Browsing by Subject "Brain"

Now showing 1 - 10 of 132
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    5. Collaborative Study on the Genetics of Alcoholism: Functional genomics
    (Wiley, 2023) Gameiro-Ros, Isabel; Popova, Dina; Prytkova, Iya; Pang, Zhiping P.; Liu, Yunlong; Dick, Danielle; Bucholz, Kathleen K.; Agrawal, Arpana; Porjesz, Bernice; Goate, Alison M.; Xuei, Xiaoling; Kamarajan, Chella; COGA Collaborators; Tischfield, Jay A.; Edenberg, Howard J.; Slesinger, Paul A.; Hart, Ronald P.; Medical and Molecular Genetics, School of Medicine
    Alcohol Use Disorder is a complex genetic disorder, involving genetic, neural, and environmental factors, and their interactions. The Collaborative Study on the Genetics of Alcoholism (COGA) has been investigating these factors and identified putative alcohol use disorder risk genes through genome-wide association studies. In this review, we describe advances made by COGA in elucidating the functional changes induced by alcohol use disorder risk genes using multimodal approaches with human cell lines and brain tissue. These studies involve investigating gene regulation in lymphoblastoid cells from COGA participants and in post-mortem brain tissues. High throughput reporter assays are being used to identify single nucleotide polymorphisms in which alternate alleles differ in driving gene expression. Specific single nucleotide polymorphisms (both coding or noncoding) have been modeled using induced pluripotent stem cells derived from COGA participants to evaluate the effects of genetic variants on transcriptomics, neuronal excitability, synaptic physiology, and the response to ethanol in human neurons from individuals with and without alcohol use disorder. We provide a perspective on future studies, such as using polygenic risk scores and populations of induced pluripotent stem cell-derived neurons to identify signaling pathways related with responses to alcohol. Starting with genes or loci associated with alcohol use disorder, COGA has demonstrated that integration of multimodal data within COGA participants and functional studies can reveal mechanisms linking genomic variants with alcohol use disorder, and potential targets for future treatments.
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    A Forward Genetic Screen Reveals that Calcium-dependent Protein Kinase 3 Regulates Egress in Toxoplasma
    (Public Library of Science, 2012) Garrison, Erin; Treeck, Moritz; Ehret, Emma; Butz, Heidi; Garbuz, Tamila; Oswald, Benji P.; Settles, Matt; Boothroyd, John; Arrizabalaga, Gustavo; Pharmacology and Toxicology, School of Medicine
    Egress from the host cell is a crucial and highly regulated step in the biology of the obligate intracellular parasite, Toxoplasma gondii. Active egress depends on calcium fluxes and appears to be a crucial step in escaping the attack from the immune system and, potentially, in enabling the parasites to shuttle into appropriate cells for entry into the brain of the host. Previous genetic screens have yielded mutants defective in both ionophore-induced egress and ionophore-induced death. Using whole genome sequencing of one mutant and subsequent analysis of all mutants from these screens, we find that, remarkably, four independent mutants harbor a mis-sense mutation in the same gene, TgCDPK3, encoding a calcium-dependent protein kinase. All four mutations are predicted to alter key regions of TgCDPK3 and this is confirmed by biochemical studies of recombinant forms of each. By complementation we confirm a crucial role for TgCDPK3 in the rapid induction of parasite egress and we establish that TgCDPK3 is critical for formation of latent stages in the brains of mice. Genetic knockout of TgCDPK3 confirms a crucial role for this kinase in parasite egress and a non-essential role for it in the lytic cycle.
