Faculty Bibliography
Searched for:
school:SOM
Department/Unit:Neuroscience Institute
Total Results:
13349
Robust chronic convulsive seizures, high-frequency oscillations, and human seizure onset patterns in an intrahippocampal kainic acid model in mice [Meeting Abstract]
Purpose: Although the intrahippocampal kainic acid (IHKA) model has been widely used to simulate temporal lobe epilepsy (TLE) in mice, there is variation in outcomes, with many studies showing few robust seizures long-term, especially convulsive seizures. We present an implementation of the IHKA model with frequent chronic convulsive seizures that are robust in frequency, duration and both sexes can be used.
Method(s): Our methods varied slightly from prior studies. We employed continuous wideband video-EEG from 2 cortical and 2 hippocampal sites to characterize chronic epilepsy outcomes in both sexes and 2 timepoints (2-4 and 10-12wks post-IHKA).
Result(s): Analysis of convulsive seizures at 2-4 and 10-12wks post-IHKA showed a robust frequency (2-4/day on average) and duration (typically 20-30 sec) at each time. Comparison of the 2 timepoints showed that seizure burden became more severe in approximately 50% of the animals. We show that almost all convulsive seizures could be characterized as either low-voltage fast or hypersynchronous onset seizures, which has not been reported in a mouse model of epilepsy and is important because these seizure types are found in humans. In addition, we report that high-frequency oscillations (HFOs, >250Hz) occur, resembling findings from IHKA in rats and TLE patients. Pathology in the hippocampus at the site of IHKA injection was similar to mesial temporal lobe sclerosis and reduced contralaterally.
Conclusion(s): In summary, our methods produce a model of TLE in mice with robust convulsive seizures, show variable progression, that HFOs are robust also, and that the model has seizures with onset patterns and pathology like human TLE. We believe our results will advance the ability to use the IHKA model of TLE in mice. The results also have important implications for our understanding of HFOs, progression and other topics of broad interest to the epilepsy research community including preclinical drug screening
Method(s): Our methods varied slightly from prior studies. We employed continuous wideband video-EEG from 2 cortical and 2 hippocampal sites to characterize chronic epilepsy outcomes in both sexes and 2 timepoints (2-4 and 10-12wks post-IHKA).
Result(s): Analysis of convulsive seizures at 2-4 and 10-12wks post-IHKA showed a robust frequency (2-4/day on average) and duration (typically 20-30 sec) at each time. Comparison of the 2 timepoints showed that seizure burden became more severe in approximately 50% of the animals. We show that almost all convulsive seizures could be characterized as either low-voltage fast or hypersynchronous onset seizures, which has not been reported in a mouse model of epilepsy and is important because these seizure types are found in humans. In addition, we report that high-frequency oscillations (HFOs, >250Hz) occur, resembling findings from IHKA in rats and TLE patients. Pathology in the hippocampus at the site of IHKA injection was similar to mesial temporal lobe sclerosis and reduced contralaterally.
Conclusion(s): In summary, our methods produce a model of TLE in mice with robust convulsive seizures, show variable progression, that HFOs are robust also, and that the model has seizures with onset patterns and pathology like human TLE. We believe our results will advance the ability to use the IHKA model of TLE in mice. The results also have important implications for our understanding of HFOs, progression and other topics of broad interest to the epilepsy research community including preclinical drug screening
EMBASE:636558747
ISSN: 0013-9580
CID: 5075632
Neurotoxic reactive astrocytes induce cell death via saturated lipids
Astrocytes regulate the response of the central nervous system to disease and injury and have been hypothesized to actively kill neurons in neurodegenerative disease1-6. Here we report an approach to isolate one component of the long-sought astrocyte-derived toxic factor5,6. Notably, instead of a protein, saturated lipids contained in APOE and APOJ lipoparticles mediate astrocyte-induced toxicity. Eliminating the formation of long-chain saturated lipids by astrocyte-specific knockout of the saturated lipid synthesis enzyme ELOVL1 mitigates astrocyte-mediated toxicity in vitro as well as in a model of acute axonal injury in vivo. These results suggest a mechanism by which astrocytes kill cells in the central nervous system.
