The relationship between risk factors and problem behaviors in adolescence : an approach to identify a latent general risk and a latent general problem behavior factors

The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file.Title from title screen of research.pdf file (viewed on November 27, 2007)Vita.Thesis (Ph. D.) University of Missouri-Columbia 2007.This investigation addressed adolescents' problem behaviors such as school failure, violence, and substance use along with casual sex by identifying a general risk factor and a general problem behavior factor. In this study the data were derived from a nationally representative dataset, commonly called ADD Health dataset. The participants were 6504 adolescents in grades 7 through 12. Testing three research questions and one research hypothesis, the existences of the general risk factor and the general problem behavior factor were supported. In addition, the hypothesized model that describes the influence of the general risk factor on the general problem behavior factor was supported, indicating a strong close relationship between these two latent factors. Lastly, the hypothesized model was tested with multiple group analyses for gender, grade-level and ethnic/racial groups. The interlinked nature of the risk statuses, shared and unique variances of individual problem behaviors, and the implications of the study to prevention and intervention programs are discussed.Includes bibliographical reference

Perfectionism, Pessimism, Optimism, and Coping Styles Among College Students [abstract]

Abstract only availableFaculty Mentor: Dr. Michael Mobley, Education, School, & Counseling PsychologyPerfectionism is a universal theme among many college students. For some students dimensions of perfectionism can have a positive or a negative impact on their lives. This study examined dimensions of perfectionism and their relationship to pessimism, optimism, and coping styles among students. 339 students in a Greek fraternity and sorority completed a survey using the following measures: The Almost Perfect Scale-Revised (APS-R), Multidimensional Perfectionism Scale, Coping Style Inventory, and Extended Life Orientation Test. Correlation analysis was conducted to determine the strength of relationships between dimensions of perfectionism, coping styles, and outlook on life (e.g. optimism and pessimism). A significant gender difference was found on high standards subscale of the APS-R. The results demonstrated that positive and negative dimensions of perfectionism do exist. Furthermore results showed that a pessimistic outlook on life significantly correlated with suppressive and reactive styles of coping, while optimism significantly correlated with reflective coping style. Implications for interventions to address both positive and negative dimensions of perfectionism among college students are discussed

Genome-wide association studies using single-nucleotide polymorphisms versus haplotypes: an empirical comparison with data from the North American Rheumatoid Arthritis Consortium

The high genomic density of the single-nucleotide polymorphism (SNP) sets that are typically surveyed in genome-wide association studies (GWAS) now allows the application of haplotype-based methods. Although the choice of haplotype-based vs. individual-SNP approaches is expected to affect the results of association studies, few empirical comparisons of method performance have been reported on the genome-wide scale in the same set of individuals. To measure the relative ability of the two strategies to detect associations, we used a large dataset from the North American Rheumatoid Arthritis Consortium to: 1) partition the genome into haplotype blocks, 2) associate haplotypes with disease, and 3) compare the results with individual-SNP association mapping. Although some associations were shared across methods, each approach uniquely identified several strong candidate regions. Our results suggest that the application of both haplotype-based and individual-SNP testing to GWAS should be adopted as a routine procedure

Elucidating the Interactive Roles of Glia in Alzheimer's Disease Using Established and Newly Developed Experimental Models

Alzheimer's disease (AD) is an irreversible neurodegenerative illness and the exact etiology of the disease remains unknown. It is characterized by long preclinical and prodromal phases with pathological features including an accumulation of amyloid-beta (Aβ) peptides into extracellular Aβ plaques in the brain parenchyma and the formation of intracellular neurofibrillary tangles (NFTs) within neurons as a result of abnormal phosphorylation of microtubule-associated tau proteins. In addition, prominent activation of innate immune cells is also observed and/or followed by marked neuroinflammation. While such neuroinflammatory responses may function in a neuroprotective manner by clearing neurotoxic factors, they can also be neurotoxic by contributing to neurodegeneration via elevated levels of proinflammatory mediators and oxidative stress, and altered levels of neurotransmitters, that underlie pathological symptoms including synaptic and cognitive impairment, neuronal death, reduced memory, and neocortex and hippocampus malfunctions. Glial cells, particularly activated microglia and reactive astrocytes, appear to play critical and interactive roles in such dichotomous responses. Accumulating evidences clearly point to their critical involvement in the prevention, initiation, and progression, of neurodegenerative diseases, including AD. Here, we review recent findings on the roles of astrocyte-microglial interactions in neurodegeneration in the context of AD and discuss newly developed in vitro and in vivo experimental models that will enable more detailed analysis of glial interplay. An increased understanding of the roles of glia and the development of new exploratory tools are likely to be crucial for the development of new interventions for early stage AD prevention and cures

