Chronic fornix deep brain stimulation in a transgenic Alzheimer’s rat model reduces amyloid burden, inflammation, and neuronal loss

Leplus, Aurélie; Lauritzen, Inger; Melon, Christophe; Goff, Lydia Kerkerian‐Le; Fontaine, Denys; Checler, Frédéric

doi:10.1007/s00429-018-1779-x

Cited by 52 publications

(46 citation statements)

References 29 publications

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“…In the present study, we confirmed that fornix stimulation within the Papez circuit could induce NAc activity and further efflux of dopamine. These findings are consistent with our large-animal fMRI and FSCV study of fornix stimulation (Ross et al, 2016) and a relevant recent rat study that showed that chronic forniceal DBS significantly reduces amyloid deposition in the hippocampus and cortex, decreases astrogliosis and microglia activation, and lowers neuronal loss (Leplus et al, 2019). The micro-PET results revealed that fornix stimulation increases glucose metabolism in medial limbic circuits, including the hippocampus, mammillary bodies, and anteromedial thalamus.…”

Section: Discussionsupporting

confidence: 92%

Fornix Stimulation Induces Metabolic Activity and Dopaminergic Response in the Nucleus Accumbens

et al. 2019

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The Papez circuit, including the fornix white matter bundle, is a well-known neural network that is involved in multiple limbic functions such as memory and emotional expression. We previously reported a large-animal study of deep brain stimulation (DBS) in the fornix that found stimulation-induced hemodynamic responses in both the medial limbic and corticolimbic circuits on functional resonance imaging (fMRI) and evoked dopamine responses in the nucleus accumbens (NAc), as measured by fast-scan cyclic voltammetry (FSCV). The effects of DBS on the fornix are challenging to analyze, given its structural complexity and connection to multiple neuronal networks. In this study, we extend our earlier work to a rodent model wherein we characterize regional brain activity changes resulting from fornix stimulation using fludeoxyglucose (18F-FDG) micro positron emission tomography (PET) and monitor neurochemical changes using FSCV with pharmacological confirmation. Both global functional changes and local changes were measured in a rodent model of fornix DBS. Functional brain activity was measured by micro-PET, and the neurochemical changes in local areas were monitored by FSCV. Micro-PET images revealed increased glucose metabolism within the medial limbic and corticolimbic circuits. Neurotransmitter efflux induced by fornix DBS was monitored at NAc by FSCV and identified by specific neurotransmitter reuptake inhibitors. We found a significant increase in the metabolic activity in several key regions of the medial limbic circuits and dopamine efflux in the NAc following fornix stimulation. These results suggest that electrical stimulation of the fornix modulates the activity of brain memory circuits, including the hippocampus and NAc within the dopaminergic pathway.

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Section: Discussionsupporting

confidence: 92%

Fornix Stimulation Induces Metabolic Activity and Dopaminergic Response in the Nucleus Accumbens

et al. 2019

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“…The animal disease models that are used to assess the efficacy of neurostimulation therapies are several (Table 1). The main categories are represented by animal models of neurodegenerative disease such as Parkinson’s disease (Badstuebner et al, 2017; Musacchio et al, 2017), Alzheimer’s disease (Leplus et al, 2018), epilepsy (Desai et al, 2016), sensory-motor deficits due to spinal cord injury (Capogrosso et al, 2018), blindness (Tang et al, 2018), hearing loss conditions (Allitt et al, 2016) and ischemic models (Yang et al, 2017). Large animals such as cats, dogs, sheep, pigs, and non-human primates, are used for chronic studies on the efficacy and safety of neural stimulators.…”

