Arts & Sciences Brown School McKelvey School Medicine Weekly Publications

WashU weekly Neuroscience publications

“Transcriptomic signatures of schizophrenia revealed by dopamine perturbation in an ex vivo model” (2018) Translational Psychiatry

Transcriptomic signatures of schizophrenia revealed by dopamine perturbation in an ex vivo model
(2018) Translational Psychiatry, 8 (1), art. no. 158, . 

Duan, J.a b , Göring, H.H.H.c , Sanders, A.R.a b , Moy, W.a b , Freda, J.a , Drigalenko, E.I.d , Kos, M.c , He, D.a , Gejman, P.V.a b , Gejman, P.V.e , Sanders, A.R.e , Duan, J.e , Levinson, D.F.f , Shi, J.g , Buccola, N.G.h , Mowry, B.J.i , Freedman, R.j , Olincy, A.j , Amin, F.k , Black, D.W.l , Silverman, J.M.m , Byerley, W.F.n , Cloninger, C.R.o , Svrakic, D.M.o , MGSp

a Center for Psychiatric Genetics, NorthShore University HealthSystem, Evanston, IL, United States
b Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL, United States
c South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, San Antonio, TX, United States
d Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX, United States
e NorthShore University HealthSystem and University of Chicago, Chicago, IL, United States
f Stanford University, Stanford, CA, United States
g National Cancer Institute, Rockville, MD, United States
h Louisiana State University Health Sciences Center, New Orleans, LA, United States
i Queensland Centre for Mental Health Research, Brisbane and Queensland Brain Institute, The University of Queensland, Brisbane, Australia
j University of Colorado, Denver, CO, United States
k Atlanta Veterans Affairs Medical Center and Emory University, Atlanta, GA, United States
l University of Iowa Carver College of Medicine, Iowa, IA, United States
m Mount Sinai School of Medicine, New York, NY, United States
n University of California, San Francisco, CA, United States
o Washington University, St. Louis, MO, United States

Abstract
The dopaminergic hypothesis of schizophrenia (SZ) postulates that dopaminergic over activity causes psychosis, a central feature of SZ, based on the observation that blocking dopamine (DA) improves psychotic symptoms. DA is known to have both receptor- and non-receptor-mediated effects, including oxidative mechanisms that lead to apoptosis. The role of DA-mediated oxidative processes in SZ has been little studied. Here, we have used a cell perturbation approach and measured transcriptomic profiles by RNAseq to study the effect of DA exposure on transcription in B-cell transformed lymphoblastoid cell lines (LCLs) from 514 SZ cases and 690 controls. We found that DA had widespread effects on both cell growth and gene expression in LCLs. Overall, 1455 genes showed statistically significant differential DA response in SZ cases and controls. This set of differentially expressed genes is enriched for brain expression and for functions related to immune processes and apoptosis, suggesting that DA may play a role in SZ pathogenesis through modulating those systems. Moreover, we observed a non-significant enrichment of genes near genome-wide significant SZ loci and with genes spanned by SZ-associated copy number variants (CNVs), which suggests convergent pathogenic mechanisms detected by both genetic association and gene expression. The study suggests a novel role of DA in the biological processes of immune and apoptosis that may be relevant to SZ pathogenesis. Furthermore, our results show the utility of pathophysiologically relevant perturbation experiments to investigate the biology of complex mental disorders. © 2018, The Author(s).

Document Type: Article
Source: Scopus

“MLL1 is essential for retinal neurogenesis and horizontal inner neuron integrity” (2018) Scientific Reports

MLL1 is essential for retinal neurogenesis and horizontal inner neuron integrity
(2018) Scientific Reports, 8 (1), art. no. 11902, . 