Inhibition of monoamine oxidase B prevents reactive astrogliosis and scar formation in stab wound injury model

© 2021 Wiley Periodicals LLC.Reactive astrocytes manifest molecular, structural, and functional alterations under various pathological conditions. We have previously demonstrated that the reactive astrocytes of the stab wound injury model (STAB) display aberrant cellular gamma-aminobutyric acid (GABA) content and tonic GABA release, whereas the active astrocytes under enriched environment (EE) express high levels of proBDNF. However, the role of monoamine oxidase B (MAO-B) in reactive astrogliosis and hypertrophy still remains unknown. Here, we investigate the role of MAO-B, a GABA-producing enzyme, in reactive astrogliosis in STAB. We observed that the genetic removal of MAO-B significantly reduced the hypertrophy, scar formation, and GABA production of reactive astrocytes, whereas the MAO-B overexpression under glial fibrillary acidic protein (GFAP) promoter enhanced the levels of GFAP and GABA. Furthermore, we found that one of the by-products of the MAO-B action, H2O2, but not GABA, was sufficient and necessary for the hypertrophy of reactive astrocytes. Notably, we identified two potent pharmacological tools to attenuate scar-forming astrogliosis—the recently developed reversible MAO-B inhibitor, KDS2010, and an H2O2 scavenger, crisdesalazine (AAD-2004). Our results implicate that inhibiting MAO-B activity has dual beneficial effects in preventing astrogliosis and scar-formation under brain injury, and that the MAO-B/H2O2 pathway can be a useful therapeutic target with a high clinical potential.11Nsciescopu

Astrocyte Specificity and Coverage of hGFAP-CreERT2 [Tg(GFAP-Cre/ERT2)13Kdmc] Mouse Line in Various Brain Regions

Astrocyte is the most abundant cell type in the central nervous system and its importance has been increasingly recognized in the brain pathophysiology. To study in vivo function of astrocyte, astrocyte-specific gene-targeting is regarded as a powerful approach. Especially, hGFAP-CreERT2, which expresses tamoxifen-inducible Cre recombinase under the human GFAP promoter, has been developed and characterized from several research groups. However, one of these mouse lines, [Tg(GFAP-Cre/ERT2)13Kdmc] from Ken McCarthy group has not been quantitatively analyzed, despite its frequent use. Here, we performed comprehensive characterization of this mouse line with quantitative analysis. By crossing this mouse line with Ail4 (RCL-tdTomato), a very sensitive Cre reporter mouse line, we visualized the Cre-expressing cells in various brain regions. For quantitative analysis, we immunostained S100 beta as an astrocytic marker and NeuN, tyrosine hydroxylase or calbindin as a neuronal marker in different brain regions. We calculated 'astrocyte specificity as the proportion of co-labelled S100 beta and tdTomato positive cells in the total number of tdTomato positive cells and the `astrocyte coverage' as the proportion of co-labelled S100 beta and tdTomato positive cells in the total number of S100 beta positive cells. Interestingly, we found varying degree of astrocyte specificity and coverage in each brain region. In cortex, hypothalamus, substantia nigra pars compacta and cerebellar Purkinje layer, we observed high astrocyte specificity (over 89%) and relatively high astrocyte coverage (over 70%). In striatum, hippocampal CAI layer, dentate gyrus and cerebellar granule layer, we observed high astrocyte specificity (over 80%), but relative low astrocyte coverage (50-60%). However, thalamus and amygdala showed low astrocyte specificity (about 65%) and significant neuron specificity (over 30%). This hGFAP-CreEKT2 mouse line can be useful for genetic modulations of target gene either in gain-of-function or loss-of-function studies in the brain regions with high astrocyte specificity and coverage. However, the use of this mouse line should be restricted to gain-of-function studies in the brain regions with high astrocyte specificity but low coverage. In conclusion, hGFAP-CreERT2 mouse line could be a powerful tool for gene-targeting of astrocytes in cortex, striatum, hippocampus, hypothalamus, substantia nigra pars compacta and cerebellum, but not in thalamus and amygdala. © Experimental Neurobiology 2018.11Nsciekc

