Publications by authors named "Bing Shuai"

32 Publications

Melatonin improves brain function in a model of chronic Gulf War Illness with modulation of oxidative stress, NLRP3 inflammasomes, and BDNF-ERK-CREB pathway in the hippocampus.

Redox Biol 2021 Jul 22;43:101973. Epub 2021 Apr 22.

Institute for Regenerative Medicine, Department of Molecular and Cellular Medicine, Texas A&M University College of Medicine, College Station, TX, USA. Electronic address:

Persistent cognitive and mood dysfunction is the primary CNS symptom in veterans afflicted with Gulf War Illness (GWI). This study investigated the efficacy of melatonin (MEL) for improving cognitive and mood function with antioxidant, antiinflammatory, and pro-cognitive effects in a rat model of chronic GWI. Six months after exposure to GWI-related chemicals and stress, rats were treated with vehicle or MEL (5, 10, 20, 40, and 80 mg/kg) for eight weeks. Behavioral tests revealed cognitive and mood dysfunction in GWI rats receiving vehicle, which were associated with elevated oxidative stress, reduced NRF2, catalase and mitochondrial complex proteins, astrocyte hypertrophy, activated microglia with NLRP3 inflammasomes, elevated proinflammatory cytokines, waned neurogenesis, and synapse loss in the hippocampus. MEL at 10 mg/kg alleviated simple and associative recognition memory dysfunction and anhedonia, along with reduced oxidative stress, enhanced glutathione and complex III, and reduced NLRP3 inflammasomes, IL-18, TNF-α, and IFN-γ. MEL at 20 mg/kg also normalized NRF2 and catalase and increased microglial ramification. MEL at 40 mg/kg, in addition, reduced astrocyte hypertrophy, activated microglia, NF-kB-NLRP3-caspase-1 signaling, IL-1β, MCP-1, and MIP-1α. Moreover, MEL at 80 mg/kg activated the BDNF-ERK-CREB signaling pathway, enhanced neurogenesis and diminished synapse loss in the hippocampus, and improved a more complex hippocampus-dependent cognitive function. Thus, MEL therapy is efficacious for improving cognitive and mood function in a rat model of chronic GWI, and MEL's effect was dose-dependent. The study provides the first evidence of MEL's promise for alleviating neuroinflammation and cognitive and mood impairments in veterans with chronic GWI.
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http://dx.doi.org/10.1016/j.redox.2021.101973DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8105671PMC
July 2021

Metformin treatment in late middle age improves cognitive function with alleviation of microglial activation and enhancement of autophagy in the hippocampus.

Aging Cell 2021 02 14;20(2):e13277. Epub 2021 Jan 14.

Institute for Regenerative Medicine, Department of Molecular and Cellular Medicine, Texas A&M University College of Medicine, College Station, TX, USA.

Metformin, a drug widely used for treating diabetes, can prolong the lifespan in several species. Metformin also has the promise to slow down age-related cognitive impairment. However, metformin's therapeutic use as an anti-aging drug is yet to be accepted because of conflicting animal and human studies results. We examined the effects of metformin treatment in late middle age on cognitive function in old age. Eighteen-month-old male C57BL6/J mice received metformin or no treatment for 10 weeks. A series of behavioral tests revealed improved cognitive function in animals that received metformin. Such findings were evident from a better ability for pattern separation, object location, and recognition memory function. Quantification of microglia revealed that metformin treatment reduced the incidence of pathological microglial clusters with alternative activation of microglia into an M2 phenotype, displaying highly ramified processes in the hippocampus. Metformin treatment also seemed to reduce astrocyte hypertrophy. Additional analysis demonstrated that metformin treatment in late middle age increased adenosine monophosphate-activated protein kinase activation, reduced proinflammatory cytokine levels, and the mammalian target of rapamycin signaling, and enhanced autophagy in the hippocampus. However, metformin treatment did not alter neurogenesis or synapses in the hippocampus, implying that improved cognitive function with metformin did not involve enhanced neurogenesis or neosynaptogenesis. The results provide new evidence that metformin treatment commencing in late middle age has promise for improving cognitive function in old age. Modulation of microglia, proinflammatory cytokines, and autophagy appear to be the mechanisms by which metformin facilitated functional benefits in the aged brain.
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http://dx.doi.org/10.1111/acel.13277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884047PMC
February 2021

Hippocampal Neural Stem Cell Grafting after Status Epilepticus Alleviates Chronic Epilepsy and Abnormal Plasticity, and Maintains Better Memory and Mood Function.

Aging Dis 2020 Dec 1;11(6):1374-1394. Epub 2020 Dec 1.

1Institute for Regenerative Medicine, Department of Molecular and Cellular Medicine, Texas A&M University College of Medicine, College Station, TX, USA.

Hippocampal damage after status epilepticus (SE) leads to multiple epileptogenic changes, which lead to chronic temporal lobe epilepsy (TLE). Morbidities such as spontaneous recurrent seizures (SRS) and memory and mood impairments are seen in a significant fraction of SE survivors despite the administration of antiepileptic drugs after SE. We examined the efficacy of bilateral intra-hippocampal grafting of neural stem/progenitor cells (NSCs) derived from the embryonic day 19 rat hippocampi, six days after SE for restraining SE-induced SRS, memory, and mood impairments in the chronic phase. Grafting of NSCs curtailed the progression of SRS at 3-5 months post-SE and reduced the frequency and severity of SRS activity when examined at eight months post-SE. Reduced SRS activity was also associated with improved memory function. Graft-derived cells migrated into different hippocampal cell layers, differentiated into GABA-ergic interneurons, astrocytes, and oligodendrocytes. Significant percentages of graft-derived cells also expressed beneficial neurotrophic factors such as the fibroblast growth factor-2, brain-derived neurotrophic factor, insulin-like growth factor-1 and glial cell line-derived neurotrophic factor. NSC grafting protected neuropeptide Y- and parvalbumin-positive host interneurons, diminished the abnormal migration of newly born neurons, and rescued the reelin+ interneurons in the dentate gyrus. Besides, grafting led to the maintenance of a higher level of normal neurogenesis in the chronic phase after SE and diminished aberrant mossy fiber sprouting in the dentate gyrus. Thus, intrahippocampal grafting of hippocampal NSCs shortly after SE considerably curbed the progression of epileptogenic processes and SRS, which eventually resulted in less severe chronic epilepsy devoid of significant cognitive and mood impairments.
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http://dx.doi.org/10.14336/AD.2020.1020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673840PMC
December 2020

Extracellular vesicles from human iPSC-derived neural stem cells: miRNA and protein signatures, and anti-inflammatory and neurogenic properties.

J Extracell Vesicles 2020 Aug 26;9(1):1809064. Epub 2020 Aug 26.

Institute for Regenerative Medicine, Department of Molecular and Cellular Medicine, Texas A&M University College of Medicine, College Station, Texas, USA.