PMID: 34616039
ISSN: 1476-4687
CID: 5045852
The commercial genetic testing landscape for Parkinson's disease
INTRODUCTION/BACKGROUND:There have been no specific guidelines regarding which genes should be tested in the clinical setting for Parkinson's disease (PD) or parkinsonism. We evaluated the types of clinical genetic testing offered for PD as the first step of our gene curation. METHODS:The National Institutes of Health (NIH) Genetic Testing Registry (GTR) was queried on 12/7/2020 to identify current commercial PD genetic test offerings by clinical laboratories, internationally. RESULTS:We identified 502 unique clinical genetic tests for PD, from 28 Clinical Laboratory Improvement Amendments (CLIA)-approved clinical laboratories. These included 11 diagnostic PD panels. The panels were notable for their differences in size, ranging from 5 to 62 genes. Five genes for variant query were included in all panels (SNCA, PRKN, PINK-1, PARK7 (DJ1), and LRRK2). Notably, the addition of the VPS35 and GBA genes was variable. Panel size differences stemmed from inclusion of genes linked to atypical parkinsonism and dystonia disorders, and genes in which the link to PD causation is controversial. CONCLUSION/CONCLUSIONS:There is an urgent need for expert opinion regarding which genes should be included in a commercial laboratory multi-gene panel for PD.
PMID: 34696975
ISSN: 1873-5126
CID: 5042312
A pilot open-label study of aldose reductase inhibition with AT-001 (caficrestat) in patients hospitalized for COVID-19 infection: Results from a registry-based matched-control analysis
BACKGROUND AND AIMS/OBJECTIVE:Cardiometabolic disease may confer increased risk of adverse outcomes in COVID-19 patients by activation of the aldose reductase pathway. We hypothesized that aldose reductase inhibition with AT-001 might reduce viral inflammation and risk of adverse outcomes in diabetic patients with COVID-19. METHODS:We conducted an open-label prospective phase 2 clinical trial to assess safety, tolerability and efficacy of AT-001 in patients hospitalized with COVID-19 infection, history of diabetes mellitus and chronic heart disease. Eligible participants were prospectively enrolled and treated with AT-001 1500Â mg BID for up to 14 days. Safety, tolerability, survival and length of hospital stay (LOS) were collected from the electronic medical record and compared with data from two matched control groups (MC1 and MC2) selected from a deidentified registry of COVID-19 patients at the same institution. RESULTS:AT-001 was safe and well tolerated in the 10 participants who received the study drug. In-hospital mortality observed in the AT-001 group was 20% vs. 31% in MC1 and 27% in MC2. Mean LOS observed in the AT-001 group was 5 days vs. 10 days in MC1 and 25 days in MC2. CONCLUSIONS:In hospitalized patients with COVID-19 and co-morbid diabetes mellitus and heart disease, treatment with AT-001 was safe and well tolerated. Exposure to AT-001 was associated with a trend of reduced mortality and shortened LOS. While the observed trend did not reach statistical significance, the present study provides the rationale for investigating potential benefit of AT-001 in COVID 19 affected patients in future studies.
PMCID:8556062
PMID: 34752935
ISSN: 1878-0334
CID: 5050382
Expression and proteolytic processing of the amyloid precursor protein is unaffected by the expression of the three human apolipoprotein E alleles in the brains of mice
The 3 human apolipoprotein E (APOE) gene alleles modify an individual's risk of developing Alzheimer's disease (AD): compared to the risk-neutral APOE ε3 allele, the ε4 allele (APOE4) is strongly associated with increased AD risk while the ε2 allele is protective. Multiple mechanisms have been shown to link APOE4 expression and AD risk, including the possibility that APOE4 increases the expression of the amyloid precursor protein (APP) (Y-W.A. Huang, B. Zhou, A.M. Nabet, M. Wernig, T.C. Südhof, 2019). In this study, we investigated the impact of APOE genotype on the expression, and proteolytic processing of endogenously expressed APP in the brains of mice humanized for the 3 APOE alleles. In contrast to prior studies using neuronal cultures, we found in the brain that both App gene expression, and the levels of APP holoprotein were not affected by APOE genotype. Additionally, our analysis of APP fragments showed that APOE genotype does not impact APP processing in the brain: the levels of both α- and β-cleaved soluble APP fragments (sAPPs) were similar across genotypes, as were the levels of the membrane-associated α- and β-cleaved C-terminal fragments (CTFs) of APP. Lastly, APOE genotype did not impact the level of soluble amyloid beta (Aβ). These findings argue that the APOE-allele-dependent AD risk is independent of the brain expression and processing of APP.
PMID: 34875506
ISSN: 1558-1497
CID: 5099572
A workflow to generate patient-specific three-dimensional augmented reality models from medical imaging data and example applications in urologic oncology
Augmented reality (AR) and virtual reality (VR) are burgeoning technologies that have the potential to greatly enhance patient care. Visualizing patient-specific three-dimensional (3D) imaging data in these enhanced virtual environments may improve surgeons' understanding of anatomy and surgical pathology, thereby allowing for improved surgical planning, superior intra-operative guidance, and ultimately improved patient care. It is important that radiologists are familiar with these technologies, especially since the number of institutions utilizing VR and AR is increasing. This article gives an overview of AR and VR and describes the workflow required to create anatomical 3D models for use in AR using the Microsoft HoloLens device. Case examples in urologic oncology (prostate cancer and renal cancer) are provided which depict how AR has been used to guide surgery at our institution.
