(Project 3) Recent clinical studies that examine prodromal subjects and recent-onset schizophrenia (SZ) have indicated that stress-associated pathways are activated prior to and at the onset of the disease, in contrast to milder changes of the pathways in the chronic stages. In addition, human postmortem studies have demonstrated changes in dendritic spines of pyramidal neurons and parvalbumin (PV)-positive interneurons. These are key neural substrates for the excitatory-inhibitory (E-I) imbalance in prefrontal cortical (PFC) neuronal networks underlying cognitive deficits in SZ. Our preliminary data show changes in stress-associated molecules and interneurons in adolescence and young adulthood in mouse models that display altered adult behaviors relevant to SZ. These models carry genetic perturbations of microtubule-associated molecules and show mild deficits in early neurodevelopment. Based on this background, we propose the following two Aims:
Aim 1 will determine and characterize the critical periods for changes in stress-associated cascades and E-I imbalance in several genetic mouse models with mild brain deficits in early development elicited by microtubule-associated genes;
and Aim 2 will study the mechanisms of neurocircuitry-based behavioral changes associated with medial PFC (mPFC) and orbitofrontal cortex (OFC), such as working memory deficits and behavioral inflexibility. We will also investigate whether adolescent social isolation exacerbates the pathological signatures. Finally, we will intervene with the stress pathways in a molecule, cell type and brain region-specific manner during adolescence to try to rescue adult phenotypes (physiology, behavior). We believe the proposed study is innovative and will lead to the development of new tools for early diagnosis and intervention in cognitive deficits relevant to SZ and related mental disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Specialized Center (P50)
Project #
5P50MH094268-07
Application #
9304365
Study Section
Special Emphasis Panel (ZMH1)
Project Start
Project End
Budget Start
2017-07-01
Budget End
2018-06-30
Support Year
7
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Type
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205
Nucifora Jr, Frederick C; Woznica, Edgar; Lee, Brian J et al. (2018) Treatment resistant schizophrenia: Clinical, biological, and therapeutic perspectives. Neurobiol Dis :
Xu, Zhexue; Zhang, Shu; Huang, Liyuan et al. (2018) Altered Resting-State Brain Activities in Drug-Naïve Major Depressive Disorder Assessed by fMRI: Associations With Somatic Symptoms Defined by Yin-Yang Theory of the Traditional Chinese Medicine. Front Psychiatry 9:195
Khambadkone, Seva G; Cordner, Zachary A; Dickerson, Faith et al. (2018) Nitrated meat products are associated with mania in humans and altered behavior and brain gene expression in rats. Mol Psychiatry :
Xiao, Jianchun; Prandovszky, Emese; Kannan, Geetha et al. (2018) Toxoplasma gondii: Biological Parameters of the Connection to Schizophrenia. Schizophr Bull 44:983-992
Uehara, Maiko; Tabata, Eri; Ishii, Kazuhiro et al. (2018) Chitinase mRNA Levels Determined by QPCR in Crab-Eating Monkey (Macaca fascicularis) Tissues: Species-Specific Expression of Acidic Mammalian Chitinase and Chitotriosidase. Genes (Basel) 9:
Posporelis, Sotirios; Coughlin, Jennifer M; Marsman, Anouk et al. (2018) Decoupling of Brain Temperature and Glutamate in Recent Onset of Schizophrenia: A 7T Proton Magnetic Resonance Spectroscopy Study. Biol Psychiatry Cogn Neurosci Neuroimaging 3:248-254
Zhu, Xiaolei; Nedelcovych, Michael T; Thomas, Ajit G et al. (2018) JHU-083 selectively blocks glutaminase activity in brain CD11b+ cells and prevents depression-associated behaviors induced by chronic social defeat stress. Neuropsychopharmacology :
Avramopoulos, Dimitrios (2018) Neuregulin 3 and its roles in schizophrenia risk and presentation. Am J Med Genet B Neuropsychiatr Genet 177:257-266
Sumitomo, Akiko; Horike, Kouta; Hirai, Kazuko et al. (2018) A mouse model of 22q11.2 deletions: Molecular and behavioral signatures of Parkinson's disease and schizophrenia. Sci Adv 4:eaar6637
Severance, Emily G; Dickerson, Faith B; Yolken, Robert H (2018) Autoimmune phenotypes in schizophrenia reveal novel treatment targets. Pharmacol Ther 189:184-198

Showing the most recent 10 out of 190 publications