Grafting of neural stem cells (NSCs) derived from human induced pluripotent stem cells (hiPSCs) has shown promise for brain repair after injury or disease, but safety issues have hindered their clinical application. Employing nano-sized extracellular vesicles (EVs) derived from hiPSC-NSCs appears to be a safer alternative because they likely have similar neuroreparative properties as NSCs and are amenable for non-invasive administration as an autologous or allogeneic off-the-shelf product. However, reliable methods for isolation, characterization and testing the biological properties of EVs are critically needed for translation. We investigated signatures of miRNAs and proteins and the biological activity of EVs, isolated from hiPSC-NSCs through a combination of anion-exchange chromatography (AEC) and size-exclusion chromatography (SEC). AEC and SEC facilitated the isolation of EVs with intact ultrastructure and expressing CD9, CD63, CD81, ALIX and TSG 101. Small RNA sequencing, proteomic analysis, pathway analysis and validation of select miRNAs and proteins revealed that EVs were enriched with miRNAs and proteins involved in neuroprotective, anti-apoptotic, antioxidant, anti-inflammatory, blood-brain barrier repairing, neurogenic and Aβ reducing activities. Besides, EVs comprised miRNAs and/or proteins capable of promoting synaptogenesis, synaptic plasticity and better cognitive function. Investigations using an macrophage assay and a mouse model of status epilepticus confirmed the anti-inflammatory activity of EVs. Furthermore, the intranasal administration of EVs resulted in the incorporation of EVs by neurons, microglia and astrocytes in virtually all adult rat and mouse brain regions, and enhancement of hippocampal neurogenesis. Thus, biologically active EVs containing miRNAs and proteins relevant to brain repair could be isolated from hiPSC-NSC cultures, making them a suitable biologic for treating neurodegenerative disorders.
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http://dx.doi.org/10.1080/20013078.2020.1809064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480597PMC
August 2020

Semantic Segmentation with Context Encoding and Multi-Path Decoding.

IEEE Trans Image Process 2020 Jan 9. Epub 2020 Jan 9.

Semantic image segmentation aims to classify every pixel of a scene image to one of many classes. It implicitly involves object recognition, localization, and boundary delineation. In this paper, we propose a segmentation network called CGBNet to enhance the paring results by context encoding and multi-path decoding. We first propose a context encoding module that generates context contrasted local feature to make use of the informative context and the discriminative local information. This context encoding module greatly improves the segmentation performance, especially for inconspicuous objects. Furthermore, we propose a scale-selection scheme to selectively fuse the parsing results from different-scales of features at every spatial position. It adaptively selects appropriate score maps from rich scales of features. To improve the parsing results of boundary, we further propose a boundary delineation module that encourages the location-specific very-low-level feature near the boundaries to take part in the final prediction and suppresses them far from the boundaries. Without bells and whistles, the proposed segmentation network achieves very competitive performance in terms of all three different evaluation metrics consistently on the four popular scene segmentation datasets, Pascal Context, SUN-RGBD, Sift Flow, and COCO Stuff.
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http://dx.doi.org/10.1109/TIP.2019.2962685DOI Listing
January 2020

Intranasally Administered Human MSC-Derived Extracellular Vesicles Pervasively Incorporate into Neurons and Microglia in both Intact and Status Epilepticus Injured Forebrain.

Int J Mol Sci 2019 Dec 26;21(1). Epub 2019 Dec 26.

Institute for Regenerative Medicine, Department of Molecular and Cellular Medicine, Texas A&M University College of Medicine, 1114 TAMU, College Station, TX 77842, USA.

Extracellular vesicles (EVs) derived from human bone marrow mesenchymal stem cells (hMSCs) have great promise as biologics to treat neurological and neurodegenerative conditions due to their robust antiinflammatory and neuroprotective properties. Besides, intranasal (IN) administration of EVs has caught much attention because the procedure is noninvasive, amenable for repetitive dispensation, and leads to a quick penetration of EVs into multiple regions of the forebrain. Nonetheless, it is unknown whether brain injury-induced signals are essential for the entry of IN-administered EVs into different brain regions. Therefore, in this study, we investigated the distribution of IN-administered hMSC-derived EVs into neurons and microglia in the intact and status epilepticus (SE) injured rat forebrain. Ten billion EVs labeled with PKH26 were dispensed unilaterally into the left nostril of naïve rats, and rats that experienced two hours of kainate-induced SE. Six hours later, PKH26 + EVs were quantified from multiple forebrain regions using serial brain sections processed for different neural cell markers and confocal microscopy. Remarkably, EVs were seen bilaterally in virtually all regions of intact and SE-injured forebrain. The percentage of neurons incorporating EVs were comparable for most forebrain regions. However, in animals that underwent SE, a higher percentage of neurons incorporated EVs in the hippocampal CA1 subfield and the entorhinal cortex, the regions that typically display neurodegeneration after SE. In contrast, the incorporation of EVs by microglia was highly comparable in every region of the forebrain measured. Thus, unilateral IN administration of EVs is efficient for delivering EVs bilaterally into neurons and microglia in multiple regions in the intact or injured forebrain. Furthermore, incorporation of EVs by neurons is higher in areas of brain injury, implying that injury-related signals likely play a role in targeting of EVs into neurons, which may be beneficial for EV therapy in various neurodegenerative conditions including traumatic brain injury, stroke, multiple sclerosis, and Alzheimer's disease.
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http://dx.doi.org/10.3390/ijms21010181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6981466PMC
December 2019

Monosodium luminol reinstates redox homeostasis, improves cognition, mood and neurogenesis, and alleviates neuro- and systemic inflammation in a model of Gulf War Illness.

Redox Biol 2020 01 18;28:101389. Epub 2019 Nov 18.

Institute for Regenerative Medicine, Department of Molecular and Cellular Medicine, Texas A&M University College of Medicine, College Station, TX, USA.

Enduring brain dysfunction is amid the highly manifested symptoms in veterans with Gulf War Illness (GWI). Animal studies have established that lasting brain dysfunction in GWI is concomitant with augmented oxidative stress, inflammation, and declined neurogenesis in the brain, and systemic inflammation. We hypothesize that drugs capable of restoring redox homeostasis in GWI will improve cognitive and mood function with modulation of neuroinflammation and neurogenesis. We examined the efficacy of monosodium luminol-GVT (MSL), a drug that promotes redox homeostasis, for improving cognitive and mood function in GWI rats. Young rats were exposed to GWI-related chemicals and moderate restraint stress for four weeks. Four months later, GWI rats received different doses of MSL or vehicle for eight weeks. Behavioral analyses in the last three weeks of treatment revealed that GWI rats receiving higher doses of MSL displayed better cognitive and mood function associated with reinstatement of redox homeostasis. Such restoration was evident from the normalized expression of multiple genes encoding proteins involved in combating oxidative stress in the brain and the return of several oxidative stress markers to control levels in the brain and the circulating blood. Sustained redox homeostasis by MSL also resulted in antiinflammatory and pro-neurogenic effects, which were apparent from reduced densities of hypertrophied astrocytes and activated microglia, and increased neurogenesis with augmented neural stem cell proliferation. Moreover, MSL treatment normalized the concentration of multiple proinflammatory markers in the circulating blood. Thus, MSL treatment reinstated redox homeostasis in an animal model of GWI, which resulted in alleviation of both brain and systemic inflammation, improved neurogenesis, and better cognitive and mood function.
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http://dx.doi.org/10.1016/j.redox.2019.101389DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6888767PMC
January 2020

A Model of Chronic Temporal Lobe Epilepsy Presenting Constantly Rhythmic and Robust Spontaneous Seizures, Co-morbidities and Hippocampal Neuropathology.

Aging Dis 2019 Oct 1;10(5):915-936. Epub 2019 Oct 1.

Institute for Regenerative Medicine, Department of Molecular and Cellular Medicine, Texas A&M Health Science Center College of Medicine, College Station, TX, USA.

