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Risacher S.L.,Center for Neuroimaging | Risacher S.L.,Stark Neurosciences Research Institute | Shen L.,Center for Neuroimaging | Shen L.,Stark Neurosciences Research Institute | And 14 more authors.
Neurobiology of Aging | Year: 2010

Atrophic changes in early Alzheimer's disease (AD) and amnestic mild cognitive impairment (MCI) have been proposed as biomarkers for detection and monitoring. We analyzed magnetic resonance imaging (MRI) atrophy rate from baseline to 1 year in 4 groups of participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI): AD (n = 152), converters from MCI to probable AD (MCI-C, n = 60), stable MCI (MCI-S, n = 261), and healthy controls (HC, n = 200). Scans were analyzed using multiple methods, including voxel-based morphometry (VBM), regions of interest (ROIs), and automated parcellation, permitting comparison of annual percent change (APC) in neurodegeneration markers. Effect sizes and the sample required to detect 25% reduction in atrophy rates were calculated. The influence of APOE genotype on APC was also evaluated. AD patients and converters from MCI to probable AD demonstrated high atrophy APCs across regions compared with minimal change in healthy controls. Stable MCI subjects showed intermediate atrophy rates. APOE genotype was associated with APC in key regions. In sum, APC rates are influenced by APOE genotype, imminent MCI to AD conversion, and AD-related neurodegeneration. © 2010 Elsevier Inc.


PubMed | Stark Neurosciences Research Institute, Indiana University – Purdue University Indianapolis and Texas A&M University
Type: Journal Article | Journal: Alcohol (Fayetteville, N.Y.) | Year: 2015

Identification of facial dysmorphology is essential for the diagnosis of fetal alcohol syndrome (FAS); however, most children with fetal alcohol spectrum disorders (FASD) do not meet the dysmorphology criterion. Additional objective indicators are needed to help identify the broader spectrum of children affected by prenatal alcohol exposure. Computed tomography (CT) was used in a sheep model of prenatal binge alcohol exposure to test the hypothesis that quantitative measures of craniofacial bone volumes and linear distances could identify alcohol-exposed lambs. Pregnant sheep were randomly assigned to four groups: heavy binge alcohol, 2.5g/kg/day (HBA); binge alcohol, 1.75g/kg/day (BA); saline control (SC); and normal control (NC). Intravenous alcohol (BA; HBA) or saline (SC) infusions were given three consecutive days per week from gestation day 4-41, and a CT scan was performed on postnatal day 182. The volumes of eight skull bones, cranial circumference, and 19 linear measures of the face and skull were compared among treatment groups. Lambs from both alcohol groups showed significant reduction in seven of the eight skull bones and total skull bone volume, as well as cranial circumference. Alcohol exposure also decreased four of the 19 craniofacial measures. Discriminant analysis showed that alcohol-exposed and control lambs could be classified with high accuracy based on total skull bone volume, frontal, parietal, or mandibular bone volumes, cranial circumference, or interorbital distance. Total skull volume was significantly more sensitive than cranial circumference in identifying the alcohol-exposed lambs when alcohol-exposed lambs were classified using the typical FAS diagnostic cutoff of 10th percentile. This first demonstration of the usefulness of CT-derived craniofacial measures in a sheep model of FASD following binge-like alcohol exposure during the first trimester suggests that volumetric measurement of cranial bones may be a novel biomarker for binge alcohol exposure during the first trimester to help identify non-dysmorphic children with FASD.


Weafer J.,Indiana University | Weafer J.,University of Chicago | Dzemidzic M.,Indiana University | Eiler W.,Indiana University | And 4 more authors.
Psychiatry Research - Neuroimaging | Year: 2015

Trait impulsivity and poor inhibitory control are well-established risk factors for alcohol misuse, yet little is known about the associated neurobiological endophenotypes. Here we examined correlations among brain physiology and self-reported trait impulsive behavior, impaired control over drinking, and a behavioral measure of response inhibition. A sample of healthy drinkers (n=117) completed a pulsed arterial spin labeling (PASL) scan to quantify resting regional cerebral blood flow (rCBF), as well as measures of self-reported impulsivity (Eysenck I7 Impulsivity scale) and impaired control over drinking. A subset of subjects (n=40) performed a stop signal task during blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging to assess brain regions involved in response inhibition. Eysenck I7 scores were inversely related to blood flow in the right precentral gyrus. Significant BOLD activation during response inhibition occurred in an overlapping right frontal motor/premotor region. Moreover, impaired control over drinking was associated with reduced BOLD response in the same region. These findings suggest that impulsive personality and impaired control over drinking are associated with brain physiology in areas implicated in response inhibition. This is consistent with the idea that difficulty controlling behavior is due in part to impairment in motor restraint systems. © 2015 Elsevier Ireland Ltd.


