2012 — 2016 |
Paz, Jeanne T [⬀] |
K99Activity Code Description: To support the initial phase of a Career/Research Transition award program that provides 1-2 years of mentored support for highly motivated, advanced postdoctoral research scientists. R00Activity Code Description: To support the second phase of a Career/Research Transition award program that provides 1 -3 years of independent research support (R00) contingent on securing an independent research position. Award recipients will be expected to compete successfully for independent R01 support from the NIH during the R00 research transition award period. |
Role of Thalamus in Post-Stroke Epileptogenesis
DESCRIPTION (provided by applicant): 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 cortial 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. PUBLIC HEALTH RELEVANCE: Stroke in the cerebral cortex is a major source of disability and a common cause of epilepsy. Recovery of function after stroke involves not only surviving neural circuits but also the establishment of new neural circuits. This proposal aims to understand how neural circuits reorganize after stroke and what aspects of this reorganization can lead to epilepsy. This may lead into new insights on therapeutic approaches that promote functional recovery while limiting its health-impairing outcomes and preventing epilepsy.
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0.975 |
2016 — 2021 |
Paz, Jeanne T |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
The Role of Inflammation in Post-Stroke Epileptogenesis @ J. David Gladstone Institutes
? DESCRIPTION (provided by applicant): Epilepsy is a common consequence of brain insults, such as brain injuries, status epilepticus, and cerebrocortical stroke in the elderly and children. Despite ongoing research, there are no treatments that prevent epilepsy after brain insults. Each year, 15 million people worldwide suffer a stroke. Stroke is followed by a latent period (month to years) during which the brain goes through changes leading to the onset of chronic epilepsy. Understanding the maladaptive process so the development of epilepsy (epileptogenesis) during the latent period can be prevented or treated is the holy grail of epilepsy research. Our preliminary data that form the basis of this proposal suggest that persistent inflammation involving glial cells may be a key component of epileptogenesis after stroke in rats. We previously found that cerebrocortical stroke leads to neural reorganization in the thalamocortical system and that the thalamus becomes hyperexcitable within the first week after stroke. Silencing the thalamic hot spot with optogenetic tools is sufficient to abort the epileptic seizures in real-time. We previously showed these hot spots to be causally involved in epileptic seizures (after the onset of chronic post-stroke epilepsy). They are associated with neural circuit plasticity co-localized with a permanent and focal astrogliosis and microgliosis and a massive upregulation of C1q, an immune molecule of the complement cascade, in the region that is causally involved in epileptic seizures. C1q is known for its role in synaptic pruning and circuit plasticity during normal development in the visual system, but our findings suggest that C1q may have a role in circuit plasticity after brain insults such as stroke. Our pilot data indicae that anti-inflammatory treatments that modify the gliosis also prevent the circuit hyperexcitabilit and deficits in synaptic inhibition and that selectively inducing gliosis via viral approaches phenocopies the deficits in synaptic inhibition and induces circuit hyperexcitability. We hypothesize that the glial-induced inflammation and C1q in the thalamus have key roles in the maladaptive cellular and circuit plasticity that leads from stroke to epilepsy. The goal of the proposed research is to determine the role of gliosis in epileptogenic circuit reorganization in th thalamocortical system. We will combine cellular physiology, systems neuroscience, and bioengineering to determine whether gliosis and/or blocking C1q actions after stroke will prevent epileptogenesis and whether disrupting the gliosis and blocking C1q actions during the chronic epileptic phase (i.e., after epilepsy has developed) will be sufficient to go back in time to modify the disease and cure epilepsy. This project may lead to novel biomarkers in epilepsy (thalamic gliosis and C1q) and novel treatments to prevent epilepsy after brain lesions, such as stroke.
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0.975 |
2020 — 2021 |
Paz, Jeanne T |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
The Role of Arteriogenesis On Structural and Functional Neurovascular Recovery After Cerebral Stroke @ J. David Gladstone Institutes
SUMMARY Cerebral stroke leads to long-term disability, yet post-stroke treatment remains primarily limited to rehabilitation. The partial functional recovery that does occur is due in part to neurovascular plasticity of the brain region adjacent to stroke damage?the peri-stroke penumbra. However, attempts to manipulate the neurovasculature post-stroke by promoting angiogenesis?sprouting of new capillary vessels?have not been successful, in part because angiogenesis can lead to tortuous, leaky vessels that do not increase blood flow. Alternatively, arteriogenesis?the generation of large-bore vessels in response to shear stress?could play an important role in post-stroke recovery and represent a novel therapeutic target. However, the lack of tools to specifically manipulate arteriogenesis has hampered efforts to test this hypothesis. We identified Dach1 as an endothelial transcription factor as a tool to specifically drive arteriogenesis. Here, we will use new mouse models that allow us to bi-directionally control Dach1 levels in endothelial cells, to determine to what extent arteriogenesis is involved in post-stroke recovery of brain functions. Specifically, we will examine the links between arteriogenesis and post-stroke recovery of the vascular network (Aim 1), neurovascular coupling (Aim 2), and behavior (Aim 3). Our long-term goal is to understand the mechanisms of adaptive post-stroke neurovascular plasticity to develop new treatments and improve brain health. Funding of this proposal will enable an unbiased study of the brain following stroke with unprecedented temporal and spatial resolution in freely behaving animals, identify the specific role of arteriogenesis in post-stroke recovery, and may unveil new therapeutic targets that enhance the therapeutic window of post-stroke rehabilitation, which is a key limiting factor in treating stroke patients.
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0.975 |