Evelyn F Mcknight Brain Institute

United States

Evelyn F Mcknight Brain Institute

United States
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Maurer A.P.,Evelyn F Mcknight Brain Institute | Maurer A.P.,Arizona Research Laboratories | Burke S.N.,Evelyn F Mcknight Brain Institute | Burke S.N.,Arizona Research Laboratories | And 6 more authors.
Hippocampus | Year: 2012

Hebb (1949) described a "phase sequence" to be the sequential activation of sets of cell assemblies. Within the hippocampus, cell assemblies have been described as groups of coactive neurons whose place fields overlap. Membership of assemblies in a phase sequence changes systematically as a rat travels through an environment, serving to accelerate the temporal order that place fields are encountered during a single theta cycle. This sweeping forward of network activity ("look ahead"), results in locations in front of the animal being transiently represented. In this experiment, a population vector-based reconstruction method was used to capture the look ahead and reveals that the composition of the phase sequence changes with velocity, such that more cell assemblies are active within a theta cycle at higher running speeds. These results are consistent with hypotheses suggesting that hippocampal networks generate short time scale predictions of future events to optimize behavior. © 2011 Wiley Periodicals, Inc.

Verkhratsky A.,University of Manchester | Verkhratsky A.,Ikerbasque | Verkhratsky A.,University of Rijeka | Parpura V.,University of the Basque Country | Parpura V.,Evelyn F Mcknight Brain Institute
Neurobiology of Disease | Year: 2016

Astroglial cells represent a main element in the maintenance of homeostasis and providing defense to the brain. Consequently, their dysfunction underlies many, if not all, neurological, neurodevelopmental and neuropsychiatric disorders. General astrogliopathy is evident in diametrically opposing morpho-functional changes in astrocytes, i.e. their hypertrophy along with reactivity or atrophy with asthenia. Neurological disorders with astroglial participation can be genetic, of which Alexander disease is a primary sporadic astrogliopathy, environmentally caused, such as heavy metal encephalopathies, or neurodevelopmental in origin. Astroglia contribute to neurodegenerative processes seen in amyotrophic lateral sclerosis, Alzheimer's and Huntington's diseases. Furthermore, astroglia also play a role in major neuropsychiatric disorders, ranging from schizophrenia to depression, as well as in addictive disorders. © 2015 Elsevier Inc.

Chen K.,Banner Alzheimers Institute | Chen K.,Arizona State University | Ayutyanont N.,Banner Alzheimers Institute | Langbaum J.B.S.,Banner Alzheimers Institute | And 12 more authors.
NeuroImage | Year: 2012

We previously introduced a voxel-based, multi-modal application of the partial least square algorithm (MMPLS) to characterize the linkage between patterns in a person's complementary complex datasets without the need to correct for multiple regional comparisons. Here we used it to demonstrate a strong correlation between MMPLS scores to characterize the linkage between the covarying patterns of fluorodeoxyglucose positron emission tomography (FDG PET) measurements of regional glucose metabolism and magnetic resonance imaging (MRI) measurements of regional gray matter associated with apolipoprotein E (APOE) ε4 gene dose (i.e., three levels of genetic risk for late-onset Alzheimer's disease (AD)) in cognitively normal, late-middle-aged persons. Coregistered and spatially normalized FDG PET and MRI images from 70% of the subjects (27 ε4 homozygotes, 36 ε4 heterozygotes and 67 ε4 non-carriers) were used in a hypothesis-generating MMPLS analysis to characterize the covarying pattern of regional gray matter volume and cerebral glucose metabolism most strongly correlated with APOE-ε4 gene dose. Coregistered and spatially normalized FDG PET and MRI images from the remaining 30% of the subjects were used in a hypothesis-testing MMPLS analysis to generate FDG PET-MRI gray matter MMPLS scores blind to their APOE genotype and characterize their relationship to APOE-ε4 gene dose. The hypothesis-generating analysis revealed covarying regional gray matter volume and cerebral glucose metabolism patterns that resembled those in traditional univariate analyses of AD and APOE-ε4 gene dose and PET-MRI scores that were strongly correlated with APOE-ε4 gene dose (p<1×10 -16). The hypothesis-testing analysis results showed strong correlations between FDG PET-MRI gray matter scores and APOE-ε4 gene dose (p=8.7×10 -4). Our findings support the possibility of using the MMPLS to analyze complementary datasets from the same person in the presymptomatic detection and tracking of AD. © 2012 Elsevier Inc..