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    A gut-derived metabolite alters brain activity and anxiety behaviour in mice
    (Springer Nature, 2022) Needham, Brittany D.; Funabashi, Masanori; Adame, Mark D.; Wang, Zhuo; Boktor, Joseph C.; Haney, Jillian; Wu, Wei-Li; Rabut, Claire; Ladinsky, Mark S.; Hwang, Son-Jong; Guo, Yumei; Zhu, Qiyun; Griffiths, Jessica A.; Knight, Rob; Bjorkman, Pamela J.; Shapiro, Mikhail G.; Geschwind, Daniel H.; Holschneider, Daniel P.; Fischbach, Michael A.; Mazmanian, Sarkis K.; Anatomy, Cell Biology and Physiology, School of Medicine
    Integration of sensory and molecular inputs from the environment shapes animal behaviour. A major site of exposure to environmental molecules is the gastrointestinal tract, in which dietary components are chemically transformed by the microbiota1 and gut-derived metabolites are disseminated to all organs, including the brain2. In mice, the gut microbiota impacts behaviour3, modulates neurotransmitter production in the gut and brain4,5, and influences brain development and myelination patterns6,7. The mechanisms that mediate the gut-brain interactions remain poorly defined, although they broadly involve humoral or neuronal connections. We previously reported that the levels of the microbial metabolite 4-ethylphenyl sulfate (4EPS) were increased in a mouse model of atypical neurodevelopment8. Here we identified biosynthetic genes from the gut microbiome that mediate the conversion of dietary tyrosine to 4-ethylphenol (4EP), and bioengineered gut bacteria to selectively produce 4EPS in mice. 4EPS entered the brain and was associated with changes in region-specific activity and functional connectivity. Gene expression signatures revealed altered oligodendrocyte function in the brain, and 4EPS impaired oligodendrocyte maturation in mice and decreased oligodendrocyte-neuron interactions in ex vivo brain cultures. Mice colonized with 4EP-producing bacteria exhibited reduced myelination of neuronal axons. Altered myelination dynamics in the brain have been associated with behavioural outcomes7,9-14. Accordingly, we observed that mice exposed to 4EPS displayed anxiety-like behaviours, and pharmacological treatments that promote oligodendrocyte differentiation prevented the behavioural effects of 4EPS. These findings reveal that a gut-derived molecule influences complex behaviours in mice through effects on oligodendrocyte function and myelin patterning in the brain.
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    A New Sparse Simplex Model for Brain Anatomical and Genetic Network Analysis
    (Springer Nature, 2013) Huang, Heng; Yan, Jingwen; Nie, Feiping; Huang, Jin; Cai, Weidong; Saykin, Andrew J.; Shen, Li; Radiology and Imaging Sciences, School of Medicine
    The Allen Brain Atlas (ABA) database provides comprehensive 3D atlas of gene expression in the adult mouse brain for studying the spatial expression patterns in the mammalian central nervous system. It is computationally challenging to construct the accurate anatomical and genetic networks using the ABA 4D data. In this paper, we propose a novel sparse simplex model to accurately construct the brain anatomical and genetic networks, which are important to reveal the brain spatial expression patterns. Our new approach addresses the shift-invariant and parameter tuning problems, which are notorious in the existing network analysis methods, such that the proposed model is more suitable for solving practical biomedical problems. We validate our new model using the 4D ABA data, and the network construction results show the superior performance of the proposed sparse simplex model.
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    A role for zinc transporter gene SLC39A12 in the nervous system and beyond
    (Elsevier, 2021) Davis, Danielle N.; Strong, Morgan D.; Chambers, Emily; Hart, Matthew D.; Bettaieb, Ahmed; Clarke, Stephen L.; Smith, Brenda J.; Stoecker, Barbara J.; Lucas, Edralin A.; Lin, Dingbo; Chowanadisai, Winyoo; Obstetrics and Gynecology, School of Medicine
    The SLC39A12 gene encodes the zinc transporter protein ZIP12, which is expressed across many tissues and is highly abundant in the vertebrate nervous system. As a zinc transporter, ZIP12 functions to transport zinc across cellular membranes, including cellular zinc influx across the plasma membrane. Genome-wide association and exome sequencing studies have shown that brain susceptibility-weighted magnetic resonance imaging (MRI) intensity is associated with ZIP12 polymorphisms and rare mutations. ZIP12 is required for neural tube closure and embryonic development in Xenopus tropicalis. Frog embryos depleted of ZIP12 by antisense morpholinos develop an anterior neural tube defect and lack viability. ZIP12 is also necessary for neurite outgrowth and mitochondrial function in mouse neural cells. ZIP12 mRNA is increased in brain regions of schizophrenic patients. Outside of the nervous system, hypoxia induces ZIP12 expression in multiple mammalian species, including humans, which leads to endothelial and smooth muscle thickening in the lung and contributes towards pulmonary hypertension. Other studies have associated ZIP12 with other diseases such as cancer. Given that ZIP12 is highly expressed in the brain and that susceptibility-weighted MRI is associated with brain metal content, ZIP12 may affect neurological diseases and psychiatric illnesses such as Parkinson's disease, Alzheimer's disease, and schizophrenia. Furthermore, the induction of ZIP12 and resultant zinc uptake under pathophysiological conditions may be a critical component of disease pathology, such as in pulmonary hypertension. Drug compounds that bind metals like zinc may be able to treat diseases associated with impaired zinc homeostasis and altered ZIP12 function.
