trauma, axons rarely disconnect, but undergo cytoskeletal disruption and transport interruption leading to protein accumulation within swellings. The amyloid precursor protein (APP) accumulates rapidly and the standard histological evaluation o...
The hippocampus is integral to working and episodic memory and is a central region of interest in diseases affecting these processes. Pig models are widely used in translational research and may provide an excellent bridge between rodents and nonhuman primates for CNS disease models because of their gyrencephalic neuroanatomy and significant white...
1) Laminar information across different deep brain structures and cortical regions need to be decoded in order to understand the spatiotemporal ensembles that represent cognition and memory. Pig models are widely used in translational research, and may provide an excellent bridge between rodents and non-human primates for CNS disease models due to...
The hippocampus is integral to working and episodic memory, and is a central region of interest in diseases affecting these processes. Pig models are widely used in translational research, and may provide an excellent bridge between rodents and non-human primates for CNS disease models due to their gyrencephalic neuroanatomy and significant white m...
Achievements in intracortical brain-machine interfaces are compromised by limitations in long-term performance and information transfer rate. A biological intermediary between devices and the brain based on synaptic integration may offer a specificity and permanence that has eluded neural interfaces to date. Accordingly, we have developed the first...
The classic motor deficits of Parkinson's disease are caused by degeneration of dopaminergic neurons in the substantia nigra pars compacta, resulting in the loss of their long‐distance axonal projections that modulate the striatum. Current treatments only minimize the symptoms of this disconnection as there is no approach capable of replacing the n...
Graphical Abstract Highlights d Single-mitochondrion sequencing shows single-mitochondrion heteroplasmy d The distribution of SNV loci suggests inheritance of variants across generations d Analysis of SNVs in human and mouse suggests distinct modes of somatic segregation In Brief Morris et al. use independent sequencing of multiple individual mitoc...
Introduction: Cell replacement therapies remain one of the more promising methods for replacing lost brain tissue and restoring neurological function. Recent advances in generating cerebral organoids (CO) from pluripotent stem cells have opened up the prospect of transplanting autologous neural tissue constructs that emulate aspects of brain archit...
Hippocampal-dependent deficits in learning and memory formation are a prominent feature of traumatic brain injury (TBI), however the role of the hippocampus in cognitive dysfunction after concussion (mild TBI) is unknown. We therefore investigated functional and structural changes in the swine hippocampus following TBI using a model of head rotatio...
Objective:
Although substantial progress has been made in mapping the connections of the brain, less is known about how this organization translates into brain function. In particular, the massive interconnectivity of the brain has made it difficult to specifically examine data transmission between two nodes of the connectome, a central component...
Investigation of human CNS disease and drug effects has been hampered by the lack of a system that enables single-cell analysis of live adult patient brain cells. We developed a culturing system, based on a papain-aided procedure, for resected adult human brain tissue removed during neurosurgery. We performed single-cell transcriptomics on over 300...
Despite increasing appreciation of the critical role that neuroinflammatory pathways play in brain injury and neurodegeneration, little is known about acute microglial reactivity following diffuse traumatic brain injury (TBI) – the most common clinical presentation that includes all concussions. Therefore, we investigated acute microglial reactivit...
Unique from other brain disorders, traumatic brain injury (TBI) generally results from a discrete biomechanical event that induces rapid head movement. The large size and high organization of the human brain makes it particularly vulnerable to traumatic injury from rotational accelerations that can cause dynamic deformation of the brain tissue. The...
Traumatic brain injury (TBI) is a heterogeneous disorder with many factors contributing to a spectrum of severity, leading to cognitive dysfunction that may last for many years after injury. Injury to axons in the white matter, which are preferentially vulnerable to biomechanical forces, is prevalent in many TBIs. Unlike focal injury to a discrete...
Restoring neurological and cognitive function in individuals who have suffered brain damage is one of the principal objectives of modern translational neuroscience. Electrical stimulation approaches, such as deep-brain stimulation, have achieved the most clinical success, but they ultimately may be limited by the computational capacity of the resid...