Many animal prototypes illustrating the various attributes of human temporal lobe epilepsy (TLE) are available. These models have been invaluable for comprehending multiple epileptogenic processes, modifications in electrophysiological properties, neuronal hyperexcitability, neurodegeneration, neural plasticity, and chronic neuroinflammation in TLE. Some models have also uncovered the efficacy of new antiepileptic drugs or biologics for alleviating epileptogenesis, cognitive impairments, or spontaneous recurrent seizures (SRS). Nonetheless, the suitability of these models for testing candidate therapeutics in conditions such as chronic TLE is debatable because of a lower frequency of SRS and an inconsistent pattern of SRS activity over days, weeks or months. An ideal prototype of chronic TLE for investigating novel therapeutics would need to display a large number of SRS with a dependable frequency and severity and related co-morbidities. This study presents a new kainic acid (KA) model of chronic TLE generated through induction of status epilepticus (SE) in 6-8 weeks old male F344 rats. A rigorous characterization in the chronic epilepsy period validated that the animal prototype mimicked the most salient features of robust chronic TLE. Animals displayed a constant frequency and intensity of SRS across weeks and months in the 5th and 6th month after SE, as well as cognitive and mood impairments. Moreover, SRS frequency displayed a rhythmic pattern with 24-hour periodicity and a consistently higher number of SRS in the daylight period. Besides, the model showed many neuropathological features of chronic TLE, which include a partial loss of inhibitory interneurons, reduced neurogenesis with persistent aberrant migration of newly born neurons, chronic neuroinflammation typified by hypertrophied astrocytes and rod-shaped microglia, and a significant aberrant mossy fiber sprouting in the hippocampus. This consistent chronic seizure model is ideal for investigating the efficacy of various antiepileptic drugs and biologics as well as understanding multiple pathophysiological mechanisms underlying chronic epilepsy.
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http://dx.doi.org/10.14336/AD.2019.0720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6764729PMC
October 2019

Neuroinflammation in Gulf War Illness is linked with HMGB1 and complement activation, which can be discerned from brain-derived extracellular vesicles in the blood.

Brain Behav Immun 2019 10 27;81:430-443. Epub 2019 Jun 27.

Institute for Regenerative Medicine, Department of Molecular and Cellular Medicine, Texas A&M University Health Science Center College of Medicine, College Station, TX, USA. Electronic address:

Cognitive dysfunction and neuroinflammation are conspicuously observed in Gulf War Illness (GWI). We investigated whether brain inflammation in GWI is associated with activation of high mobility group box-1 (HMGB1) and complement-related proteins in neurons and astrocytes, and brain inflammation can be tracked through neuron-derived extracellular vesicles (NDEVs) and astrocyte-derived EVs (ADEVs) found in the circulating blood. We exposed animals to GWI-related chemicals pyridostigmine bromide, DEET and permethrin, and moderate stress for 28 days. We performed behavioral tests 10 months post-exposure and quantified activated microglia and reactive astrocytes in the cerebral cortex. Then, we measured the concentration of HMGB1, proinflammatory cytokines, and complement activation-related proteins in the cerebral cortex, and NDEVs and ADEVs in the circulating blood. Cognitive impairments persisted in GWI rats at 10 months post-exposure, which were associated with increased density of activated microglia and reactive astrocytes in the cerebral cortex. Moreover, the level of HMGB1 was elevated in the cerebral cortex with altered expression in the cytoplasm of neuronal soma and dendrites as well as the extracellular space. Also, higher levels of proinflammatory cytokines (TNFa, IL-1b, and IL-6), and complement activation-related proteins (C3 and TccC5b-9) were seen in the cerebral cortex. Remarkably, increased levels of HMGB1 and proinflammatory cytokines observed in the cerebral cortex of GWI rats could also be found in NDEVs isolated from the blood. Similarly, elevated levels of complement proteins seen in the cerebral cortex could be found in ADEVs. The results provide new evidence that persistent cognitive dysfunction and chronic neuroinflammation in a model of GWI are linked with elevated HMGB1 concentration and complement activation. Furthermore, the results demonstrated that multiple biomarkers of neuroinflammation could be tracked reliably via analyses of NDEVs and ADEVs in the circulating blood. Execution of such a liquid biopsy approach is especially useful in clinical trials for monitoring the remission, persistence or progression of brain inflammation in GWI patients with drug treatment.
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http://dx.doi.org/10.1016/j.bbi.2019.06.040DOI Listing
October 2019

Human induced pluripotent stem cell-derived MGE cell grafting after status epilepticus attenuates chronic epilepsy and comorbidities via synaptic integration.

Proc Natl Acad Sci U S A 2019 01 17;116(1):287-296. Epub 2018 Dec 17.

Institute for Regenerative Medicine, Texas A&M Health Science Center College of Medicine, Temple, TX 76502;

Medial ganglionic eminence (MGE)-like interneuron precursors derived from human induced pluripotent stem cells (hiPSCs) are ideal for developing patient-specific cell therapy in temporal lobe epilepsy (TLE). However, their efficacy for alleviating spontaneous recurrent seizures (SRS) or cognitive, memory, and mood impairments has never been tested in models of TLE. Through comprehensive video- electroencephalographic recordings and a battery of behavioral tests in a rat model, we demonstrate that grafting of hiPSC-derived MGE-like interneuron precursors into the hippocampus after status epilepticus (SE) greatly restrained SRS and alleviated cognitive, memory, and mood dysfunction in the chronic phase of TLE. Graft-derived cells survived well, extensively migrated into different subfields of the hippocampus, and differentiated into distinct subclasses of inhibitory interneurons expressing various calcium-binding proteins and neuropeptides. Moreover, grafting of hiPSC-MGE cells after SE mediated several neuroprotective and antiepileptogenic effects in the host hippocampus, as evidenced by reductions in host interneuron loss, abnormal neurogenesis, and aberrant mossy fiber sprouting in the dentate gyrus (DG). Furthermore, axons from graft-derived interneurons made synapses on the dendrites of host excitatory neurons in the DG and the CA1 subfield of the hippocampus, implying an excellent graft-host synaptic integration. Remarkably, seizure-suppressing effects of grafts were significantly reduced when the activity of graft-derived interneurons was silenced by a designer drug while using donor hiPSC-MGE cells expressing designer receptors exclusively activated by designer drugs (DREADDs). These results implied the direct involvement of graft-derived interneurons in seizure control likely through enhanced inhibitory synaptic transmission. Collectively, the results support a patient-specific MGE cell grafting approach for treating TLE.
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http://dx.doi.org/10.1073/pnas.1814185115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6320542PMC
January 2019

Towards Achieving Robust Low-level and High-level Scene Parsing.

IEEE Trans Image Process 2018 Oct 31. Epub 2018 Oct 31.

In this paper, we address the challenging task of scene segmentation. We first discuss and compare two widely used approaches to retain detailed spatial information from pretrained CNN - "dilation" and "skip". Then, we demonstrate that the parsing performance of "skip" network can be noticeably improved by modifying the parameterization of skip layers. Furthermore, we introduce a "dense skip" architecture to retain a rich set of low-level information from pre-trained CNN, which is essential to improve the low-level parsing performance. Meanwhile, we propose a convolutional context network (CCN) and place it on top of pre-trained CNNs, which is used to aggregate contexts for high-level feature maps so that robust high-level parsing can be achieved. We name our segmentation network enhanced fully convolutional network (EFCN) based on its significantly enhanced structure over FCN. Extensive experimental studies justify each contribution separately. Without bells and whistles, EFCN achieves state-of-the-arts on segmentation datasets of ADE20K, Pascal Context, SUN-RGBD and Pascal VOC 2012.
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http://dx.doi.org/10.1109/TIP.2018.2878975DOI Listing
October 2018

Wwox deletion leads to reduced GABA-ergic inhibitory interneuron numbers and activation of microglia and astrocytes in mouse hippocampus.