Longitudinal intravital imaging of cerebral microinfarction reveals a dynamic astrocyte reaction leading to glial scar formation

© 2022 Wiley Periodicals LLC.Cerebral microinfarct increases the risk of dementia. But how microscopic cerebrovascular disruption affects the brain tissue in cellular-level are mostly unknown. Herein, with a longitudinal intravital imaging, we serially visualized in vivo dynamic cellular-level changes in astrocyte, pericyte and neuron as well as microvascular integrity after the induction of cerebral microinfarction for 1 month in mice. At day 2–3, it revealed a localized edema with acute astrocyte loss, neuronal death, impaired pericyte-vessel coverage and extravascular leakage of 3 kDa dextran (but not 2 MDa dextran) indicating microinfarction-related blood–brain barrier (BBB) dysfunction for small molecules. At day 5, the local edema disappeared with the partial restoration of microcirculation and recovery of pericyte-vessel coverage and BBB integrity. But brain tissue continued to shrink with persisted loss of astrocyte and neuron in microinfarct until 30 days, resulting in a collagen-rich fibrous scar surrounding the microinfarct. Notably, reactive astrocytes expressing glial fibrillary acidic protein (GFAP) appeared at the peri-infarct area early at day 2 and thereafter accumulated in the peri-infarct until 30 days, inducing glial scar formation in cerebral cortex. Our longitudinal intravital imaging of serial microscopic neurovascular pathophysiology in cerebral microinfarction newly revealed that astrocytes are critically susceptible to the acute microinfarction and their reactive response leads to the fibrous glial scar formation.11Nsciescopu

Astrocytes render memory flexible by releasing D-serine and regulating NMDAR tone in the hippocampus

BACKGROUND: NMDA receptor (NMDAR) hypofunction has been implicated in several psychiatric disorders with impairment of cognitive flexibility. However, the molecular mechanism of how NMDAR hypofunction with decreased NMDAR tone causes the impairment of cognitive flexibility has been minimally understood. Furthermore, it has been unclear whether hippocampal astrocytes regulate NMDAR tone and cognitive flexibility. METHODS: We employed cell type–specific genetic manipulations, ex vivo electrophysiological recordings, sniffer patch recordings, cutting-edge biosensor for norepinephrine, and behavioral assays to investigate whether astrocytes can regulate NMDAR tone by releasing D-serine and glutamate. Subsequently, we further investigated the role of NMDAR tone in heterosynaptic long-term depression, metaplasticity, and cognitive flexibility. RESULTS: We found that hippocampal astrocytes regulate NMDAR tone via BEST1-mediated corelease of D-serine and glutamate. Best1 knockout mice exhibited reduced NMDAR tone and impairments of homosynaptic and a1 adrenergic receptor–dependent heterosynaptic long-term depression, which leads to defects in metaplasticity and cognitive flexibility. These impairments in Best1 knockout mice can be rescued by hippocampal astrocyte-specific BEST1 expression or enhanced NMDAR tone through D-serine supplement. D-serine injection in Best1 knockout mice during initial learning rescues subsequent reversal learning. CONCLUSIONS: These findings indicate that NMDAR tone during initial learning is important for subsequent learning, and hippocampal NMDAR tone regulated by astrocytic BEST1 is critical for heterosynaptic long-term depression, metaplasticity, and cognitive flexibility.11Nsciescopu