Moon Y.P.,Columbia University | Paik M.C.,Columbia University | Sacco R.L.,Evelyn F Mcknight Brain Institute | Sacco R.L.,University of Miami | Elkind M.S.V.,Mount Sinai School of Medicine
Stroke | Year: 2011

Background and Purpose-The Framingham coronary heart disease (CHD) risk score estimates 10-year risk of myocardial infarction (MI) and CHD death. Because preventive approaches to CHD and stroke are similar, a composite outcome may be more appropriate. We compared 10-year risk of (1) MI or CHD death; and (2) stroke, MI, or CHD death among individuals free of vascular disease. Methods-The Northern Manhattan Study contains a prospective, population-based study of stroke-and CHD-free individuals 40 years of age followed for a median of 10 years for vascular events. Framingham coronary heart disease risk score was calculated for each individual and for each category of predicted risk, Kaplan-Meier observed 10-year cumulative probabilities were calculated for (1) MI or CHD death; and (2) stroke, MI, or CHD death. The cumulative probability of (1) was subtracted from (2), and 95% CIs for the difference were obtained with 1000 bootstrap samples. Using stratified analyses by race-ethnicity, we compared risk differences among race-ethnic groups. RESULTS-: Among 2613 participants (53% Hispanic, 25% non-Hispanic black, and 20% non-Hispanic white), observed 10-year risk of MI or CHD death was 14.20%. With stroke in the outcome, observed risk was 21.98% (absolute risk difference, 7.78%; 95% CI, 5.86% to 9.75%). The absolute risk difference among blacks was significantly larger than among whites (P=0.01). Conclusions-In this multiethnic urban population, adding stroke to the risk stratification outcome cluster resulted in a 55% relative increase in estimated risk and crossing of the absolute risk threshold (>20% over 10 years) considered for preventive treatments such as statins. © 2011 American Heart Association, Inc.

Shan D.,University of Alabama at Birmingham | Mount D.,University of Alabama at Birmingham | Moore S.,University of Alabama | Haroutunian V.,Mount Sinai School of Medicine | And 3 more authors.
Schizophrenia Research | Year: 2014

Excitatory amino acid transporter 2 (EAAT2) belongs to a family of Na+ dependent glutamate transporters that maintain a low synaptic concentration of glutamate by removing glutamate from the synaptic cleft into astroglia and neurons. EAAT2 activity depends on Na+ and K+ gradients generated by Na+/K+ ATPase and ATP. Hexokinase 1 (HK1), an initial enzyme of glycolysis, binds to mitochondrial outer membrane where it couples cytosolic glycolysis to mitochondrial oxidative phosphorylation, producing ATP utilized by the EAAT2/Na+/K+ ATPase protein complex to facilitate glutamate reuptake. In this study, we hypothesized that the protein complex formed by EAAT2, Na+/K+ ATPase and mitochondrial proteins in human postmortem prefrontal cortex may be disrupted, leading to abnormal glutamate transmission in schizophrenia. We first determined that EAAT2, Na+/K+ ATPase, HK1 and aconitase were found in both EAAT2 and Na+/K+ ATPase interactomes by immunoisolation and mass spectrometry in human postmortem prefrontal cortex. Next, we measured levels of glutamate transport complex proteins in subcellular fractions in the dorsolateral prefrontal cortex and found increases in the EAAT2B isoform of EAAT2 in a fraction containing extrasynaptic membranes and increased aconitase 1 in a mitochondrial fraction. Finally, an increased ratio of HK1 protein in the extrasynaptic membrane/mitochondrial fraction was found in subjects with schizophrenia, suggesting that HK1 protein is abnormally partitioned in this illness. Our findings indicate that the integrity of the glutamate transport protein complex may be disrupted, leading to decreased perisynaptic buffering and reuptake of glutamate, as well as impaired energy metabolism in schizophrenia. © 2014 Elsevier B.V.

