WashU weekly Neuroscience publications

Cueing natural event boundaries improves memory in people with post-traumatic stress disorder
(2023) Cognitive Research: Principles and Implications, 8 (1), art. no. 26, . 

Pitts, B.L.^a , Eisenberg, M.L.^b , Bailey, H.R.^a , Zacks, J.M.^b

^a Kansas State University, Manhattan, KS 66506, United States
^b Washington University in St. Louis, St. Louis, MO 63130, United States

Abstract
People with post-traumatic stress disorder (PTSD) often report difficulty remembering information in their everyday lives. Recent findings suggest that such difficulties may be due to PTSD-related deficits in parsing ongoing activity into discrete events, a process called event segmentation. Here, we investigated the causal relationship between event segmentation and memory by cueing event boundaries and evaluating its effect on subsequent memory in people with PTSD. People with PTSD (n = 38) and trauma-matched controls (n = 36) watched and remembered videos of everyday activities that were either unedited, contained visual and auditory cues at event boundaries, or contained visual and auditory cues at event middles. PTSD symptom severity varied substantial within both the group with a PTSD diagnosis and the control group. Memory performance did not differ significantly between groups, but people with high symptoms of PTSD remembered fewer details from the videos than those with lower symptoms of PTSD. Both those with PTSD and controls remembered more information from the videos in the event boundary cue condition than the middle cue or unedited conditions. This finding has important implications for translational work focusing on addressing everyday memory complaints in people with PTSD. © 2023, The Author(s).

Author Keywords
Cueing;  Event segmentation;  Memory;  PTSD;  Symptom severity

Funding details
National Institutes of HealthNIHP20GM113109
Defense Advanced Research Projects AgencyDARPAD13AP00009

Document Type: Article
Publication Stage: Final
Source: Scopus

Ligand and G-protein selectivity in the κ-opioid receptor
(2023) Nature, . 

Han, J.^a b , Zhang, J.^c d l m , Nazarova, A.L.^e f g , Bernhard, S.M.^a b , Krumm, B.E.^h , Zhao, L.^a , Lam, J.H.^e f g , Rangari, V.A.^b , Majumdar, S.^a b i , Nichols, D.E.^j , Katritch, V.^e f g , Yuan, P.^c d l m , Fay, J.F.^k , Che, T.^a b i

^a Department of Anesthesiology, Washington University in St Louis, St Louis, MO, United States
^b Center for Clinical Pharmacology, University of Health Sciences and Pharmacy in St Louis and Washington University School of Medicine, St Louis, MO, United States
^c Department of Cell Biology and Physiology, Washington University School of Medicine, St Louis, MO, United States
^d Center for the Investigation of Membrane Excitability Diseases, Washington University School of Medicine, St Louis, MO, United States
^e Department of Quantitative and Computational Biology, University of Southern California, Los Angeles, CA, United States
^f Department of Chemistry, University of Southern California, Los Angeles, CA, United States
^g Center for New Technologies in Drug Discovery and Development, Bridge Institute, Michelson Center for Convergent Biosciences, University of Southern California, Los Angeles, CA, United States
^h Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, NC, United States
ⁱ Washington University Pain Center, Washington University in St Louis, St Louis, MO, United States
^j Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, United States
^k Department of Biochemistry and Molecular Biology, University of Maryland Baltimore, Baltimore, MD, United States
^l Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States
^m Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, United States

Abstract
The κ-opioid receptor (KOR) represents a highly desirable therapeutic target for treating not only pain but also addiction and affective disorders1. However, the development of KOR analgesics has been hindered by the associated hallucinogenic side effects2. The initiation of KOR signalling requires the Gi/o-family proteins including the conventional (Gi1, Gi2, Gi3, GoA and GoB) and nonconventional (Gz and Gg) subtypes. How hallucinogens exert their actions through KOR and how KOR determines G-protein subtype selectivity are not well understood. Here we determined the active-state structures of KOR in a complex with multiple G-protein heterotrimers—Gi1, GoA, Gz and Gg—using cryo-electron microscopy. The KOR–G-protein complexes are bound to hallucinogenic salvinorins or highly selective KOR agonists. Comparisons of these structures reveal molecular determinants critical for KOR–G-protein interactions as well as key elements governing Gi/o-family subtype selectivity and KOR ligand selectivity. Furthermore, the four G-protein subtypes display an intrinsically different binding affinity and allosteric activity on agonist binding at KOR. These results provide insights into the actions of opioids and G-protein-coupling specificity at KOR and establish a foundation to examine the therapeutic potential of pathway-selective agonists of KOR. © 2023, The Author(s).

Funding details
National Institutes of HealthNIHR01NS099341, R35GM143061

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

Steady-state memory-phenotype conventional CD4+ T cells exacerbate autoimmune neuroinflammation in a bystander manner via the Bhlhe40/GM-CSF axis
(2023) Experimental and Molecular Medicine, . 