Neurobiol Dis 2019 01 2;121:163-176. Epub 2018 Oct 2.

Department of Epigenetics and Molecular Carcinogenesis, Science Park, The University of Texas MD Anderson Cancer Center, Smithville, TX, United States. Electronic address:

The association of WW domain-containing oxidoreductase WWOX gene loss of function with central nervous system (CNS) related pathologies is well documented. These include spinocerebellar ataxia, epilepsy and mental retardation (SCAR12, OMIM: 614322) and early infantile epileptic encephalopathy (EIEE28, OMIM: 616211) syndromes. However, there is complete lack of understanding of the pathophysiological mechanisms at play. In this study, using a Wwox knockout (Wwox KO) mouse model (2 weeks old, both sexes) and stereological studies we observe that Wwox deletion leads to a significant reduction in the number of hippocampal GABA-ergic (γ-aminobutyric acid) interneurons. Wwox KO mice displayed significantly reduced numbers of calcium-binding protein parvalbumin (PV) and neuropeptide Y (NPY) expressing interneurons in different subfields of the hippocampus in comparison to Wwox wild-type (WT) mice. We also detected decreased levels of Glutamic Acid Decarboxylase protein isoforms GAD65/67 expression in Wwox null hippocampi suggesting lower levels of GABA synthesis. In addition, Wwox deficiency was associated with signs of neuroinflammation such as evidence of activated microglia, astrogliosis, and overexpression of inflammatory cytokines Tnf-a and Il6. We also performed comparative transcriptome-wide expression analyses of neural stem cells grown as neurospheres from hippocampi of Wwox KO and WT mice thus identifying 283 genes significantly dysregulated in their expression. Functional annotation of transcriptome profiling differences identified 'neurological disease' and 'CNS development related functions' to be significantly enriched. Several epilepsy-related genes were found differentially expressed in Wwox KO neurospheres. This study provides the first genotype-phenotype observations as well as potential mechanistic clues associated with Wwox loss of function in the brain.
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http://dx.doi.org/10.1016/j.nbd.2018.09.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7104842PMC
January 2019

Chronic Oxidative Stress, Mitochondrial Dysfunction, Nrf2 Activation and Inflammation in the Hippocampus Accompany Heightened Systemic Inflammation and Oxidative Stress in an Animal Model of Gulf War Illness.

Front Mol Neurosci 2017 14;10:182. Epub 2017 Jun 14.

Research Service, Olin E. Teague Veterans' Medical Center, Central Texas Veterans Health Care System, TempleTX, United States.

Memory and mood dysfunction are the key symptoms of Gulf war illness (GWI), a lingering multi-symptom ailment afflicting >200,000 veterans who served in the Persian Gulf War-1. Research probing the source of the disease has demonstrated that concomitant exposures to anti-nerve gas agent pyridostigmine bromide (PB), pesticides, and war-related stress are among the chief causes of GWI. Indeed, exposures to GWI-related chemicals (GWIR-Cs) and mild stress in animal models cause memory and mood impairments alongside reduced neurogenesis and chronic low-level inflammation in the hippocampus. In the current study, we examined whether exposure to GWIR-Cs and stress causes chronic changes in the expression of genes related to increased oxidative stress, mitochondrial dysfunction, and inflammation in the hippocampus. We also investigated whether GWI is linked with chronically increased activation of Nrf2 (a master regulator of antioxidant response) in the hippocampus, and inflammation and enhanced oxidative stress at the systemic level. Adult male rats were exposed daily to low-doses of PB and pesticides (DEET and permethrin), in combination with 5 min of restraint stress for 4 weeks. Analysis of the hippocampus performed 6 months after the exposure revealed increased expression of many genes related to oxidative stress response and/or antioxidant activity (, and ), reactive oxygen species metabolism (, and ) and oxygen transport ( and ). Furthermore, multiple genes relevant to mitochondrial respiration (, and ) and neuroinflammation (, and ) were up-regulated, alongside 73-88% reduction in the expression of anti-inflammatory genes and , and nuclear translocation and increased expression of Nrf2 protein. These hippocampal changes were associated with elevated levels of pro-inflammatory cytokines and chemokines (Tnfa, IL1b, IL1a, Tgfb, and Fgf2) and lipid peroxidation byproduct malondialdehyde in the serum, suggesting the presence of an incessant systemic inflammation and elevated oxidative stress. These results imply that chronic oxidative stress, inflammation, and mitochondrial dysfunction in the hippocampus, and heightened systemic inflammation and oxidative stress likely underlie the persistent memory and mood dysfunction observed in GWI.
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http://dx.doi.org/10.3389/fnmol.2017.00182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5469946PMC
June 2017

Scene Segmentation with DAG-Recurrent Neural Networks.

IEEE Trans Pattern Anal Mach Intell 2018 06 6;40(6):1480-1493. Epub 2017 Jun 6.

In this paper, we address the challenging task of scene segmentation. In order to capture the rich contextual dependencies over image regions, we propose Directed Acyclic Graph-Recurrent Neural Networks (DAG-RNN) to perform context aggregation over locally connected feature maps. More specifically, DAG-RNN is placed on top of pre-trained CNN (feature extractor) to embed context into local features so that their representative capability can be enhanced. In comparison with plain CNN (as in Fully Convolutional Networks-FCN), DAG-RNN is empirically found to be significantly more effective at aggregating context. Therefore, DAG-RNN demonstrates noticeably performance superiority over FCNs on scene segmentation. Besides, DAG-RNN entails dramatically less parameters as well as demands fewer computation operations, which makes DAG-RNN more favorable to be potentially applied on resource-constrained embedded devices. Meanwhile, the class occurrence frequencies are extremely imbalanced in scene segmentation, so we propose a novel class-weighted loss to train the segmentation network. The loss distributes reasonably higher attention weights to infrequent classes during network training, which is essential to boost their parsing performance. We evaluate our segmentation network on three challenging public scene segmentation benchmarks: Sift Flow, Pascal Context and COCO Stuff. On top of them, we achieve very impressive segmentation performance.
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http://dx.doi.org/10.1109/TPAMI.2017.2712691DOI Listing
June 2018

Intranasal MSC-derived A1-exosomes ease inflammation, and prevent abnormal neurogenesis and memory dysfunction after status epilepticus.

Proc Natl Acad Sci U S A 2017 04 10;114(17):E3536-E3545. Epub 2017 Apr 10.

