Chemogenetics-mediated acute inhibition of excitatory neuronal activity improves stroke outcome

Wang, Yachao; Galeffi, Francesca; Wang, Wei; Li, Xuan; Lu, Liping; Sheng, Huaxin; Hoffmann, Ulrich; Turner, Dennis A.; Yang, Wei

doi:10.1016/j.expneurol.2020.113206

Cited by 13 publications

(7 citation statements)

References 31 publications

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“…Furthermore, CLZ-ChemoNM produced functional changes in microPET images of the brain, in agreement with our previous findings that behavioral recovery is correlated with a reduction in diaschisis volume and activation of a corticostriatal recovery circuit [25,26]. We thus suggest that CLZ-ChemoNM has the potential to replace conventional electrical stimulation and other neuromodulatory methods to reverse post-stroke deficits [12]. Despite the promising potential of chemogenetic neuromodulation, there are two critical factors that need to be considered before the technique can be translated to humans: the safety and transduction efficiency of the virus and the pharmacodynamics of the DREADD agonist.…”

Section: Discussionsupporting

confidence: 90%

“…Recently, chemogenetic and optogenetic neuromodulation have revolutionized brain stimulation because these tools allow selective modulation of neural activity and mapping of brain circuits. Cortical stimulation using these new techniques has significant potential to treat brain disorders that require induction of brain plasticity (e.g., stroke) [10][11][12]. Optogenetic stimulation provides on-off control of neurons or neural circuits with millisecond precision; however, this technique requires not only the implantation of optical devices targeting the particular brain area but also the delivery of a considerable level of energy during prolonged stimulation [13].…”

Section: Introductionmentioning

confidence: 99%

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Clozapine-Induced Chemogenetic Neuromodulation Rescues Post-Stroke Deficits After Chronic Capsular Infarct

Cho

Ryu

Lee

et al. 2022

Transl. Stroke Res.

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Long-term disabilities induced by stroke impose a heavy burden on patients, families, caregivers, and public health systems. Extensive studies have demonstrated the therapeutic value of neuromodulation in enhancing post-stroke recovery. Among them, chemogenetic neuromodulation activated by clozapine-N-oxide (CNO) has been proposed as the potential tool of neuromodulation. However, recent evidence showed that CNO does not cross the blood − brain barrier and may in fact have low binding affinity for chemogenetic tool. Thus, clozapine (CLZ) has been suggested for use in chemogenetic neuromodulation, in place of CNO, because it readily crosses the blood–brain barrier. Previously we reported that low doses of CLZ (0.1 mg/kg) successfully induced neural responses without off-target effects. Here, we show that low-dose clozapine (0.1 mg/kg) can induce prolonged chemogenetic activation while avoiding permeability issues and minimizing off-target effects. In addition, clozapine-induced excitatory chemogenetic neuromodulation (CLZ-ChemoNM) of sensory-parietal cortex with hsyn-hM3Dq-YFP-enhanced motor recovery in a chronic capsular infarct model of stroke in rats, improving post-stroke behavioral scores to 56% of pre-infarct levels. Longitudinal 2-deoxy-2-[18F]-fluoro-D-glucose microPET (FDG-microPET) scans showed that a reduction in diaschisis volume and activation of corticostriatal circuits were both correlated with post-stroke recovery. We also found c-Fos increases in bilateral cortices and BDNF increases in the cortices and striatum after CLZ-ChemoNM, indicating an increase in neural plasticity. These findings suggest the translational feasibility of CLZ-ChemoNM for augmenting recovery in chronic stroke.

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Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Clozapine-Induced Chemogenetic Neuromodulation Rescues Post-Stroke Deficits After Chronic Capsular Infarct

Cho

Ryu

Lee

et al. 2022

Transl. Stroke Res.

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“…The back‐conversion of CNO to clozapine could cause complex effects including its interaction with other pharmacological agents including nicotine 40 . CNO alone does not affect rotarod learning, 97,98 and the dose used in our study (0.3 mg/kg) has been reported not to significantly affect baseline behaviors in rodents 40,99 . However, the potential interaction between CNO and nicotine should still be carefully inspected.…”

Section: Discussionmentioning

confidence: 80%

Chronic nicotine impairs sparse motor learning via striatal fast‐spiking parvalbumin interneurons