Brightman, D.S.a c f , Grant, R.L.e , Ruzycki, P.A.d , Suzuki, R.e , Hennig, A.K.a , Chen, S.a b

a Department of Ophthalmology and Visual Sciences, Washington University, Saint Louis, MO, United States
b Department of Developmental Biology, Washington University, Saint Louis, MO, United States
c Molecular Cell Biology graduate program, Division of Biology & Biomedical Sciences, Washington University, Saint Louis, MO, United States
d Molecular Genetics and Genomics graduate program, Division of Biology & Biomedical Sciences, Washington University, Saint Louis, MO, United States
e College of Arts and Sciences, Washington University, Saint Louis, MO, United States
f Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, ML 4006, Cincinnati, OH, United States

Abstract
Development of retinal structure and function is controlled by cell type-specific transcription factors and widely expressed co-regulators. The latter includes the mixed-lineage leukemia (MLL) family of histone methyltransferases that catalyze histone H3 lysine 4 di- and tri-methylation associated with gene activation. One such member, MLL1, is widely expressed in the central nervous system including the retina. However, its role in retinal development is unknown. To address this question, we knocked out Mll1 in mouse retinal progenitors, and discovered that MLL1 plays multiple roles in retinal development by regulating progenitor cell proliferation, cell type composition and neuron-glia balance, maintenance of horizontal neurons, and formation of functional synapses between neuronal layers required for visual signal transmission and processing. Altogether, our results suggest that MLL1 is indispensable for retinal neurogenesis and function development, providing a new paradigm for cell type-specific roles of known histone modifying enzymes during CNS tissue development. © 2018, The Author(s).

Document Type: Article
Source: Scopus
Access Type: Open Access

“Role of DHEA and cortisol in prefrontal-amygdalar development and working memory” (2018) Psychoneuroendocrinology

Role of DHEA and cortisol in prefrontal-amygdalar development and working memory
(2018) Psychoneuroendocrinology, 98, pp. 86-94. 

Farooqi, N.A.I.a , Scotti, M.a , Lew, J.M.b , Botteron, K.N.c d , Karama, S.a e f , McCracken, J.T.d i , Nguyen, T.-V.a g h

a Department of Psychiatry, McGill University, Montreal, QC, Canada
b Department of Psychology, McGill University, Montreal, QC, Canada
c Washington University School of Medicine, St. Louis, MO, United States
d Brain Development Cooperative Group, United States
e McConnell Brain imaging Centre, Montreal Neurological Institute, Montreal, QC, Canada
f Douglas Mental Health University Institute, Montreal, QC, Canada
g Research Institute of McGill University Health Center, Montreal, QC, Canada
h Department of Obstetrics-Gynecology, McGill University, Montreal, QC, Canada
i Department of Child and Adolescent Psychiatry, University of California in Los Angeles, Los Angeles, CA, United States

Abstract
There is accumulating evidence that both dehydroepiandrosterone (DHEA) and cortisol play an important role in regulating physical maturation and brain development. High DHEA levels tend to be associated with neuroprotective and indirect anabolic effects, while high cortisol levels tend to be associated with catabolic and neurotoxic properties. Previous literature has linked the ratio between DHEA and cortisol levels (DC ratio) to disorders of attention, emotional regulation and conduct, but little is known as to the relationship between this ratio and brain development. Due to the extensive links between the amygdala and the cortex as well as the known amygdalar involvement in emotional regulation, we examined associations between DC ratio, structural covariance of the amygdala with whole-brain cortical thickness, and validated report-based measures of attention, working memory, internalizing and externalizing symptoms, in a longitudinal sample of typically developing children and adolescents 6–22 years of age. We found that DC ratio predicted covariance between amygdalar volume and the medial anterior cingulate cortex, particularly in the right hemisphere. DC ratio had a significant indirect effect on working memory through its impact on prefrontal-amygdalar covariance, with higher DC ratios associated with a prefrontal-amygdalar covariance pattern predictive of higher scores on a measure of working memory. Taken together, these findings support the notion, as suggested by animal and in vitro studies, that there are opposing effects of DHEA and cortisol on brain development in humans, and that these effects may especially target prefrontal-amygdalar development and working memory, in a lateralized fashion. © 2018 Elsevier Ltd

Author Keywords
Adolescence;  Adrenarche;  Androgens;  Attention;  Human brain;  Puberty

Document Type: Article
Source: Scopus

“A microfluidic platform to study the effects of GDNF on neuronal axon entrapment” (2018) Journal of Neuroscience Methods

A microfluidic platform to study the effects of GDNF on neuronal axon entrapment
(2018) Journal of Neuroscience Methods, 308, pp. 183-191. 