Institute for Regenerative Medicine, Texas A&M Health Science Center College of Medicine, Temple, TX 76502;

Status epilepticus (SE), a medical emergency that is typically terminated through antiepileptic drug treatment, leads to hippocampus dysfunction typified by neurodegeneration, inflammation, altered neurogenesis, as well as cognitive and memory deficits. Here, we examined the effects of intranasal (IN) administration of extracellular vesicles (EVs) secreted from human bone marrow-derived mesenchymal stem cells (MSCs) on SE-induced adverse changes. The EVs used in this study are referred to as A1-exosomes because of their robust antiinflammatory properties. We subjected young mice to pilocarpine-induced SE for 2 h and then administered A1-exosomes or vehicle IN twice over 24 h. The A1-exosomes reached the hippocampus within 6 h of administration, and animals receiving them exhibited diminished loss of glutamatergic and GABAergic neurons and greatly reduced inflammation in the hippocampus. Moreover, the neuroprotective and antiinflammatory effects of A1-exosomes were coupled with long-term preservation of normal hippocampal neurogenesis and cognitive and memory function, in contrast to waned and abnormal neurogenesis, persistent inflammation, and functional deficits in animals receiving vehicle. These results provide evidence that IN administration of A1-exosomes is efficient for minimizing the adverse effects of SE in the hippocampus and preventing SE-induced cognitive and memory impairments.
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http://dx.doi.org/10.1073/pnas.1703920114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5410779PMC
April 2017

Learning Contextual Dependence With Convolutional Hierarchical Recurrent Neural Networks.

IEEE Trans Image Process 2016 07;25(7):2983-2996

Deep convolutional neural networks (CNNs) have shown their great success on image classification. CNNs mainly consist of convolutional and pooling layers, both of which are performed on local image areas without considering the dependence among different image regions. However, such dependence is very important for generating explicit image representation. In contrast, recurrent neural networks (RNNs) are well known for their ability of encoding contextual information in sequential data, and they only require a limited number of network parameters. Thus, we proposed the hierarchical RNNs (HRNNs) to encode the contextual dependence in image representation. In HRNNs, each RNN layer focuses on modeling spatial dependence among image regions from the same scale but different locations. While the cross RNN scale connections target on modeling scale dependencies among regions from the same location but different scales. Specifically, we propose two RNN models: 1) hierarchical simple recurrent network (HSRN), which is fast and has low computational cost and 2) hierarchical long-short term memory recurrent network, which performs better than HSRN with the price of higher computational cost. In this paper, we integrate CNNs with HRNNs, and develop end-to-end convolutional hierarchical RNNs (C-HRNNs) for image classification. C-HRNNs not only utilize the discriminative representation power of CNNs, but also utilize the contextual dependence learning ability of our HRNNs. On four of the most challenging object/scene image classification benchmarks, our C-HRNNs achieve the state-of-the-art results on Places 205, SUN 397, and MIT indoor, and the competitive results on ILSVRC 2012.
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http://dx.doi.org/10.1109/TIP.2016.2548241DOI Listing
July 2016

Voluntary Running Exercise-Mediated Enhanced Neurogenesis Does Not Obliterate Retrograde Spatial Memory.

J Neurosci 2016 08;36(31):8112-22

Institute for Regenerative Medicine, Texas A&M Health Science Center College of Medicine at Scott and White, Temple, Texas 76502, Research Service, Olin E. Teague Veterans' Medical Center, Central Texas Veterans Health Care System, Temple, Texas 76502, and Department of Molecular and Cellular Medicine, Texas A&M Health Science Center College of Medicine, College Station, Texas 77843

Unlabelled: Running exercise (RE) improves cognition, formation of anterograde memories, and mood, alongside enhancing hippocampal neurogenesis. A previous investigation in a mouse model showed that RE-induced increased neurogenesis erases retrograde memory (Akers et al., 2014). However, it is unknown whether RE-induced forgetting is common to all species. We ascertained whether voluntary RE-induced enhanced neurogenesis interferes with the recall of spatial memory in rats. Young rats assigned to either sedentary (SED) or running exercise (RE) groups were first subjected to eight learning sessions in a water maze. A probe test (PT) conducted 24 h after the final training session confirmed that animals in either group had a similar ability for the recall of short-term memory. Following this, rats in the RE group were housed in larger cages fitted with running wheels, whereas rats in the SED group remained in standard cages. Animals in the RE group ran an average of 78 km in 4 weeks. A second PT performed 4 weeks after the first PT revealed comparable ability for memory recall between animals in the RE and SED groups, which was evidenced through multiple measures of memory retrieval function. The RE group displayed a 1.5- to 2.1-fold higher hippocampal neurogenesis than SED rats. Additionally, both moderate and brisk RE did not interfere with the recall of memory, although increasing amounts of RE proportionally enhanced neurogenesis. In conclusion, RE does not impair memory recall ability in a rat model despite substantially increasing neurogenesis.

Significance Statement: Running exercise (RE) improves new memory formation along with an increased neurogenesis in the hippocampus. In view of a recent study showing that RE-mediated increased hippocampal neurogenesis promotes forgetfulness in a mouse model, we ascertained whether a similar adverse phenomenon exists in a rat model. Memory recall ability examined 4 weeks after learning confirmed that animals that had run a mean of 78 km and displayed a 1.5- to 2.1-fold increase in hippocampal neurogenesis demonstrated similar proficiency for memory recall as animals that had remained sedentary. Furthermore, both moderate and brisk RE did not interfere with memory recall, although increasing amounts of RE proportionally enhanced neurogenesis, implying that RE has no adverse effects on memory recall.
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http://dx.doi.org/10.1523/JNEUROSCI.0766-16.2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6601951PMC
August 2016

Scene Parsing With Integration of Parametric and Non-Parametric Models.

IEEE Trans Image Process 2016 May;25(5):2379-91

We adopt convolutional neural networks (CNNs) to be our parametric model to learn discriminative features and classifiers for local patch classification. Based on the occurrence frequency distribution of classes, an ensemble of CNNs (CNN-Ensemble) are learned, in which each CNN component focuses on learning different and complementary visual patterns. The local beliefs of pixels are output by CNN-Ensemble. Considering that visually similar pixels are indistinguishable under local context, we leverage the global scene semantics to alleviate the local ambiguity. The global scene constraint is mathematically achieved by adding a global energy term to the labeling energy function, and it is practically estimated in a non-parametric framework. A large margin-based CNN metric learning method is also proposed for better global belief estimation. In the end, the integration of local and global beliefs gives rise to the class likelihood of pixels, based on which maximum marginal inference is performed to generate the label prediction maps. Even without any post-processing, we achieve the state-of-the-art results on the challenging SiftFlow and Barcelona benchmarks.
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http://dx.doi.org/10.1109/TIP.2016.2533862DOI Listing
May 2016

Resveratrol Treatment after Status Epilepticus Restrains Neurodegeneration and Abnormal Neurogenesis with Suppression of Oxidative Stress and Inflammation.

Sci Rep 2015 Dec 7;5:17807. Epub 2015 Dec 7.

Institute for Regenerative Medicine, Texas A &M Health Science Center College of Medicine at Scott &White, Temple, Texas, USA.