Kim

2020

Addiction Biology

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Nicotine can diversely affect neural activity and motor learning in animals. However, the impact of chronic nicotine on striatal activity in vivo and motor learning at long‐term sparse timescale remains unknown. Here, we demonstrate that chronic nicotine persistently suppresses the activity of striatal fast‐spiking parvalbumin interneurons, which mediate nicotine‐induced deficit in sparse motor learning. Six weeks of longitudinal in vivo single‐unit recording revealed that mice show reduced activity of fast‐spiking interneurons in the dorsal striatum during chronic nicotine exposure and withdrawal. The reduced firing of fast‐spiking interneurons was accompanied by spike broadening, diminished striatal delta oscillation power, and reduced sample entropy in local field potential. In addition, chronic nicotine withdrawal impaired motor learning with a weekly sparse training regimen but did not affect general locomotion and anxiety‐like behavior. Lastly, the excitatory DREADD hM3Dq‐mediated activation of striatal fast‐spiking parvalbumin interneurons reversed the chronic nicotine withdrawal‐induced deficit in sparse motor learning. Taken together, we identified that chronic nicotine withdrawal impairs sparse motor learning via disruption of activity in striatal fast‐spiking parvalbumin interneurons. These findings suggest that sparse motor learning paradigm can reveal the subtle effect of nicotine withdrawal on motor function and that striatal fast‐spiking parvalbumin interneurons are a neural substrate of nicotine's effect on motor learning.

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“…A 48-point scoring system was utilized to assess neurological deficits, as described previously [ 18 ]. This scoring system includes general status (spontaneous activity, body symmetry, and gait; 0-12), simple motor deficit (forelimb asymmetry, circling, and hind-limb placement; 0-14), complex motor deficits (vertical screen climbing and beam walking; 0-8), and sensory deficits (hind limb, trunk, vibrissae, and face touch; 0-14).…”

Section: Methodsmentioning

confidence: 99%

A Linarin Derivative Protects against Ischemia-Induced Neuronal Injury in Mice by Promoting Cerebral Blood Flow Recovery via KDELR-Dependent CSPG4 Activation

Xie

Yue

et al. 2022

Oxidative Medicine and Cellular Longevity

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The cerebral ischemic microvascular response and collateral circulation compensatory capacity are important for the outcome of ischemic stroke. Here, we sought to evaluate the effect of a linarin derivate 4 ′ -benzylapigenin-7-β-rutinoside (BLR) on neurological function and cerebral blood flow restoration in ischemic stroke. A mouse model of middle cerebral artery occlusion (30 min) with reperfusion (24 h) was used to mimic ischemic stroke in vivo, and 2,3,5-triphenyltetrazolium chloride (TTC) staining, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays, and immunofluorescence microscopy were used to assess the protective effects of BLR on infarct volume, neurological function, neuronal apoptosis, and inflammatory damage. Cerebral blood flow was assayed by laser speckle contrast imaging. Double immunostaining of GFAP-collagen IV and brain lucidification were performed to determine the protective effects of BLR on the disruption of brain vasculature. Differential gene expression was assessed by RNA sequencing. Coimmunoprecipitation and western blotting were used to explore the mechanism of BLR-induced neuroprotection. The results of in vivo experiments showed that BLR administration after reperfusion onset reduced infarct volume, improved neurological function, and decreased the neural cell apoptosis and inflammatory response in the ischemic brain, which was accompanied by increased cerebral blood flow and reduced detachment of astrocyte endfeet from the capillary basement membrane. The RNA sequencing data showed that BLR promoted the upregulation of extracellular matrix and angiogenesis pathway-related genes; in particular, BLR significantly increased the expression of the chondroitin sulfate proteoglycan 4 (CSPG4) gene, enhanced the membrane location of CSPG4, and promoted its downstream signaling protein expression, which is associated with KDEL receptor (KDELR) activation. In addition, activated KDELR further increased the phosphorylation of mitogen-activated protein kinases after BLR treatment. Taken together, our data showed that BLR could protect against ischemic brain injury and may serve as a new promising therapeutic candidate drug for ischemic stroke, and that KDELR might act as both a sensor and effector to activate CSPG4 to increase cerebral blood flow.

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Chemogenetics-mediated acute inhibition of excitatory neuronal activity improves stroke outcome

Cited by 13 publications

References 31 publications

Clozapine-Induced Chemogenetic Neuromodulation Rescues Post-Stroke Deficits After Chronic Capsular Infarct

Clozapine-Induced Chemogenetic Neuromodulation Rescues Post-Stroke Deficits After Chronic Capsular Infarct

Chronic nicotine impairs sparse motor learning via striatal fast‐spiking parvalbumin interneurons

A Linarin Derivative Protects against Ischemia-Induced Neuronal Injury in Mice by Promoting Cerebral Blood Flow Recovery via KDELR-Dependent CSPG4 Activation

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