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Role of Thalamus in Post-stroke epileptogenesis

丘脑在中风后癫痫发生中的作用

基本信息

批准号：
8881344
负责人：
Jeanne T Paz
金额：
$ 24.9万
依托单位：
J. DAVID GLADSTONE INSTITUTES
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-01 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8881344
关键词：
Animals Area Axon Behavioral Biological Neural Networks Cell Death Cell Nucleus Cells Cerebral cortex Child Data Development Elderly Electrodes Electroencephalography Electrophysiology (science)Epilepsy Epileptogenesis Equilibrium Evolution Frequencies Generalized Epilepsy Glutamates Goals Hyperactive behavior Image Impaired health In Vitro Infarction Injury Lasers Lead Learning Maps Mediating Mentors Methodology Neuronal Plasticity Neurons Outcome Output Parkinson Disease Partial Epilepsies Phase Probability Rattus Recovery Recovery of Function Research Proposals Role Seizures Sensory Slice Somatosensory Cortex Source Stroke Synapses Techniques Technology Thalamic Nuclei Thalamic structure Therapeutic Time Training base complement C2a design disability extracellular in vivo inhibitory neuron injured insight nervous system disorder neural circuit optogenetics patch clamp post stroke presynaptic prevent research study

项目摘要

Stroke in the cerebral cortex is a major source of disability and a common cause of epilepsy in the elderly and in children. Neural plasticity after stroke that tends to compensate lost functions involves reorganization of the surviving neural circuits. However, some aspects of the reorganization might be maladaptive and lead to epileptogenesis over time. Thalamocortical circuits mediate neural network oscillations associated with epilepsy. While there is a large body of evidence supporting thalamic involvement in the generalized idiopathic epilepsies, very little is known about the role of thalamus in post-injury epileptogenesis. Cortical infarcts lead to retrograde cell death of a subset of excitatory but not inhibitory thalamic cells. My preliminary data indicate that after several weeks following focal cortical infarcts, isolated thalamic slices (that do not contain the cortex) spontaneously generate epileptiform network oscillations. This is paralleled by increases in intra-thalamic excitatory connectivity and decreases in intra-thalamic inhibition. Surprisingly, despite a major loss of excitatory afferents from the cortex, synaptic excitation is enhanced in thalamocortical cells located in the gliotic area functionally related to the region of focal cortical stroke. Altogether, these results suggest that cortical infarcts lead to robust circuit rewiring within the thalamus. Some aspects of this reorganization could support functional recovery. For example, reduced inhibition of relay nuclei could increase the output of TC cells and enhance thalamocortical excitation, which may facilitate recovery of thalamic and cortical sensory circuits. However, the presence of epileptiform network oscillations in the injured thalamus suggests that some aspects of the thalamic reorganization could be maladaptive, participating in injury-induced epilepsy. The two main goals of this research proposal are as follows: (1) To determine the mechanisms underlying the aberrant network excitability and synaptic excitation in the thalamus; (2) To determine whether this enhanced activity in the injured thalamus might amplify corticothalamic network excitability and contribute to epileptogenesis. These questions are crucial to our understanding of the mechanisms of post-stroke thalamocortical reorganization leading to epilepsy. I have designed several experiments to answer these goals. Several of them rely on techniques optrodes using optogenetic approaches in vivo , glutamate imaging, laser photostimulation/ glutamate uncaging, EEG recordings in freely moving animals that I will learn from my mentor and consultants who have agreed to train me during the mentored phase of the proposal. My long- term goal is to continue studying the mechanisms generating abnormal neural network oscillations associated with neurological disorders such as epilepsy or Parkinson's disease in an independent academic setting.

大脑皮层中风是残疾的主要来源，也是老年人癫痫的常见原因