Antiepileptic drug therapy, though beneficial for restraining seizures, cannot thwart status epilepticus (SE) induced neurodegeneration or down-stream detrimental changes. We investigated the efficacy of resveratrol (RESV) for preventing SE-induced neurodegeneration, abnormal neurogenesis, oxidative stress and inflammation in the hippocampus. We induced SE in young rats and treated with either vehicle or RESV, commencing an hour after SE induction and continuing every hour for three-hours on SE day and twice daily thereafter for 3 days. Seizures were terminated in both groups two-hours after SE with a diazepam injection. In contrast to the vehicle-treated group, the hippocampus of animals receiving RESV during and after SE presented no loss of glutamatergic neurons in hippocampal cell layers, diminished loss of inhibitory interneurons expressing parvalbumin, somatostatin and neuropeptide Y in the dentate gyrus, reduced aberrant neurogenesis with preservation of reelin + interneurons, lowered concentration of oxidative stress byproduct malondialdehyde and pro-inflammatory cytokine tumor necrosis factor-alpha, normalized expression of oxidative stress responsive genes and diminished numbers of activated microglia. Thus, 4 days of RESV treatment after SE is efficacious for thwarting glutamatergic neuron degeneration, alleviating interneuron loss and abnormal neurogenesis, and suppressing oxidative stress and inflammation. These results have implications for restraining SE-induced chronic temporal lobe epilepsy.
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http://dx.doi.org/10.1038/srep17807DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4671086PMC
December 2015

Resveratrol prevents age-related memory and mood dysfunction with increased hippocampal neurogenesis and microvasculature, and reduced glial activation.

Sci Rep 2015 Jan 28;5:8075. Epub 2015 Jan 28.

1] Institute for Regenerative Medicine, Texas A&M Health Science Center College of Medicine at Scott &White, Temple, Texas, USA [2] Research Service, Olin E. Teague Veterans Affairs Medical Center, Central Texas Veterans Health Care System, Temple, Texas, USA [3] Department of Molecular and Cellular Medicine, Texas A&M Health Science Center College of Medicine, College Station, Texas, USA [4] Department of Surgery (Neurosurgery) and Research Service, Duke University and Veterans' Affairs Medical Centers, Durham, North Carolina, USA.

Greatly waned neurogenesis, diminished microvasculature, astrocyte hypertrophy and activated microglia are among the most conspicuous structural changes in the aged hippocampus. Because these alterations can contribute to age-related memory and mood impairments, strategies efficacious for mitigating these changes may preserve cognitive and mood function in old age. Resveratrol, a phytoalexin found in the skin of red grapes having angiogenic and antiinflammatory properties, appears ideal for easing these age-related changes. Hence, we examined the efficacy of resveratrol for counteracting age-related memory and mood impairments and the associated detrimental changes in the hippocampus. Two groups of male F344 rats in late middle-age having similar learning and memory abilities were chosen and treated with resveratrol or vehicle for four weeks. Analyses at ~25 months of age uncovered improved learning, memory and mood function in resveratrol-treated animals but impairments in vehicle-treated animals. Resveratrol-treated animals also displayed increased net neurogenesis and microvasculature, and diminished astrocyte hypertrophy and microglial activation in the hippocampus. These results provide novel evidence that resveratrol treatment in late middle age is efficacious for improving memory and mood function in old age. Modulation of the hippocampus plasticity and suppression of chronic low-level inflammation appear to underlie the functional benefits mediated by resveratrol.
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http://dx.doi.org/10.1038/srep08075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4894403PMC
January 2015

Parvalbumin and neuropeptide Y expressing hippocampal GABA-ergic inhibitory interneuron numbers decline in a model of Gulf War illness.

Front Cell Neurosci 2014 8;8:447. Epub 2015 Jan 8.

Research Service, Olin E. Teague Veterans' Medical Center, Central Texas Veterans Health Care System Temple, TX, USA ; Institute for Regenerative Medicine, Texas A&M Health Science Center College of Medicine at Scott & White Temple, TX, USA ; Department of Molecular and Cellular Medicine, Texas A&M Health Science Center College of Medicine College Station, TX, USA.

Cognitive dysfunction is amongst the most conspicuous symptoms in Gulf War illness (GWI). Combined exposure to the nerve gas antidote pyridostigmine bromide (PB), pesticides and stress during the Persian Gulf War-1 (PGW-1) are presumed to be among the major causes of GWI. Indeed, our recent studies in rat models have shown that exposure to GWI-related (GWIR) chemicals and mild stress for 4 weeks engenders cognitive impairments accompanied with several detrimental changes in the hippocampus. In this study, we tested whether reduced numbers of hippocampal gamma-amino butyric acid (GABA)-ergic interneurons are among the pathological changes induced by GWIR-chemicals and stress. Animals were exposed to low doses of GWIR-chemicals and mild stress for 4 weeks. Three months after this exposure, subpopulations of GABA-ergic interneurons expressing the calcium binding protein parvalbumin (PV), the neuropeptide Y (NPY) and somatostatin (SS) in the hippocampus were stereologically quantified. Animals exposed to GWIR-chemicals and stress for 4 weeks displayed reduced numbers of PV-expressing GABA-ergic interneurons in the dentate gyrus and NPY-expressing interneurons in the CA1 and CA3 subfields. However, no changes in SS+ interneuron population were observed in the hippocampus. Furthermore, GABA-ergic interneuron deficiency in these animals was associated with greatly diminished hippocampus neurogenesis. Because PV+ and NPY+ interneurons play roles in maintaining normal cognitive function and neurogenesis, and controlling the activity of excitatory neurons in the hippocampus, reduced numbers of these interneurons may be one of the major causes of cognitive dysfunction and reduced neurogenesis observed in GWI. Hence, strategies that improve inhibitory neurotransmission in the hippocampus may prove beneficial for reversing cognitive dysfunction in GWI.
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http://dx.doi.org/10.3389/fncel.2014.00447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4288040PMC
January 2015

[Stereological study of the placenta in patients receiving different vasopressors for hypotension during cesarean section].

Nan Fang Yi Ke Da Xue Xue Bao 2014 Jul;34(8):1154-7

Hexian Memorial Hospital Affiliated to Southern Medical University, Guangzhou 511400, China.E-mail:

Objective: To study the effects of dopamine and phenylephrine for treatment of hypotension during cesarean section under combined spinal epidural anesthesia (CSEA) on the stereology of the placenta.

Methods: Forty puerperants undergoing cesarean section under CSEA were randomly divided into dopamine group and phenylephrine group. Ropivacaine (16 mg) was administered immediately after spinal anethesia. Blood pressure was maintained near the baseline by adjusting the drug infusion rate. Fetal blood gas, Apgar score, and placental villus microvascular stereological changes were observed during the operation.

Results: The microvascular density was significantly lower in dopamine group than in phenylephrine group (P<0.05). Phenylephrine group showed significantly lower umbilical artery blood pH than dopamine group (P<0.05). The Apgar score and blood pressure were comparable between the two groups (P>0.05). Compared to the baseline, both of the two groups showed significantly lowered heart rate during the operation (P<0.01).

Conclusion: Dopamine is associated with the risk of fetal acidosis. Phenylephrine is helpful for preventing hypotension by increasing placental blood flow and improving oxygen supply to ensure maternal and fetal safety during cesarean section.
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July 2014

Object location and object recognition memory impairments, motivation deficits and depression in a model of Gulf War illness.

Front Behav Neurosci 2014 13;8:78. Epub 2014 Mar 13.

Research Service, Olin E. Teague Veterans' Medical Center, Central Texas Veterans Health Care System Temple, TX, USA ; Institute for Regenerative Medicine, Texas A&M Health Science Center College of Medicine at Scott and White Temple, TX, USA ; Department of Molecular and Cellular Medicine, Texas A&M Health Science Center College of Medicine College Station, TX, USA.

