Ischemic brain injury is a major cause of death and disability with few effective treatments. Spreading depression (SD) can enhance brain injury if it occurs less than a day before ischemia. However, SD also can reduce injury if it occurs 1-3 days before ischemia, so-called ischemic tolerance. Thus, neural cells and tissues have an endogenous ability to modulate the extent of their own injury. SD itself is noninjurious. Furthermore it induces astrogliosis over the same time period as SD- induced ischemic tolerance. Since glia vitalize neurons, SD-induced gliosis may be a key transformation needed for the development of SD- induced tolerance to ischemic injury. Accordingly, the general goal of this proposal is to define the fundamental signaling mechanisms responsible for SD and so begin to define the basic triggers needed for SD-induced gliosis and SD-induced tolerance to excitotoxic injury. Experiments will systematically combine an innovative in vitro preparation with modern investigative tools to explore fundamental physiologic and anatomic changes of SID. Hippocampal organ cultures (HOTCs) will be used throughout this project because: (A) the HOTC is an intact area of brain tissue that maintains many cell-to-cell relationships found in vivo yet HOTCs survive in vitro for months; (B) microenvironmental conditions of HOTCs can be easily controlled; (C) individual cells within the HOTC can be followed in space and time; (D) we have shown that HOTCs support SD and develop astrogliosis like that seen in vivo. Thus, SD, SD-induced gliosis and SD-induced tolerance which require days to evolve, can now be examined for the first time in vitro. This means that the experimental advantages of easy access and microenvironmental control of in vitro preparations can be applied to answer 'mechanistic' questions at the cellular and molecular level of events that require intact tissues. Patch clamp technology, computer- based imaging strategies, and molecular biologic techniques will be used to accomplish the following specific aims. (1) Examine the spatiotemporal dynamics of gap junction functional changes between neurons and between astrocytes associated with SD. (2) Examine the spatiotemporal changes and identity of SD-induced currents in hippocampal pyramidal cells. (3) Examine the mechanisms of cellular and interstitial Ca2+ changes of SD. (4) Examine how modulation of Ca2+ or acid-base changes of SD influence SD-induced gliosis and tolerance to excitotoxic injury.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS019108-18
Application #
6330411
Study Section
Special Emphasis Panel (ZRG1-BDCN-3 (01))
Program Officer
Behar, Toby
Project Start
1983-04-01
Project End
2003-11-30
Budget Start
2000-12-01
Budget End
2001-11-30
Support Year
18
Fiscal Year
2001
Total Cost
$282,773
Indirect Cost
Name
University of Chicago
Department
Neurology
Type
Schools of Medicine
DUNS #
225410919
City
Chicago
State
IL
Country
United States
Zip Code
60637
Grinberg, Yelena Y; Zitzow, Lois A; Kraig, Richard P (2017) Intranasally administered IGF-1 inhibits spreading depression in vivo. Brain Res 1677:47-57
Ochocinska, Margaret J; Zlokovic, Berislav V; Searson, Peter C et al. (2017) NIH workshop report on the trans-agency blood-brain interface workshop 2016: exploring key challenges and opportunities associated with the blood, brain and their interface. Fluids Barriers CNS 14:12
Pusic, Kae M; Pusic, Aya D; Kraig, Richard P (2016) Environmental Enrichment Stimulates Immune Cell Secretion of Exosomes that Promote CNS Myelination and May Regulate Inflammation. Cell Mol Neurobiol 36:313-325
Pusic, Aya D; Mitchell, Heidi M; Kunkler, Phillip E et al. (2015) Spreading depression transiently disrupts myelin via interferon-gamma signaling. Exp Neurol 264:43-54
Pusic, Aya D; Kraig, Richard P (2015) Phasic Treatment with Interferon Gamma Stimulates Release of Exosomes that Protect Against Spreading Depression. J Interferon Cytokine Res 35:795-807
Pusic, Aya D; Pusic, Kae M; Clayton, Benjamin L L et al. (2014) IFN?-stimulated dendritic cell exosomes as a potential therapeutic for remyelination. J Neuroimmunol 266:12-23
Pusic, Aya D; Pusic, Kae M; Kraig, Richard P (2014) What are exosomes and how can they be used in multiple sclerosis therapy? Expert Rev Neurother 14:353-5
Pusic, Kae M; Pusic, Aya D; Kemme, Jordan et al. (2014) Spreading depression requires microglia and is decreased by their M2a polarization from environmental enrichment. Glia 62:1176-94
Pusic, Aya D; Kraig, Richard P (2014) Youth and environmental enrichment generate serum exosomes containing miR-219 that promote CNS myelination. Glia 62:284-99
Grinberg, Yelena Y; Dibbern, Megan E; Levasseur, Victoria A et al. (2013) Insulin-like growth factor-1 abrogates microglial oxidative stress and TNF-? responses to spreading depression. J Neurochem 126:662-72

Showing the most recent 10 out of 60 publications