Wang, Z.Z.a , Wood, M.D.b , Mackinnon, S.E.b , Sakiyama-Elbert, S.E.c

a Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States
b Division of Plastic and Reconstructive Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, MO, United States
c Department of Biomedical Engineering, University of Texas at Austin, Austin, TX, United States

Abstract
Background: One potential treatment strategy to enhance axon regeneration is transplanting Schwann Cells (SCs) that overexpress glial cell line-derived neurotrophic factor (GDNF). Unfortunately, constitutive GDNF overexpression in vivo can result in failure of regenerating axons to extend beyond the GDNF source, a phenomenon termed the “candy-store” effect. Little is known about the mechanism of this axon entrapment in vivo. New Method: We present a reproducible in vitro culture platform using a microfluidic device to model axon entrapment and investigate mechanisms by which GDNF causes axon entrapment. The device is comprised of three culture chambers connected by two sets of microchannels, which prevent cell soma from moving between chambers but allow neurites to grow between chambers. Neurons from dorsal root ganglia were seeded in one end chamber while the effect of different conditions in the other two chambers was used to study neurite entrapment. Results: The results showed that GDNF-overexpressing SCs (G-SCs) can induce axon entrapment in vitro. We also found that while physiological levels of GDNF (100 ng/mL) promoted neurite extension, supra-physiological levels of GDNF (700 ng/mL) induced axon entrapment. Comparison with Existing Method: All previous work related to the “candy-store” effect were done in vivo. Here, we report the first in vitro platform that can recapitulate the axonal entrapment and investigate the mechanism of the phenomenon. Conclusions: This platform facilitates investigation of the “candy-store” effect and shows the effects of high GDNF concentrations on neurite outgrowth. © 2018 Elsevier B.V.

Author Keywords
Gene therapy;  Neurite extension;  Peripheral nerve injury;  Schwann cells

Document Type: Article
Source: Scopus

“The region of interest localization for glaucoma analysis from retinal fundus image using deep learning” (2018) Computer Methods and Programs in Biomedicine

The region of interest localization for glaucoma analysis from retinal fundus image using deep learning
(2018) Computer Methods and Programs in Biomedicine, 165, pp. 25-35. 

Mitra, A.a b , Banerjee, P.S.b , Roy, S.a c , Roy, S.a , Setua, S.K.a

a Department of Computer Science & Engineering, Calcutta University Technology Campus, JD-2, Sector-III, Salt Lake, Kolkata, India
b Department of Computer Science & Engineering, Academy of Technology, Adisaptagram, West Bengal, India
c Mallinckrodt Institute of Radiology Department (MIR), Washington University School of Medicine, Campus Box 8225, 510 South Kingshighway Boulevard, Saint Louis, MO, United States

Abstract
Background and objectives: Retinal fundus image analysis without manual intervention has been rising as an imperative analytical approach for early detection of eye-related diseases such as glaucoma and diabetic retinopathy. For analysis and detection of Glaucoma and some other disease from retinal image, there is a significant role of predicting the bounding box coordinates of Optic Disc (OD) that acts as a Region of Interest (ROI). Methods: We reframe ROI detection as a solitary regression predicament, from image pixel values to ROI coordinates including class probabilities. A Convolution Neural Network (CNN) has trained on full images to predict bounding boxes along with their analogous probabilities and confidence scores. The publically available MESSIDOR and Kaggle datasets have been used to train the network. We adopted various data augmentation techniques to amplify our dataset so that our network becomes less sensitive to noise. From a very high-level perspective, every image is divided into a 13 × 13 grid. Every grid cell envisages 5 bounding boxes along with the corresponding class probability and a confidence score. Before training, the network and the bounding box priors or anchors are initialized using k-means clustering on the original dataset using a distance metric based on Intersection of the Union (IOU) over ground-truth bounding boxes. During training in fact, a sum-squared loss function is used as the prediction’s error function. Finally, Non-maximum suppression is applied by the proposed methodology to reach the concluding prediction. Results: The following projected method accomplish an accuracy of 99.05% and 98.78% on the Kaggle and MESSIDOR test sets for ROI detection. Results of proposed methodology indicates that proposed network is able to perceive ROI in fundus images in 0.0045 s at 25 ms of latency, which is far better than the recent-time and using no handcrafted features. Conclusions: The network predicts accurate results even on low-quality images without being biased towards any particular type of image. The network prepared to see more summed up depiction rather than past works in the field. Going by the results, our novel method has better diagnosis of eye diseases in the future in a faster and reliable way. © 2018 Elsevier B.V.