Kim H.-S.,University of Alabama at Birmingham | Montana V.,Evelyn F Mcknight Brain Institute | Jang H.-J.,University of Alabama at Birmingham | Parpura V.,Evelyn F Mcknight Brain Institute | And 3 more authors.
Journal of Biological Chemistry | Year: 2013

Background: Green tea polyphenol (EGCG) has beneficial effects on cardiovascular dysfunction. Results: EGCG stimulates autophagy through a CaMKKβ-mediated mechanism, which contributes to degradation of lipid droplets. Conclusion: Regulation of autophagic flux by EGCG plays a role in intracellular lipid accumulation. Significance: Findings show a novel mechanism for beneficial effects of EGCG in cardiovascular complications. © 2013 by The American Society for Biochemistry and Molecular Biology, Inc.

Xue B.,University of Iowa | Zhang Z.,Nanyang Institute of Technology | Beltz T.G.,University of Iowa | Guo F.,University of Iowa | And 3 more authors.
American Journal of Physiology - Regulatory Integrative and Comparative Physiology | Year: 2015

The present study tested the hypotheses that 1) ERα in the brain plays a key role in the estrogen-protective effects against ANG II-induced hypertension, and 2) that the subfornical organ (SFO) is a key site where ERα mediates these protective actions. In this study, a “floxed” ERα transgenic mouse line (ERαflox) was used to create models in which ERα was knocked down in the brain or just in the SFO. Female mice with ERα ablated in the nervous system (Nestin-ERα– mice) showed greater increases in blood pressure (BP) in response to ANG II. Furthermore, females with ERα knockdown specifically in the SFO [SFO adenovirus-Cre (Ad-Cre) injected ERαflox mice] also showed an enhanced pressor response to ANG II. Immunohistochemical (IHC), RT-PCR, and Western blot analyses revealed a marked reduction in the expression of ERα in nervous tissues and, in particular, in the SFO. These changes were not present in peripheral tissues in Nestin- ERα– mice or Ad-Cre-injected ERαflox mice. mRNA expression of components of the renin-angiotensin system in the lamina terminalis were upregulated in Nestin-ERα– mice. Moreover, ganglionic blockade on day 7 after ANG II infusions resulted in a greater reduction of BP in Nestin-ERα– mice or SFO Ad-Cre-injected mice, suggesting that knockdown of ERα in the nervous system or the SFO alone augments central ANG II-induced increase in sympathetic tone. The results indicate that interfering with the action of estrogen on SFO ERα is sufficient to abolish the protective effects of estrogen against ANG II-induced hypertension. © 2015 the American Physiological Society.

Gardener H.,Evelyn F Mcknight Brain Institute | Rundek T.,Evelyn F Mcknight Brain Institute | Wright C.B.,Evelyn F Mcknight Brain Institute | Wright C.B.,University of Miami | And 3 more authors.
Stroke | Year: 2012

Background and Purpose-The American Heart Association recommends limiting sodium intake to ≤1500 mg/day for ideal cardiovascular health. Although sodium intake has been linked to vascular disease by direct relationship with hypertension, few studies have supported an association with stroke risk. Methods-Participants were from the Northern Manhattan Study (mean age 69± 10 years, 64% women, 21% white, 53% Hispanic, 24% black), a population-based cohort study of stroke incidence. Sodium intake was assessed with a food frequency questionnaire at baseline and evaluated continuously and categorically: ≤1500 mg/day (12%), 1501 to 2300 mg/day (24%), 2301 to 3999 mg/day (43%), and 4000 mg/day (21%). Over a mean follow-up of 10 years, we examined the association between sodium consumption and 235 strokes using Cox models adjusting for sociodemographics, diet, behavioral/lifestyle, and vascular risk factors. RESULTS-: Of 2657 participants with dietary data, the mean sodium intake was 3031±1470 mg/day (median, 2787; interquartile range, 1966-3815 mg/day). Participants who consumed 4000 mg/day sodium had an increased risk of stroke (hazard ratio, 2.59; 95% CI, 1.27-5.28) versus those who consumed ≤1500 mg/day with a 17% increased risk of stroke for each 500-mg/day increase (95% CI, 1.07-1.27). Conclusions-High sodium intake was prevalent and associated with an increased risk of stroke independent of vascular risk factors. The new American Heart Association dietary sodium goals will help reduce stroke risk. © 2012 American Heart Association, Inc.