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    ADAM10 Expression and Promoter Haplotype in Alzheimer’s Disease
    (Elsevier, 2012) Bekris, L. M.; Lutz, F.; Li, G.; Galasko, D. R.; Farlow, M. R.; Quinn, J. F.; Kaye, J. A.; Leverenz, J. B.; Tsuang, D. W.; Montine, T. J.; Peskind, E. R.; Yu, C. E.; Neurology, School of Medicine
    Alzheimer's disease is confirmed at autopsy according to the accumulation of brain neuritic plaques and neurofibrillary tangles in the brain. Neuritic plaques contain amyloid-β (Aβ) and lower levels of Aβ correspond to an increase in ADAM10 α-secretase activity. ADAM10 α-secretase activity produces a soluble amyloid precursor protein (APP) alpha (sAPPα) product and negates the pathological production of Aβ. In this investigation, it was hypothesized that genetic variation with the ADAM10 promoter is associated with ADAM10 expression levels as well as cerebrospinal fluid sAPPα levels. Results from this investigation suggest that the ADAM10 rs514049-rs653765 C-A promoter haplotype is associated with: (1) higher CSF sAPPα levels in cognitively normal controls compared with Alzheimer's disease (AD) patients, (2) higher postmortem brain hippocampus, but not cerebellum, ADAM10 protein levels in subjects with low plaque scores compared with those with high plaque scores, and (3) higher promoter activity for promoter-only reporter constructs compared with promoter 3' untranslated region (3'UTR) constructs in the human neuroblastoma SHSY5Y cell line, but not in HepG2 or U118 cell lines. Taken together, these findings suggest that ADAM10 expression is modulated according to a promoter haplotype that is influenced in a brain region- and cell type-specific manner.
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    Alexa, let's train now! - A systematic review and classification approach to digital and home-based physical training interventions aiming to support healthy cognitive aging
    (Elsevier, 2023) Herold, Fabian; Theobald, Paula; Gronwald, Thomas; Kaushal, Navin; Zou, Liye; de Bruin, Eling D.; Bherer, Louis; Müller, Notger G.; Health Sciences, School of Health and Human Sciences
    Background There is mounting evidence that regular physical activity is an important prerequisite for healthy cognitive aging. Consequently, the finding that almost one-third of the adult population does not reach the recommended level of regular physical activity calls for further public health actions. In this context, digital and home-based physical training interventions might be a promising alternative to center-based intervention programs. Thus, this systematic review aimed to summarize the current state of the literature on the effects of digital and home-based physical training interventions on adult cognitive performance. Methods In this pre-registered systematic review (PROSPERO; ID: CRD42022320031), 5 electronic databases (PubMed, Web of Science, PsycInfo, SPORTDiscus, and Cochrane Library) were searched by 2 independent researchers (FH and PT) to identify eligible studies investigating the effects of digital and home-based physical training interventions on cognitive performance in adults. The systematic literature search yielded 8258 records (extra 17 records from other sources), of which 27 controlled trials were considered relevant. Two reviewers (FH and PT) independently extracted data and assessed the risk of bias using a modified version of the Tool for the assEssment of Study qualiTy and reporting in EXercise (TESTEX scale). Results Of the 27 reviewed studies, 15 reported positive effects on cognitive and motor-cognitive outcomes (i.e., performance improvements in measures of executive functions, working memory, and choice stepping reaction test), and a considerable heterogeneity concerning study-related, population-related, and intervention-related characteristics was noticed. A more detailed analysis suggests that, in particular, interventions using online classes and technology-based exercise devices (i.e., step-based exergames) can improve cognitive performance in healthy older adults. Approximately one-half of the reviewed studies were rated as having a high risk of bias with respect to completion adherence (≤85%) and monitoring of the level of regular physical activity in the control group. Conclusion The current state of evidence concerning the effectiveness of digital and home-based physical training interventions is mixed overall, though there is limited evidence that specific types of digital and home-based physical training interventions (e.g., online classes and step-based exergames) can be an effective strategy for improving cognitive performance in older adults. However, due to the limited number of available studies, future high-quality studies are needed to buttress this assumption empirically and to allow for more solid and nuanced conclusions.