Author Keywords
Anchor Boxes;  Batch Normalization;  Convolution Neural Networks;  Intersection over Union;  K-means clustering;  Leaky ReLU, Max Pooling;  Non-maximum suppression;  Optic Disc Localization

Document Type: Article
Source: Scopus

“Angiotensin II triggers peripheral macrophage-to-sensory neuron redox crosstalk to elicit pain” (2018) Journal of Neuroscience

Angiotensin II triggers peripheral macrophage-to-sensory neuron redox crosstalk to elicit pain
(2018) Journal of Neuroscience, 38 (32), pp. 7032-7057. Cited 1 time.

Shepherd, A.J.a b , Copits, B.A.a , Mickle, A.D.a b , Karlsson, P.c d , Kadunganattil, S.a , Haroutounian, S.a , Tadinada, S.M.b , De Kloet, A.D.e , Valtcheva, M.V.a , McIlvried, L.A.a , Sheahan, T.D.a , Jain, S.f , Ray, P.R.g , Usachev, Y.M.b , Dussor, G.g , Krause, E.G.h , Price, T.J.g , Gereau, R.W., IVa i , Mohapatra, D.P.a b j

a Department of Anesthesiology, Washington University Pain Center, Washington University School of Medicine, St. Louis, MO, United States
b Department of Pharmacology, The University of Iowa Carver College of Medicine, Iowa City, IA, United States
c Danish Pain Research Center, Department of Clinical Medicine, Aarhus University Hospital, Aarhus C, Denmark
d Department of Clinical Medicine, Core Center for Molecular Morphology, Section for Stereology and Microscopy, Aarhus University Hospital, Aarhus C, Denmark
e Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville, FL, United States
f Departments of Medicine, Pathology, and Immunology, Washington University School of Medicine, St. Louis, MO, United States
g School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, TX, United States
h Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL, United States
i Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, United States
j Center for the Investigation of Membrane Excitability Diseases, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Injury, inflammation, and nerve damage initiate a wide variety of cellular and molecular processes that culminate in hyperexcitation of sensory nerves, which underlies chronic inflammatory and neuropathic pain. Using be avioral readouts of pain hypersensitivity induced by angiotensin II (Ang II) injection into mouse hindpaws, our study shows that activation of the type 2 Ang II receptor (AT2R) and the cell-damage-sensing ion channel TRPA1 are required for peripheral mechanical pain sensitization induced by Ang II in male and female mice. However, we show that AT2R is not expressed in mouse and human dorsal root ganglia (DRG) sensory neurons. Instead, expression/ activation of AT2R on peripheral/skin macrophages (Mɸs) constitutes a critical trigger of mouse and human DRG sensory neuron excitation. Ang II-induced peripheral mechanical pain hypersensitivity can be atten ated by chemogenetic depletion of peripheralM_s. Furthermore, AT2R activation in Mɸs triggers production of reactive oxygen/nitrogen species, which trans-activate TRPA1 on mouse and human DRG sensory neurons via cysteine modification of the channel. Our study thus identifies a translatable immune cell-tosensory neuron signaling crosstalk underlying peripheral nociceptor sensitization. This form of cell-to-cell signaling represents a critical peripheral mechanism for chronic pain and thus identifies multiple druggable analgesic targets. © 2018 the authors.

Author Keywords
Angiotensin II;  AT2R;  Neuroimmune interaction;  Oxidative stress;  Pain;  TRPA1

Document Type: Article
Source: Scopus

“PET Imaging in Movement Disorders” (2018) Seminars in Nuclear Medicine

PET Imaging in Movement Disorders
(2018) Seminars in Nuclear Medicine, . Article in Press. 