Birch S.M.,Texas A&M University | Lenox M.W.,Texas A&M University | Kornegay J.N.,Texas A&M University | Paniagua B.,University of North Carolina at Chapel Hill | And 5 more authors.
Alcohol | Year: 2016

Fetal alcohol spectrum disorder (FASD) is a leading potentially preventable birth defect. Poor nutrition may contribute to adverse developmental outcomes of prenatal alcohol exposure, and supplementation of essential micronutrients such as choline has shown benefit in rodent models. The sheep model of first-trimester binge alcohol exposure was used in this study to model the dose of maternal choline supplementation used in an ongoing prospective clinical trial involving pregnancies at risk for FASD. Primary outcome measures including volumetrics of the whole brain, cerebellum, and pituitary derived from magnetic resonance imaging (MRI) in 6-month-old lambs, testing the hypothesis that alcohol-exposed lambs would have brain volume reductions that would be ameliorated by maternal choline supplementation. Pregnant sheep were randomly assigned to one of five groups – heavy binge alcohol (HBA; 2.5 g/kg/treatment ethanol), heavy binge alcohol plus choline supplementation (HBC; 2.5 g/kg/treatment ethanol and 10 mg/kg/day choline), saline control (SC), saline control plus choline supplementation (SCC; 10 mg/kg/day choline), and normal control (NC). Ewes were given intravenous alcohol (HBA, HBC; mean peak BACs of ∼280 mg/dL) or saline (SC, SCC) on three consecutive days per week from gestation day (GD) 4–41; choline was administered on GD 4–148. MRI scans of lamb brains were performed postnatally on day 182. Lambs from both alcohol groups (with or without choline) showed significant reductions in total brain volume; cerebellar and pituitary volumes were not significantly affected. This is the first report of MRI-derived volumetric brain reductions in a sheep model of FASD following binge-like alcohol exposure during the first trimester. These results also indicate that maternal choline supplementation comparable to doses in human studies fails to prevent brain volume reductions typically induced by first-trimester binge alcohol exposure. Future analyses will assess behavioral outcomes along with regional brain and neurohistological measures. © 2016 Elsevier Inc.


Molosh A.I.,Indiana University | Molosh A.I.,Stark Neurosciences Research Institute | Sajdyk T.J.,Indiana University | Sajdyk T.J.,Clinical Translational Science Institute | And 6 more authors.
Neuropsychopharmacology | Year: 2013

Neuropeptide Y (NPY) administration into the basolateral amygdala (BLA) decreases anxiety-like behavior, mediated in part through the Y 1 receptor (Y 1 R) isoform. Activation of Y 1 Rs results in G-protein-mediated reduction of cAMP levels, which results in reduced excitability of amygdala projection neurons. Understanding the mechanisms linking decreased cAMP levels to reduced excitability in amygdala neurons is important for identifying novel anxiolytic targets. We studied the intracellular mechanisms of activation of Y 1 Rs on synaptic transmission in the BLA. Activating Y 1 Rs by Leu 31,Pro 34 -NPY (L-P NPY) reduced the amplitude of evoked NMDA-mediated excitatory postsynaptic currents (eEPSCs), without affecting AMPA-mediated eEPSCs, but conversely increased the amplitude of GABA A-mediated evoked inhibitory postsynaptic currents (eIPSCs). Both effects were abolished by the Y 1 R antagonist, PD160170. Intracellular GDP-β-S, or pre-treatment with either forskolin or 8Br-cAMP, eliminated the effects of L-P NPY on both NMDA-and GABA A-mediated currents. Thus, both the NMDA and GABA A effects of Y 1 R activation in the BLA are G-protein-mediated and cAMP-dependent. Pipette inclusion of protein kinase A (PKA) catalytic subunit blocked the effect of L-P NPY on GABA A-mediated eIPSCs, but not on NMDA-mediated eEPSCs. Conversely, activating the exchange protein activated by cAMP (Epac) with 8CPT-2Me-cAMP blocked the effect of L-P NPY on NMDA-mediated eEPSCs, but not on GABA A-mediated eIPSCs. Thus, NPY regulates amygdala excitability via two signal-transduction events, with reduced PKA activity enhancing GABA A-mediated eIPSCs and Epac deactivation reducing NMDA-mediated eEPSCs. This multipathway regulation of NMDA-and GABA A-mediated currents may be important for NPY plasticity and stress resilience in the amygdala. © 2013 American College of Neuropsychopharmacology.