The ideal neuroprosthetic interface permits high-quality neural recording and stimulation of the nervous system while reliably providing clinical benefits over chronic periods. Although current technologies have made notable strides in this direction, significant improvements must be made to better achieve these design goals and satisfy clinical ne...
The electrophysiological and morphological phenotyping of human neurons was performed on resected cortical and hippocampal tissue from cases of Communicating Hydrocephalus (CH), Epilepsy, Normal Pressure Hydrocephalus (NPH) as well as primary and secondary brain tumors. The differences in electrophysiological properties of adult human neurons are b...
Despite the high demand for and potential utility of human primary brain cell cultures in various scientific interests, the methodology has been regarded as extremely difficult to achieve and maintain long-term cultures. With IRB approval, various resected brain tissues, including cortical and hippocampal tissues from different disease cases such a...
Prominent neuropathology following trauma, stroke and various neurodegenerative diseases includes neuronal degeneration as well as loss of long-distance axonal connections. While cell replacement and axonal pathfinding strategies are often explored independently, there is no strategy capable of simultaneously replacing lost neurons and re-establish...
The electro physio logical and morphological phenotyping of human neu rons was performed on resected cortical and hippo - campal tissue from cases of Communicating Hydrocephalus, Epilepsy, Normal Pre ssure Hydrocephalus and brain tumor. A clinical history of traumatic brain injury (TBI) was pre sent in a number of these cases. The differences in el...
Striatal medium spiny neurons (MSNs) receive lateral inhibitory projections from other MSNs and feedforward inhibitory projections from fast-spiking, parvalbumin-containing striatal interneurons (FSIs). The functional roles of these connections are unknown, and difficult to study in an experimental preparation. We therefore investigated the functio...
Transcriptome profiling of single cells resident in their natural microenvironment depends upon RNA capture methods that are both noninvasive and spatially precise. We engineered a transcriptome in vivo analysis (TIVA) tag, which upon photoactivation enables mRNA capture from single cells in live tissue. Using the TIVA tag in combination with RNA s...
Functional and circuit level activity changes in the hippocampus induced by mild traumatic brain injury (mTBI) were studied using a swine model of closed-head rotational acceleration. In order to replicate the range of forces experienced by the brain during mTBI, we utilized coronal rotational accelerations (200-300 rads/sec) that induce little or...
Hedonic overconsumption contributing to obesity involves altered activation within the mesolimbic dopamine system. Dysregulation of dopamine signaling in the nucleus accumbens shell (NAS) has been implicated in reward-seeking behaviors, such as binge eating, which contributes to treatment resistance in obesity (Wise, 2012). Direct modulation of the...
The success of deep brain stimulation (DBS) for movement disorders and the improved understanding of the neurobiologic and neuroanatomic bases of psychiatric diseases have led to proposals to expand current DBS applications. Recent preclinical and clinical work with Alzheimer's disease and obsessive-compulsive disorder, for example, supports the sa...
As a common feature of many neurological diseases and injury, the loss of axon pathways can have devastating effects on function. Here, we demonstrate a new strategy to restore damaged axon pathways using transplantable miniature constructs consisting of living neurons and axonal tracts internalized within hydrogel tubes. These hydrogel microcondui...
The indications for deep brain stimulation (DBS) are expanding, and the feasibility and efficacy of this surgical procedure in various neurologic and neuropsychiatric disorders continue to be tested. This review attempts to provide background and rationale for applying this therapeutic option to obesity and addiction. We review neural targets curre...
A high incidence of blast exposure is a 21st century reality in counter-insurgency warfare. However, thresholds for closed-head blast-induced traumatic brain injury (bTBI) remain unknown. Moreover, without objective information about relative blast exposure, warfighters with bTBI may not receive appropriate medical care and may remain in harm's way...
