Chemogenetics-mediated acute inhibition of excitatory neuronal activity improves stroke outcome.
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2020-04
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Abstract
Background and purpose
Ischemic stroke significantly perturbs neuronal homeostasis leading to a cascade of pathologic events causing brain damage. In this study, we assessed acute stroke outcome after chemogenetic inhibition of forebrain excitatory neuronal activity.Methods
We generated hM4Di-TG transgenic mice expressing the inhibitory hM4Di, a Designer Receptors Exclusively Activated by Designer Drugs (DREADD)-based chemogenetic receptor, in forebrain excitatory neurons. Clozapine-N-oxide (CNO) was used to activate hM4Di DREADD. Ischemic stroke was induced by transient occlusion of the middle cerebral artery. Neurologic function and infarct volumes were evaluated. Excitatory neuronal suppression in the hM4Di-TG mouse forebrain was assessed electrophysiologically in vitro and in vivo, based on evoked synaptic responses, and in vivo based on occurrence of potassium-induced cortical spreading depolarizations.Results
Detailed characterization of hM4Di-TG mice confirmed that evoked synaptic responses in both in vitro hippocampal slices and in vivo motor cortex were significantly reduced after CNO-mediated activation of the inhibitory hM4Di DREADD. Further, CNO treatment had no obvious effects on physiology and motor function in either control or hM4Di-TG mice. Importantly, hM4Di-TG mice treated with CNO at either 10 min before ischemia or 30 min after reperfusion exhibited significantly improved neurologic function and smaller infarct volumes compared to CNO-treated control mice. Mechanistically, we showed that potassium-induced cortical spreading depression episodes were inhibited, including frequency and duration of DC shift, in CNO-treated hM4Di-TG mice.Conclusions
Our data demonstrate that acute inhibition of a subset of excitatory neurons after ischemic stroke can prevent brain injury and improve functional outcome. This study, together with the previous work in optogenetic neuronal modulation during the chronic phase of stroke, supports the notion that targeting neuronal activity is a promising strategy in stroke therapy.Type
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Wang, Ya-Chao, Francesca Galeffi, Wei Wang, Xuan Li, Liping Lu, Huaxin Sheng, Ulrike Hoffmann, Dennis A Turner, et al. (2020). Chemogenetics-mediated acute inhibition of excitatory neuronal activity improves stroke outcome. Experimental neurology, 326. p. 113206. 10.1016/j.expneurol.2020.113206 Retrieved from https://hdl.handle.net/10161/23241.
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Scholars@Duke
Huaxin Sheng
We have successfully developed various rodent models of brain and spinal cord injuries in our lab, such as focal cerebral ischemia, global cerebral ischemia, head trauma, subarachnoid hemorrhage, intracerebral hemorrhage, spinal cord ischemia and compression injury. We also established cardiac arrest and hemorrhagic shock models for studying multiple organ dysfunction. Our current studies focus on two projects. One is to examine the efficacy of catalytic antioxidant in treating cerebral ischemia and the other is to examine the efficacy of post-conditioning on outcome of subarachnoid hemorrhage induced cognitive dysfunction.
Dennis Alan Turner
Current clinical research interests include clinical trials regarding adaptive or closed-loop deep brain stimulation with novel devices, cellular, and gene therapy in Parkinson disease. Additional trials have included gene therapy for Alzheimer's disease and sensory restoration for development of brain machine interfaces. Clinical treatments include deep brain stimulation, which is now a common procedure for treating Parkinson disease and tremor. Translational approaches include testing new devices and stimulation patterns in the operating room. Pre-clinical research interests focus on evaluation of cerebral perfusion and metabolism changes with stroke, aging and Alzheimer's disease, using both in vivo and in vitro approaches. These basic science interests include new approaches to cerebral blood flow enhancement with brain stimulation, optical imaging of the brain, cellular understanding of metabolism using direct substrate recordings (ie, oxygen, glucose, lactate, respirometry) and developing new methods to understand neurovascular coupling, analyzing complex interactions between neurons, astrocytes and blood vessels. Further interests include changes in cerebral blood flow with stroke and enhanced recovery after stroke.
Wei Yang
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