Maiti, B.a , Perlmutter, J.S.a b c d e

a Department of Neurology, Washington University in St. Louis, St Louis, MO., United States
b Department of Radiology, Washington University in St. Louis, St Louis, MO., United States
c Department of Neuroscience, Washington University in St. Louis, St Louis, MO., United States
d Department of Physical Therapy, Washington University in St. Louis, St Louis, MO., United States
e Department of Occupational Therapy, Washington University in St. Louis, St Louis, MO., United States

Abstract
Positron emission tomography (PET) has revealed key insights into the pathophysiology of movement disorders. This paper will focus on how PET investigations of pathophysiology are particularly relevant to Parkinson disease, a neurodegenerative condition usually starting later in life marked by a varying combination of motor and nonmotor deficits. Various molecular imaging modalities help to determine what changes in brain herald the onset of pathology; can these changes be used to identify presymptomatic individuals who may be appropriate for to-be-developed treatments that may forestall onset of symptoms or slow disease progression; can PET act as a biomarker of disease progression; can molecular imaging help enrich homogenous cohorts for clinical studies; and what other pathophysiologic mechanisms relate to nonmotor manifestations. PET methods include measurements of regional cerebral glucose metabolism and blood flow, selected receptors, specific neurotransmitter systems, postsynaptic signal transducers, and abnormal protein deposition. We will review each of these methodologies and how they are relevant to important clinical issues pertaining to Parkinson disease. © 2018 Elsevier Inc.

Document Type: Article in Press
Source: Scopus

“Suicidal Ideation Assessment in Individuals with Premanifest and Manifest Huntington Disease” (2018) Journal of Huntington’s Disease

Suicidal Ideation Assessment in Individuals with Premanifest and Manifest Huntington Disease
(2018) Journal of Huntington’s Disease, 7 (3), pp. 239-249. 

Wesson, M.a , Boileau, N.R.b , Perlmutter, J.S.c d , Paulsen, J.S.e , Barton, S.K.c , McCormack, M.K.f g , Carlozzi, N.E.b

a Department of Medical and Molecular Genetics, Indiana University, Indianapolis, IN, United States
b Department of Physical Medicine and Rehabilitation, University of Michigan, North Campus Research Complex, 2800 Plymouth Road, Building NCRC B14, Ann Arbor, MI, United States
c Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
d Radiology, Neuroscience, Physical Therapy, Occupational Therapy, Washington University in St. Louis, St. Louis, MO, United States
e Neurology, Psychiatry, Psychological and Brain Sciences, University of Iowa, Iowa City, IA, United States
f Department of Pathology, Rowan University School of Medicine, Glassboro, NJ, United States
g Department of Psychiatry, Rutgers-RWJMS, Piscataway Township, NJ, United States

Abstract
Background: Huntington disease (HD) is associated with increased risk of suicide. Objective: This study compares suicide ideation in HD to the general population, assesses factors associated with increased prevalence of suicidal thoughts, and compares clinician-rated to self-reported assessments of suicidal ideation. Methods: We examined 496 participants with premanifest or manifest HD. Clinician-rated suicidal ideation was measured using the Problem Behaviors Assessment – short form. Self-reported ideation was measured using two items from the HDQLIFE Concern with Death and Dying item bank. Independent sample t-tests were conducted to compare the prevalence of suicidal thoughts between our HD sample and the U.S. population. Logistic regression analyses were used to determine characteristics associated with higher odds of clinically significant suicidal ideation. Kappa agreement coefficients were calculated to evaluate concurrence between clinician-rated and self-reported assessments. Results: Our sample had a significantly higher occurrence of suicidal ideation (19.76%) and suicidal plans (2.1%) than the general population (p < 0.0001). Odds of clinically significant suicidal ideation were 6.8 times higher in females (p = 0.04) on the clinician measure, and Hispanic/Latinos had 10.9 times higher odds than non-Hispanics (p = 0.025) on the self-report measure. Clinician-rated assessment had fair agreement (k = 0.2-0.4) with self-reported assessments, except in early stage HD where there was no overlap in the identification of participants with clinically significant suicidal ideation. Discussion: Assessment for suicidal ideation and clinically significant suicidal thoughts in HD with a multimodal approach that includes clinician-rated and self-report measures is critical at all stages of the disease. © 2018 – IOS Press and the authors. All rights reserved.

Author Keywords
comparing methods;  Huntington disease;  suicidal ideation;  suicide;  suicide assessment

Document Type: Article
Source: Scopus