Insel N.,Evelyn F Mcknight Brain Institute | Barnes C.A.,Evelyn F Mcknight Brain Institute | Barnes C.A.,University of Arizona
Cerebral Cortex | Year: 2015

The medial prefrontal cortex is thought to be important for guiding behavior according to an animal's expectations. Efforts to decode the region have focused not only on the question of what information it computes, but also how distinct circuit components become engaged during behavior. We find that the activity of regular-firing, putative projection neurons contains rich information about behavioral context and firing fields cluster around reward sites, while activity among putative inhibitory and fast-spiking neurons is most associated with movement and accompanying sensory stimulation. These dissociations were observed even between adjacent neurons with apparently reciprocal, inhibitory-excitatory connections. A smaller population of projection neurons with burst-firing patterns did not show clustered firing fields around rewards; these neurons, although heterogeneous, were generally less selective for behavioral context than regular-firing cells. The data suggest a network that tracks an animal's behavioral situation while, at the same time, regulating excitation levels to emphasize high valued positions. In this scenario, the function of fast-spiking inhibitory neurons is to constrain network output relative to incoming sensory flow. This scheme could serve as a bridge between abstract sensorimotor information and singledimensional codes for value, providing a neural framework to generate expectations from behavioral state. © The Author 2014. Published by Oxford University Press. All rights reserved.

Economos A.,Evelyn F Mcknight Brain Institute | Economos A.,University of Miami | Wright C.B.,Evelyn F Mcknight Brain Institute | Wright C.B.,University of Miami | And 9 more authors.
Neuroepidemiology | Year: 2013

Background: Interleukin 6 (IL-6) is an inflammatory cytokine that has been associated with vascular disease and cognitive impairment, but few studies have examined these relationships in population-based studies that include Hispanic and Black people who often have a greater prevalence of vascular risk factors and are at an elevated risk of dementia than Whites. We examined relative elevations of plasma IL-6 concentrations in relation to cognitive decline in a stroke-free racially/ethnically diverse community-based sample from Northern Manhattan. Methods: We used mixed effects models to measure the effect of IL-6 on change in performance on the modified Telephone Interview for Cognitive Status (TICS-m) measured annually in our cohort, adjusting for sociodemographic and vascular risk factors. Results: There were 1,224 participants with IL-6 levels (median 1.5 pg/ml, interquartile range 0.83-2.57 pg/ml) and TICS-m data available (mean = 31.6 points, SD 6.5). The mean age was 71 (SD 9.3; 64% women, 59% Hispanic, 19% Black, 19% White) with 3,406 person-years and a median 3.0 years of follow-up (interquartile range 1.1-4.0 years). Participants with IL-6 levels above the median showed greater cognitive decline on the TICS-m compared to those with levels below the median, adjusting for sociodemographic and vascular factors (β = -0.17 points/year, p = 0.02). Decline on the TICS-m among participants with IL-6 above the median differed by age (p for interaction <0.001). There was no interaction by race/ethnicity, vascular risk factors, C-reactive protein, apolipoprotein ε4 allele status, or the metabolic syndrome among nondiabetics. Conclusions: IL-6 associated with cognitive decline among older participants in this racially/ethnically diverse sample independent of other vascular risk factors and C-reactive protein. Copyright © 2013 S. Karger AG, Basel.

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