PMCID:8554989
PMID: 34709482
ISSN: 2365-6271
CID: 5042602
Transcriptomic analysis of loss of Gli1 in neural stem cells responding to demyelination in the mouse brain
In the adult mammalian brain, Gli1 expressing neural stem cells reside in the subventricular zone and their progeny are recruited to sites of demyelination in the white matter where they generate new oligodendrocytes, the myelin forming cells. Remarkably, genetic loss or pharmacologic inhibition of Gli1 enhances the efficacy of remyelination by these neural stem cells. To understand the molecular mechanisms involved, we performed a transcriptomic analysis of this Gli1-pool of neural stem cells. We compared murine NSCs with either intact or deficient Gli1 expression from adult mice on a control diet or on a cuprizone diet which induces widespread demyelination. These data will be a valuable resource for identifying therapeutic targets for enhancing remyelination in demyelinating diseases like multiple sclerosis.
PMCID:8553940
PMID: 34711861
ISSN: 2052-4463
CID: 5042772
Proceedings of the National Academy of Sciences of the United States of America (PNAS). 2021:118(42).DOI: 10.1073/pnas.2101209118
The human olfactory bulb processes odor valence representation and cues motor avoidance behavior
Determining the valence of an odor to guide rapid approach-avoidance behavior is thought to be one of the core tasks of the olfactory system, and yet little is known of the initial neural mechanisms supporting this process or of its subsequent behavioral manifestation in humans. In two experiments, we measured the functional processing of odor valence perception in the human olfactory bulb (OB)-the first processing stage of the olfactory system-using a noninvasive method as well as assessed the subsequent motor avoidance response. We demonstrate that odor valence perception is associated with both gamma and beta activity in the human OB. Moreover, we show that negative, but not positive, odors initiate an early beta response in the OB, a response that is linked to a preparatory neural motor response in the motor cortex. Finally, in a separate experiment, we show that negative odors trigger a full-body motor avoidance response, manifested as a rapid leaning away from the odor, within the time period predicted by the OB results. Taken together, these results demonstrate that the human OB processes odor valence in a sequential manner in both the gamma and beta frequency bands and suggest that rapid processing of unpleasant odors in the OB might underlie rapid approach-avoidance decisions.
PMCID:8545486
PMID: 34645711
ISSN: 1091-6490
CID: 5061982
Decoding pain from brain activity
Pain is a dynamic, complex and multidimensional experience. The identification of pain from brain activity as neural readout may effectively provide a neural code for pain, and further provide useful information for pain diagnosis and treatment. Advances in neuroimaging and large-scale electrophysiology have enabled us to examine neural activity with improved spatial and temporal resolution, providing opportunities to decode pain in humans and freely behaving animals. This topical review provides a systematical overview of state-of-the-art methods for decoding pain from brain signals, with special emphasis on electrophysiological and neuroimaging modalities. We show how pain decoding analyses can help pain diagnosis and discovery of neurobiomarkers for chronic pain. Finally, we discuss the challenges in the research field and point to several important future research directions.
PMID: 34608868
ISSN: 1741-2552
CID: 5039502
A multimodal cell census and atlas of the mammalian primary motor cortex
Here we report the generation of a multimodal cell census and atlas of the mammalian primary motor cortex as the initial product of the BRAIN Initiative Cell Census Network (BICCN). This was achieved by coordinated large-scale analyses of single-cell transcriptomes, chromatin accessibility, DNA methylomes, spatially resolved single-cell transcriptomes, morphological and electrophysiological properties and cellular resolution input-output mapping, integrated through cross-modal computational analysis. Our results advance the collective knowledge and understanding of brain cell-type organization1-5. First, our study reveals a unified molecular genetic landscape of cortical cell types that integrates their transcriptome, open chromatin and DNA methylation maps. Second, cross-species analysis achieves a consensus taxonomy of transcriptomic types and their hierarchical organization that is conserved from mouse to marmoset and human. Third, in situ single-cell transcriptomics provides a spatially resolved cell-type atlas of the motor cortex. Fourth, cross-modal analysis provides compelling evidence for the transcriptomic, epigenomic and gene regulatory basis of neuronal phenotypes such as their physiological and anatomical properties, demonstrating the biological validity and genomic underpinning of neuron types. We further present an extensive genetic toolset for targeting glutamatergic neuron types towards linking their molecular and developmental identity to their circuit function. Together, our results establish a unifying and mechanistic framework of neuronal cell-type organization that integrates multi-layered molecular genetic and spatial information with multi-faceted phenotypic properties.
PMCID:8494634
PMID: 34616075
ISSN: 1476-4687
CID: 5136522