Memory and mood deficits are the enduring brain-related symptoms in Gulf War illness (GWI). Both animal model and epidemiological investigations have indicated that these impairments in a majority of GW veterans are linked to exposures to chemicals such as pyridostigmine bromide (PB, an antinerve gas drug), permethrin (PM, an insecticide) and DEET (a mosquito repellant) encountered during the Persian Gulf War-1. Our previous study in a rat model has shown that combined exposures to low doses of GWI-related (GWIR) chemicals PB, PM, and DEET with or without 5-min of restraint stress (a mild stress paradigm) causes hippocampus-dependent spatial memory dysfunction in a water maze test (WMT) and increased depressive-like behavior in a forced swim test (FST). In this study, using a larger cohort of rats exposed to GWIR-chemicals and stress, we investigated whether the memory deficiency identified earlier in a WMT is reproducible with an alternative and stress free hippocampus-dependent memory test such as the object location test (OLT). We also ascertained the possible co-existence of hippocampus-independent memory dysfunction using a novel object recognition test (NORT), and alterations in mood function with additional tests for motivation and depression. Our results provide new evidence that exposure to low doses of GWIR-chemicals and mild stress for 4 weeks causes deficits in hippocampus-dependent object location memory and perirhinal cortex-dependent novel object recognition memory. An open field test performed prior to other behavioral analyses revealed that memory impairments were not associated with increased anxiety or deficits in general motor ability. However, behavioral tests for mood function such as a voluntary physical exercise paradigm and a novelty suppressed feeding test (NSFT) demonstrated decreased motivation levels and depression. Thus, exposure to GWIR-chemicals and stress causes both hippocampus-dependent and hippocampus-independent memory impairments as well as mood dysfunction in a rat model.
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http://dx.doi.org/10.3389/fnbeh.2014.00078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3952084PMC
March 2014

Mood and memory deficits in a model of Gulf War illness are linked with reduced neurogenesis, partial neuron loss, and mild inflammation in the hippocampus.

Neuropsychopharmacology 2013 Nov 28;38(12):2348-62. Epub 2013 Jun 28.

1] Research Service, Durham Veterans Affairs Medical Center, Durham, NC, USA [2] Department of Surgery (Neurosurgery), Duke University Medical Center, Durham, NC, USA.

Impairments in mood and cognitive function are the key brain abnormalities observed in Gulf war illness (GWI), a chronic multisymptom health problem afflicting ∼25% of veterans who served in the Persian Gulf War-1. Although the precise cause of GWI is still unknown, combined exposure to a nerve gas prophylaxis drug pyridostigmine bromide (PB) and pesticides DEET and permethrin during the war has been proposed as one of the foremost causes of GWI. We investigated the effect of 4 weeks of exposure to Gulf war illness-related (GWIR) chemicals in the absence or presence of mild stress on mood and cognitive function, dentate gyrus neurogenesis, and neurons, microglia, and astrocytes in the hippocampus. Combined exposure to low doses of GWIR chemicals PB, DEET, and permethrin induced depressive- and anxiety-like behavior and spatial learning and memory dysfunction. Application of mild stress in the period of exposure to chemicals exacerbated the extent of mood and cognitive dysfunction. Furthermore, these behavioral impairments were associated with reduced hippocampal volume and multiple cellular alterations such as chronic reductions in neural stem cell activity and neurogenesis, partial loss of principal neurons, and mild inflammation comprising sporadic occurrence of activated microglia and significant hypertrophy of astrocytes. The results show the first evidence of an association between mood and cognitive dysfunction and hippocampal pathology epitomized by decreased neurogenesis, partial loss of principal neurons, and mild inflammation in a model of GWI. Hence, treatment strategies that are efficacious for enhancing neurogenesis and suppressing inflammation may be helpful for alleviation of mood and cognitive dysfunction observed in GWI.
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http://dx.doi.org/10.1038/npp.2013.158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3799073PMC
November 2013

Effects of colloid preload on placenta stereology and cord blood S100β protein during cesarean section under spinal anesthesia.

Nan Fang Yi Ke Da Xue Xue Bao 2013 Feb;33(2):161-5

Department of Anesthesiology, First Affiliated Hospital of Jinan University, Guangzhou, China.

Objective: To determine the optimal dose of colloid preload, which is both safe and effective, for preventing hypotension in parturients undergoing cesarean section under spinal anesthesia.

Methods: Forty-five healthy, termed parturients scheduled for cesarean delivery under spinal anesthesia were randomly assigned to 3 colloid preload groups to receive gelofusine infusion at the rates of 5, 10, or 15 ml·kg(-1)·h(-1) (groups I, II, and III, respectively). Colloid preload was administered 10 min before spinal anesthesia and maintained until the delivery. Blood pressure (BP) and heart rate (HR) of the parturients were monitored during the operation, and Apgar scores at 1 and 5 min after birth were recorded. S100β protein concentration and blood gas values of the umbilical artery were also measured. The vascular adaptation in the placental villous capillary was evaluated stereologically.

Results: At each time point of measurement, BP and HR showed no significant differences among the 3 groups during the operation (P>0.05), but within the same group, BP and HR underwent significant variations during the operation; groups II and III maintained more stable hemodynamics compared to group I. Apgar scores and blood gas analysis, pH value, and S100β protein in the umbilical artery showed no significant differences among the 3 groups (P>0.05). The 3 groups exhibited no significant differences in the length and volume density of the placental villous capillaries (P>0.05).

Conclusion: Colloid preload with gelofusine administered at the rate of 10 ml·kg(-1)·h(-1) can reduce the incidence and severity of hypotension in cesarean section under spinal anesthesia with the least adverse maternal and fetal effects.
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February 2013

Neurogenesis response of middle-aged hippocampus to acute seizure activity.

PLoS One 2012 17;7(8):e43286. Epub 2012 Aug 17.

Research Service, Veterans Affairs Medical Centers of Durham, North Carolina, and Temple, Texas, United States of America.

Acute Seizure (AS) activity in young adult age conspicuously modifies hippocampal neurogenesis. This is epitomized by both increased addition of new neurons to the granule cell layer (GCL) by neural stem/progenitor cells (NSCs) in the dentate subgranular zone (SGZ), and greatly enhanced numbers of newly born neurons located abnormally in the dentate hilus (DH). Interestingly, AS activity in old age does not induce such changes in hippocampal neurogenesis. However, the effect of AS activity on neurogenesis in the middle-aged hippocampus is yet to be elucidated. We examined hippocampal neurogenesis in middle-aged F344 rats after a continuous AS activity for >4 hrs, induced through graded intraperitoneal injections of the kainic acid. We labeled newly born cells via daily intraperitoneal injections of the 5'-bromodeoxyuridine (BrdU) for 12 days, commencing from the day of induction of AS activity. AS activity enhanced the addition of newly born BrdU+ cells by 5.6 fold and newly born neurons (expressing both BrdU and doublecortin [DCX]) by 2.2 fold to the SGZ-GCL. Measurement of the total number of DCX+ newly born neurons also revealed a similar trend. Furthermore, AS activity increased DCX+ newly born neurons located ectopically in the DH (2.7 fold increase and 17% of total newly born neurons). This rate of ectopic migration is however considerably less than what was observed earlier for the young adult hippocampus after similar AS activity. Thus, the plasticity of hippocampal neurogenesis to AS activity in middle age is closer to its response observed in the young adult age. However, the extent of abnormal migration of newly born neurons into the DH is less than that of the young adult hippocampus after similar AS activity. These results also point out a highly divergent response of neurogenesis to AS activity between middle age and old age.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0043286PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3422269PMC
May 2013

Differential susceptibility of interneurons expressing neuropeptide Y or parvalbumin in the aged hippocampus to acute seizure activity.