Oberlin B.G.,Indiana University | Albrecht D.S.,Indiana University | Albrecht D.S.,Stark Neurosciences Research Institute | Herring C.M.,Indiana University | And 7 more authors.
Psychopharmacology | Year: 2015

Abstract Rationale: Dopamine (DA) in the ventral striatum (VST) has long been implicated in addiction pathologies, yet its role in temporal decision-making is not well-understood. Objectives: To determine if VST DA D2 receptor availability corresponds with greater impulsive choice in both nontreatment-seeking alcoholics (NTS) and social drinkers (SD). Methods: NTS subjects (n=10) and SD (n=13) received PET scans at baseline with the D2/D3 radioligand [11C]raclopride (RAC). Outside the scanner, subjects performed a delay discounting procedure with monetary rewards. RAC binding potential (BPND) was estimated voxelwise, and correlations were performed to test for relationships between VST BPND and delay discounting performance. Self-reported impulsivity was also tested for correlations with BPND. Results: Across all subjects, greater impulsive choice for $20 correlated with lower BPND in the right VST. NTS showed greater impulsive choice than SD and were more impulsive by self-report. Across all subjects, the capacity of larger rewards to reduce impulsive choice (the magnitude effect) correlated negatively (p=0.028) with problematic alcohol use (AUDIT) scores. Self-reported impulsivity did not correlate with BPND in VST. Conclusions: Preference for immediate reinforcement may reflect greater endogenous striatal DA or lower D2 number, or both. Alcoholic status did not mediate significant effects on VST BPND, suggesting minimal effects from alcohol exposure. The apparent lack of BPND correlation with self-reported impulsivity highlights the need for objective behavioral assays in the study of the neurochemical substrates of behavior. Finally, our results suggest that the magnitude effect may be more sensitive to alcohol-induced problems than single discounting measures. © 2015 Springer-Verlag Berlin Heidelberg.


Oberlin B.G.,Indiana University | Dzemidzic M.,Indiana University | Dzemidzic M.,Center for Neuroimaging | Tran S.M.,Indiana University | And 9 more authors.
Psychopharmacology | Year: 2015

Rationale: Although striatal dopamine (DA) is important in alcohol abuse, the nature of DA release during actual alcohol drinking is unclear, since drinking includes self-administration of both conditioned flavor stimuli (CS) of the alcoholic beverage and subsequent intoxication, the unconditioned stimulus (US). Objectives: Here, we used a novel self-administration analog to distinguish nucleus accumbens (NAcc) DA responses specific to the CS and US. Methods: Right-handed male heavy drinkers (n∈=∈26) received three positron emission tomography (PET) scans with the D2/D3 radioligand [11C]raclopride (RAC) and performed a pseudo self-administration task that separately administered a flavor CS of either a habitually consumed beer or the appetitive control Gatorade®, concomitant with the US of ethanol intoxication (0.06 g/dL intravenous (IV) administration) or IV saline. Scan conditions were Gatorade flavor∈+∈saline (Gat&Sal), Gatorade flavor∈+∈ethanol (Gat&Eth), and beer flavor∈+∈ethanol (Beer&Eth). Results: Ethanol (US) reduced RAC binding (inferring DA release) in the left (L) NAcc [Gat&Sal∈>∈Gat&Eth]. Beer flavor (CS) increased DA in the right (R) NAcc [Gat&Eth∈>∈Beer&Eth]. The combination of beer flavor and ethanol (CS∈+∈US), [Gat&Sal∈>∈Beer&Eth], induced DA release in bilateral NAcc. Self-reported intoxication during scanning correlated with L NAcc DA release. Relative to saline, infusion of ethanol increased alcoholic drink wanting. Conclusions: Our findings suggest lateralized DA function in the NAcc, with L NAcc DA release most reflecting intoxication, R NAcc DA release most reflecting the flavor CS, and the conjoint CS∈+∈US producing a bilateral NAcc response. © 2014 Springer-Verlag Berlin Heidelberg.