Cho, M.-J.^a , Lee, H.-G.^a b , Yoon, J.-W.^a , Kim, G.-R.^a , Koo, J.-H.^a c , Taneja, R.^d , Edelson, B.T.^e , Lee, Y.J.^f , Choi, J.-M.^a g h i

^a Department of Life Science, College of Natural Sciences, Hanyang University, Seoul, 04763, South Korea
^b Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, United States
^c The Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02139, United States
^d Department of Physiology and Healthy Longevity Translation Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117593, Singapore
^e Department of Pathology and Immunology, Division of Laboratory and Genomic Medicine, Washington University School of Medicine, St. Louis, MO 63119, United States
^f Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, South Korea
^g Research Institute for Natural Sciences, Hanyang University, Seoul, 04763, South Korea
^h Research Institute for Convergence of Basic Sciences, Hanyang University, Seoul, 04763, South Korea
ⁱ Hanyang Institute of Bioscience and Biotechnology, Hanyang University, Seoul, 04763, South Korea

Abstract
Memory-phenotype (MP) CD4+ T cells are a substantial population of conventional T cells that exist in steady-state mice, yet their immunological roles in autoimmune disease remain unclear. In this work, we unveil a unique phenotype of MP CD4+ T cells determined by analyzing single-cell transcriptomic data and T cell receptor (TCR) repertoires. We found that steady-state MP CD4+ T cells in the spleen were composed of heterogeneous effector subpopulations and existed regardless of germ and food antigen exposure. Distinct subpopulations of MP CD4+ T cells were specifically activated by IL-1 family cytokines and STAT activators, revealing that the cells exerted TCR-independent bystander effector functions similar to innate lymphoid cells. In particular, CCR6high subpopulation of MP CD4+ T cells were major responders to IL-23 and IL-1β without MOG35-55 antigen reactivity, which gave them pathogenic Th17 characteristics and allowed them to contribute to autoimmune encephalomyelitis. We identified that Bhlhe40 in CCR6high MP CD4+ T cells as a key regulator of GM-CSF expression through IL-23 and IL-1β signaling, contributing to central nervous system (CNS) pathology in experimental autoimmune encephalomyelitis. Collectively, our findings reveal the clearly distinct effector-like heterogeneity of MP CD4+ T cells in the steady state and indicate that CCR6high MP CD4+ T cells exacerbate autoimmune neuroinflammation via the Bhlhe40/GM-CSF axis in a bystander manner. © 2023, The Author(s).

Funding details
National Research Foundation of KoreaNRF

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

Stronger Microstructural Damage Revealed in Multiple Sclerosis Lesions With Central Vein Sign by Quantitative Gradient Echo MRI
(2022) Journal of Central Nervous System Disease, 14, . 

Levasseur, V.A.^a , Xiang, B.^b , Salter, A.^c , Yablonskiy, D.A.^a , Cross, A.H.^b

^a Department of Neurology, Washington University School of Medicine, St Louis, MO, United States
^b Department of Radiology, Washington University School of Medicine, St Louis, MO, United States
^c Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX, United States

Abstract
Background: Multiple sclerosis (MS) lesions typically form around a central vein that can be visualized with FLAIR* MRI, creating the central vein sign (CVS) which may reflect lesion pathophysiology. Herein we used gradient echo plural contrast imaging (GEPCI) MRI to simultaneously visualize CVS and measure tissue damage in MS lesions. We examined CVS in relation to tissue integrity in white matter (WM) lesions and among MS subtypes. Objective: We aimed to determine if CVS positive lesions were specific to MS subtype, if CVS can be detected consistently among readers using the GEPCI method, and if there were differences in tissue damage in lesions with vs without CVS. Subjects and Methods: Thirty relapsing-remitting MS (RRMS) subjects and 38 primary and secondary progressive MS (PMS) subjects were scanned with GEPCI protocol at 3T. GEPCI T2*-SWI images were generated to visualize CVS. Two investigators independently evaluated WM lesions for CVS and measured lesion volumes. To estimate tissue damage severity, total lesion volume, and mean lesion volume, R2t*-based tissue damage score (TDS) of individual lesions and tissue damage load (TDL) were measured for CVS+, CVS-, and confluent lesions. Spearman correlations were made between MRI and clinical data. One-way ANCOVA with age and sex as covariates was used to compare measurements of CVS+ vs CVS- lesions in each individual. Results: 398 of 548 lesions meeting inclusion criteria showed CVS. Most patients had ≥40% CVS+ lesions. CVS+ lesions were present in similar proportion among MS subtypes. Interobserver agreement was high for CVS detection. CVS+ and confluent lesions had higher average and total volumes vs CVS- lesions. CVS+ and confluent lesions had more tissue damage than CVS- lesions based on TDL and mean TDS. Conclusion: CVS occurred in RRMS and PMS in similar proportions. CVS+ lesions had greater tissue damage and larger size than CVS- lesions. © The Author(s) 2022.

Author Keywords
central vein sign;  gradient echo plural contrast imaging;  progressive MS;  relapsing remitting multiple sclerosis

Document Type: Article
Publication Stage: Final
Source: Scopus