Section: Experimental Models To Study Foreign Body Response To Neuralmentioning

confidence: 99%

Tissue Response to Neural Implants: The Use of Model Systems Toward New Design Solutions of Implantable Microelectrodes

et al. 2019

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The development of implantable neuroelectrodes is advancing rapidly as these tools are becoming increasingly ubiquitous in clinical practice, especially for the treatment of traumatic and neurodegenerative disorders. Electrodes have been exploited in a wide number of neural interface devices, such as deep brain stimulation, which is one of the most successful therapies with proven efficacy in the treatment of diseases like Parkinson or epilepsy. However, one of the main caveats related to the clinical application of electrodes is the nervous tissue response at the injury site, characterized by a cascade of inflammatory events, which culminate in chronic inflammation, and, in turn, result in the failure of the implant over extended periods of time. To overcome current limitations of the most widespread macroelectrode based systems, new design strategies and the development of innovative materials with superior biocompatibility characteristics are currently being investigated. This review describes the current state of the art of in vitro, ex vivo , and in vivo models available for the study of neural tissue response to implantable microelectrodes. We particularly highlight new models with increased complexity that closely mimic in vivo scenarios and that can serve as promising alternatives to animal studies for investigation of microelectrodes in neural tissues. Additionally, we also express our view on the impact of the progress in the field of neural tissue engineering on neural implant research.

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“…This is supported by the view that large myelinated axons produce excitatory responses upon electrical stimulation [85]. Electrically stimulating the fornix proves to be effective in decreasing rates of cognitive decline [72,74], enhancing memory [15], aiding visuo-spatial memory [86], improving verbal recollection [15], reducing Aβ 42 -related plaques and neuroinflammation [76], decreasing astrogliosis and migroglia levels [76], and increasing metabolism [72,73].…”

Section: Discussionmentioning

confidence: 96%

“…BDNF and VEGF were also significantly increased 2.5 h after stimulation, suggesting that neurotrophic and proliferating factors are associated with electrical stimulation [40]. Chronic fornix DBS was performed in transgenic AD rats and showed Aβ 42 plaque clearance in the cortex and hippocampus [76]. Moreover, it decreased astrogliosis and microglial activation and partly rescued neuronal loss in both cortex and the hippocampus.…”

Section: Modulating Memory Loss With Dbsmentioning

confidence: 97%

“…In a preclinical study that was the first to report about chronic fornix DBS in a transgenic rat model of Alzheimer's disease, the effects of chronic fornix stimulation on amyloid burden, inflammation, and neuronal loss were investigated [76]. Researchers applied permanent, bilateral, and unipolar stimulation (130 Hz, 80 µs, 100 µA) 10 days after implantation surgery [76]. Results showed that amyloidosis, inflammatory responses, and neuronal loss decreased in both cortex and hippocampus after DBS in the fornix.…”

Section: Alzheimer's Disease (Ad)mentioning

confidence: 99%

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The effect of fornix deep brain stimulation in brain diseases

Liu

Temel

Boonstra

et al. 2020

Cell. Mol. Life Sci.

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Deep brain stimulation is used to alleviate symptoms of neurological and psychiatric disorders including Parkinson's disease, epilepsy, and obsessive-compulsive-disorder. Electrically stimulating limbic structures has been of great interest, and in particular, the region of the fornix. We conducted a systematic search for studies that reported clinical and preclinical outcomes of deep brain stimulation within the fornix up to July 2019. We identified 13 studies (7 clinical, 6 preclinical) that examined the effects of fornix stimulation in Alzheimer's disease (n = 9), traumatic brain injury (n = 2), Rett syndrome (n = 1), and temporal lobe epilepsy (n = 1). Overall, fornix stimulation can lead to decreased rates of cognitive decline (in humans), enhanced memory (in humans and animals), visuo-spatial memorization (in humans and animals), and improving verbal recollection (in humans). While the exact mechanisms of action are not completely understood, studies suggest fornix DBS to be involved with increased functional connectivity and neurotransmitter levels, as well as enhanced neuroplasticity.

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Chronic fornix deep brain stimulation in a transgenic Alzheimer’s rat model reduces amyloid burden, inflammation, and neuronal loss

Cited by 52 publications

References 29 publications

Fornix Stimulation Induces Metabolic Activity and Dopaminergic Response in the Nucleus Accumbens

Fornix Stimulation Induces Metabolic Activity and Dopaminergic Response in the Nucleus Accumbens

Tissue Response to Neural Implants: The Use of Model Systems Toward New Design Solutions of Implantable Microelectrodes

The effect of fornix deep brain stimulation in brain diseases

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