PLoS One 2011 6;6(9):e24493. Epub 2011 Sep 6.

Medical Research and Surgery Services, Veterans Affairs Medical Center, Durham, North Carolina, United States of America.

Acute seizure (AS) activity in old age has an increased predisposition for evolving into temporal lobe epilepsy (TLE). Furthermore, spontaneous seizures and cognitive dysfunction after AS activity are often intense in the aged population than in young adults. This could be due to an increased vulnerability of inhibitory interneurons in the aged hippocampus to AS activity. We investigated this issue by comparing the survival of hippocampal GABA-ergic interneurons that contain the neuropeptide Y (NPY) or the calcium binding protein parvalbumin (PV) between young adult (5-months old) and aged (22-months old) F344 rats at 12 days after three-hours of AS activity. Graded intraperitoneal injections of the kainic acid (KA) induced AS activity and a diazepam injection at 3 hours after the onset terminated AS-activity. Measurement of interneuron numbers in different hippocampal subfields revealed that NPY+ interneurons were relatively resistant to AS activity in the aged hippocampus in comparison to the young adult hippocampus. Whereas, PV+ interneurons were highly susceptible to AS activity in both age groups. However, as aging alone substantially depleted these populations, the aged hippocampus after three-hours of AS activity exhibited 48% reductions in NPY+ interneurons and 70% reductions in PV+ interneurons, in comparison to the young hippocampus after similar AS activity. Thus, AS activity-induced TLE in old age is associated with far fewer hippocampal NPY+ and PV+ interneuron numbers than AS-induced TLE in the young adult age. This discrepancy likely underlies the severe spontaneous seizures and cognitive dysfunction observed in the aged people after AS activity.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0024493PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3167860PMC
February 2012

[Inhalation of aerosolized perfluorocarbon combined with tetramethylpyrazine ameliorates hemodynamics and pulmonary histopathology in a porcine model of acute lung injury].

Nan Fang Yi Ke Da Xue Xue Bao 2011 Aug;31(8):1382-6

Department of Anesthesia, First Affiliated Hospital of Jinan University, Guangzhou, China.

Objective: To observe the effect of inhalation of aerosolized perfluorocarbon combined with tetramethylpyrazine on the hemodynamics and histopathology in a porcine model of acute lung injury.

Methods: Normal adult pigs were subjected to saline lavage of the bilateral lungs to induce acute lung injury and randomized subsequently into 3 groups for treatment with inhalation of perfluorocarbon, combined inhalation of perfluorocarbon and tetramethylpyrazine, or inhalation of tetramethylpyrazine. The changes of mean arterial pressure (MAP), PetCO(2), mPAP, CVP and PAWP were recorded at different time points following the lung injury, and the lung tissues were sampled for histological observations.

Results: The MAP, mPAP, CVP and PAWP all increased significantly in the 3 groups after acute lung injury. Interventions with combined tetramethylpyrazine and perfluorocarbon inhalation significantly improved these indices as compared with inhalation of tetramethylpyrazine or perfluorocarbon alone (P<0.05). The pulmonary pathology was the mildest in the combined inhalation group, and the most severe in tetramethylpyrazine group.

Conclusion: Combined inhalation of perfluorocarbon and tetramethylpyrazine can effectively improve the oxygenation, reduce pulmonary arterial pressure?and ameliorate lung pathology in pigs with acute lung injury.
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August 2011

[Stereological study of the placenta in parturients with different prophylactic measures for hypotension during spinal anesthesia for cesarean section].

Nan Fang Yi Ke Da Xue Xue Bao 2011 Jun;31(7):1240-4

Department of Anesthesiology, First Affiliated Hospital of Jinan University, Guangzhou 510630, China.

Objective: To explore the optimal approach to the prevention of hypotension during cesarean section for the benefits of both the parturients and the newborns.

Methods: Forty singleton full-term pregnant women undergoing elective cesarean delivery were randomly allocated into two equal groups. For prevention of hypotension during spinal anesthesia, ephedrine or pre-anesthetic volume with Voluven was administered. The changes of blood pressure, heart rate, and Apgar scores of the newborns were monitored and recorded, and the umbilical arterial blood gas variables were compared between the two groups. The placental samples were collected and immunohistochemistry for CD34 was performed for stereological study of the placental villous capillaries.

Results: The umbilical arterial PaCO(2), PaO(2) and Apgar scores showed no significant differences between the two groups (P<0.05). The heart rate, incidence of hypotension and the lactic acid value were significantly higher, and the umbilical arterial pH significantly lower in ephedrine group than in the Voluven group (P>0.05). While the length density of the villous capillaries was comparable between the two groups (P>0.05), the volume density of the villous capillaries was significantly decreased in ephedrine group (P<0.05).

Conclusion: Pre-anesthetic volume expansion with Voluven can maintain stable hemodynamics during spinal anesthesia and also efficiently improve the tissue perfusion, microcirculation and uteroplacental blood flow, thus increasing the oxygen supply to the fetus.
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June 2011

Deafferentation enhances neurogenesis in the young and middle aged hippocampus but not in the aged hippocampus.

Hippocampus 2011 Jun 23;21(6):631-46. Epub 2010 Mar 23.

Medical Research and Surgery Services, Veterans Affairs Medical Center, Durham, North Carolina, USA.

Increased neurogenesis in the dentate gyrus (DG) after brain insults such as excitotoxic lesions, seizures, or stroke is a well known phenomenon in the young hippocampus. This plasticity reflects an innate compensatory response of neural stem cells (NSCs) in the young hippocampus to preserve function or minimize damage after injury. However, injuries to the middle-aged and aged hippocampi elicit either no or dampened neurogenesis response, which could be due to an altered plasticity of NSCs and/or the hippocampus with age. We examined whether the plasticity of NSCs to increase neurogenesis in response to a milder injury such as partial deafferentation is preserved during aging. We quantified DG neurogenesis in the hippocampus of young, middle-aged, and aged F344 rats after partial deafferentation. A partial deafferentation of the left hippocampus without any apparent cell loss was induced via administration of Kainic acid (0.5 μg in 1.0 μl) into the right lateral ventricle of the brain. In this model, degeneration of CA3 pyramidal neurons and dentate hilar neurons in the right hippocampus results in loss of commissural axons which leads to partial deafferentation of the dendrites of dentate granule cells and CA1-CA3 pyramidal neurons in the left hippocampus. Quantification of newly born cells that are added to the dentate granule cell layer at postdeafferentation days 4-15 using 5'-bromodeoxyuridine (BrdU) labeling revealed greatly increased addition of newly born cells (∼three fold increase) in the deafferented young and middle-aged hippocampi but not in the deafferented aged hippocampus. Measurement of newly born neurons using doublecortin (DCX) immunostaining also revealed similar findings. Analyses using BrdU-DCX dual immunofluorescence demonstrated no changes in neuronal fate-choice decision of newly born cells after deafferentation, in comparison to the age-matched naive hippocampus in all age groups. Thus, the plasticity of hippocampal NSCs to increase DG neurogenesis in response to a milder injury such as partial hippocampal deafferentation is preserved until middle age but lost at old age.
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http://dx.doi.org/10.1002/hipo.20776DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2927723PMC
June 2011