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    Alzheimer disease brain atrophy subtypes are associated with cognition and rate of decline
    (American Academy of Neurology, 2017-11-21) Risacher, Shannon L.; Anderson, Wesley H.; Charil, Arnaud; Castelluccio, Peter F.; Shcherbinin, Sergey; Saykin, Andrew J.; Schwarz, Adam J.; Radiology and Imaging Sciences, School of Medicine
    OBJECTIVE: To test the hypothesis that cortical and hippocampal volumes, measured in vivo from volumetric MRI (vMRI) scans, could be used to identify variant subtypes of Alzheimer disease (AD) and to prospectively predict the rate of clinical decline. METHODS: Amyloid-positive participants with AD from the Alzheimer's Disease Neuroimaging Initiative (ADNI) 1 and ADNI2 with baseline MRI scans (n = 229) and 2-year clinical follow-up (n = 100) were included. AD subtypes (hippocampal sparing [HpSpMRI], limbic predominant [LPMRI], typical AD [tADMRI]) were defined according to an algorithm analogous to one recently proposed for tau neuropathology. Relationships between baseline hippocampal volume to cortical volume ratio (HV:CTV) and clinical variables were examined by both continuous regression and categorical models. RESULTS: When participants were divided categorically, the HpSpMRI group showed significantly more AD-like hypometabolism on 18F-fluorodeoxyglucose-PET (p < 0.05) and poorer baseline executive function (p < 0.001). Other baseline clinical measures did not differ across the 3 groups. Participants with HpSpMRI also showed faster subsequent clinical decline than participants with LPMRI on the Alzheimer's Disease Assessment Scale, 13-Item Subscale (ADAS-Cog13), Mini-Mental State Examination (MMSE), and Functional Assessment Questionnaire (all p < 0.05) and tADMRI on the MMSE and Clinical Dementia Rating Sum of Boxes (CDR-SB) (both p < 0.05). Finally, a larger HV:CTV was associated with poorer baseline executive function and a faster slope of decline in CDR-SB, MMSE, and ADAS-Cog13 score (p < 0.05). These associations were driven mostly by the amount of cortical rather than hippocampal atrophy. CONCLUSIONS: AD subtypes with phenotypes consistent with those observed with tau neuropathology can be identified in vivo with vMRI. An increased HV:CTV ratio was predictive of faster clinical decline in participants with AD who were clinically indistinguishable at baseline except for a greater dysexecutive presentation.
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    Alzheimer's Disease Narratives and the Myth of Human Being
    (2012-12-11) Rieske, Tegan Echo; Schultz, Jane E.; Johnson, Karen Ramsay; Tilley, John J.
    The ‘loss of self’ trope is a pervasive shorthand for the prototypical process of Alzheimer's disease (AD) in the popular imagination. Turned into an effect of disease, the disappearance of the self accommodates a biomedical story of progressive deterioration and the further medicalization of AD, a process which has been storied as an organic pathology affecting the brain or, more recently, a matter of genetic calamity. This biomedical discourse of AD provides a generic framework for the disease and is reproduced in its illness narratives. The disappearance of self is a mythic element in AD narratives; it necessarily assumes the existence of a singular and coherent entity which, from the outside, can be counted as both belonging to and representing an individual person. The loss of self, as the rhetorical locus of AD narrative, limits the privatization of the experience and reinscribes cultural storylines---storylines about what it means to be a human person. The loss of self as it occurs in AD narratives functions most effectively in reasserting the presence of the human self, in contrast to an anonymous, inhuman nonself; as AD discourse details a loss of self, it necessarily follows that the thing which is lost (the self) always already existed. The private, narrative self of individual experience thus functions as proxy to a collective human identity predicated upon exceptionalism: an escape from nature and the conditions of the corporeal environment.