Thapa P.,University of Hawaii at Manoa | Cabalteja C.C.,University of Hawaii at Manoa | Philips E.E.,University of Hawaii at Manoa | Espiritu M.J.,University of Hawaii at Manoa | And 6 more authors.
Biopolymers | Year: 2016

Tert-butyloxycarbonyl (t-Boc)-based native chemical ligation (NCL) techniques commonly employ hydrogen fluoride (HF) to create the thioester fragment required for the ligation process. Our research aimed to assess the replacement of HF with Trifluoromethanesulfonic acid (TFMSA). Here we examined a 33 amino acid test peptide, Huwentoxin-I (HwTx-I) as a novel candidate for our TFMSA cleavage protocol. Structurally HwTx-I has an X-Cys16-Cys17-X sequence mid-region, which makes it an ideal candidate for NCL. Experiments determined that the best yields (16.8%) obtained for 50 mg of a thioester support resin were achieved with a TFMSA volume of 100 μL with a 0.5-h incubation on ice, followed by 2.0 h at room temperature. RP-HPLC/UV and mass spectra indicated the appropriate parent mass and retention of the cleaved HwTx-I N-terminal thioester fragment (Ala1-Cys16), which was used in preparation for NCL. The resulting chemically ligated HwTx-I was oxidized/folded, purified, and then assessed for pharmacological target selectivity. Native-like HwTx-I produced by this method yielded an EC50 value of 340.5 ± 26.8 nM for Nav1.2 and an EC50 value of 504.1 ± 81.3 nM for Nav1.3, this being similar to previous literature results using native material. This article represents the first NCL based synthesis of this potent sodium channel blocker. Our illustrated approach removes potential restrictions in the advancement of NCL as a common peptide laboratory technique with minimal investment, and removes the hazards associated with HF usage. © 2016 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 737–745, 2016. © 2016 Wiley Periodicals, Inc.


Ben-Yaakov K.,Weizmann Institute of Science | Dagan S.Y.,Weizmann Institute of Science | Segal-Ruder Y.,Weizmann Institute of Science | Shalem O.,Weizmann Institute of Science | And 11 more authors.
EMBO Journal | Year: 2012

Retrograde axonal injury signalling stimulates cell body responses in lesioned peripheral neurons. The involvement of importins in retrograde transport suggests that transcription factors (TFs) might be directly involved in axonal injury signalling. Here, we show that multiple TFs are found in axons and associate with dynein in axoplasm from injured nerve. Biochemical and functional validation for one TF family establishes that axonal STAT3 is locally translated and activated upon injury, and is transported retrogradely with dynein and importin α5 to modulate survival of peripheral sensory neurons after injury. Hence, retrograde transport of TFs from axonal lesion sites provides a direct link between axon and nucleus. © 2012 European Molecular Biology Organization.


PubMed | Stark Neurosciences Research Institute
Type: | Journal: BMC neuroscience | Year: 2011

The use of induced pluripotent stem cells (iPSCs) for the functional replacement of damaged neurons and in vitro disease modeling is of great clinical relevance. Unfortunately, the capacity of iPSC lines to differentiate into neurons is highly variable, prompting the need for a reliable means of assessing the differentiation capacity of newly derived iPSC cell lines. Extended passaging is emerging as a method of ensuring faithful reprogramming. We adapted an established and efficient embryonic stem cell (ESC) neural induction protocol to test whether iPSCs (1) have the competence to give rise to functional neurons with similar efficiency as ESCs and (2) whether the extent of neural differentiation could be altered or enhanced by increased passaging.Our gene expression and morphological analyses revealed that neural conversion was temporally delayed in iPSC lines and some iPSC lines did not properly form embryoid bodies during the first stage of differentiation. Notably, these deficits were corrected by continual passaging in an iPSC clone. iPSCs with greater than 20 passages (late-passage iPSCs) expressed higher expression levels of pluripotency markers and formed larger embryoid bodies than iPSCs with fewer than 10 passages (early-passage iPSCs). Moreover, late-passage iPSCs started to express neural marker genes sooner than early-passage iPSCs after the initiation of neural induction. Furthermore, late-passage iPSC-derived neurons exhibited notably greater excitability and larger voltage-gated currents than early-passage iPSC-derived neurons, although these cells were morphologically indistinguishable.These findings strongly suggest that the efficiency neuronal conversion depends on the complete reprogramming of iPSCs via extensive passaging.

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