Intensity-Dependent Gamma Electrical Stimulation Regulates Microglial Activation, Reduces Beta-Amyloid Load, and Facilitates Memory in a Mouse Model of Alzheimer's Disease

Liu, Qian; Contreras, Adam; Afaq, Muhammad Shan; Yang, Wankou; Hsu, Daniel K.; Russell, Michael J.; Lyeth, Bruce G.; Zanto, Theodore P.; Zhao, Min

doi:10.2139/ssrn.4168479

Cited by 3 publications

(6 citation statements)

References 57 publications

(54 reference statements)

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“…Endogenous neurogenesis can be induced by exogenous chemical and physical stimulations. Our work contributed to this discussion, showing that electric stimulation can promote neuronal differentiation from neural stem cells, and enhance endogenous neurogenesis in healthy and AD rat brain 21,22,28 . For the underlying molecular mechanism, we have observed the phosphoinositide‐3‐kinase (PI3K)/Akt (also called protein kinase B or PKB)/Glycogen xynthase kinase‐3 beta (GSK‐3β)/β‐catenin pathway in previous study.…”

Section: Discussionmentioning

confidence: 72%

“…Our work contributed to this discussion, showing that electric stimulation can promote neuronal differentiation from neural stem cells, and enhance endogenous neurogenesis in healthy and AD rat brain. 21,22,28 For the underlying molecular mechanism, we have observed the phosphoinositide-3-kinase (PI3K)/Akt (also called protein kinase B or PKB)/Glycogen xynthase kinase-3 beta (GSK-3β)/β-catenin pathway in previous study. Here, to further explore the underlying mechanism and primary regulating gene, we dissected the snRNA-seq data for the gene expression changes by iACS, finding Rgs9 as a unique downregulating gene under the ips-iACS.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, we also observed an augmentation in neuronal differentiation of neural stem cells by in vitro electric stimulation. [21][22][23] These preliminary studies inspired further exploration on the precise cellular and genetic mechanisms by EBS, an area of research that, to our knowledge, remains largely unexplored.…”

Section: Introductionmentioning

confidence: 99%

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Transcriptomic analysis of rat brain response to alternating current electrical stimulation: unveiling insights via single‐nucleus RNA sequencing

Wang,

Ma,

Zhong

et al. 2024

MedComm

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Electrical brain stimulation (EBS) has gained popularity for laboratory and clinical applications. However, comprehensive characterization of cellular diversity and gene expression changes induced by EBS remains limited, particularly with respect to specific brain regions and stimulation sites. Here, we presented the initial single‐nucleus RNA sequencing profiles of rat cortex, hippocampus, and thalamus subjected to intracranial alternating current stimulation (iACS) at 40 Hz. The results demonstrated an increased number of neurons in all three regions in response to iACS. Interestingly, less than 0.1% of host gene expression in neurons was significantly altered by iACS. In addition, we identified Rgs9, a known negative regulator of dopaminergic signaling, as a unique downregulated gene in neurons. Unilateral iACS produced a more focused local effect in attenuating the proportion of Rgs9+ neurons in the ipsilateral compared to bilateral iACS treatment. The results suggested that unilateral iACS at 40 Hz was an efficient approach to increase the number of neurons and downregulate Rgs9 gene expression without affecting other cell types or genes in the brain. Our study presented the direct evidence that EBS could boost cerebral neurogenesis and enhance neuronal sensitization to dopaminergic drugs and agonists, through its downregulatory effect on Rgs9 in neurons.

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Section: Discussionmentioning

confidence: 72%

Section: Discussionmentioning

confidence: 99%

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Transcriptomic analysis of rat brain response to alternating current electrical stimulation: unveiling insights via single‐nucleus RNA sequencing

Wang,

Ma,

Zhong

et al. 2024

MedComm

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“…The tACS was delivered through an 8-channel mobile Starstim device (Neuroelectrics, Spain) with NG Pistim electrodes (contact area: 3.14 cm 2 ). On each session, the tACS current was ramped up slowly over 4 min to a total of 1.6 mA (0.4 mA per electrode baseline to peak, with ( Liu et al, 2022 ) the 4 contralateral electrodes set to 180° offset), maintained full strength for 52 min, then ramp back down to 0 mA over 4 min. The electrode configuration was selected based on models of the tACS electric field (EF) distribution, where we sought to target multiple regions of the cortex known to be related to episodic memory processing: the Hipp, IPL, and Pars.…”

Section: Methodsmentioning

confidence: 99%

“…Using NIC2 software (Neuroelectrics, Spain), we identified the electrode configuration that achieved a balanced EF distribution across our ROIs. The current intensity was selected based on our preliminary research in mouse models of AD (under review: Liu et al, 2022 ), which tested whether there was a dose-response curve between gamma stimulation strengths and efficacy. We observed that higher current intensities of gamma stimulation had the strongest effects.…”

Section: Methodsmentioning

confidence: 99%

Gamma neuromodulation improves episodic memory and its associated network in amnestic mild cognitive impairment: a pilot study

Jones¹,

Gallen²,

Ostrand³

et al. 2023

Neurobiology of Aging

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Impairment of hippocampal astrocyte-mediated striatal dopamine release and locomotion in Alzheimer’s disease

Tournier,

Ceyzériat,

Badina

et al. 2023

Preprint

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Clinical and translational research has identified deficits in the dopaminergic neurotransmission in the striatum in Alzheimer’s disease (AD) and this could be related to the pathophysiology of psychiatric symptoms appearing even at early stages of the pathology. We hypothesized that AD pathology in the hippocampus may influence dopaminergic neurotransmission even in the absence of AD-related lesion in the mesostriatal circuit. We thus chemogenetically manipulated the activity of hippocampal neurons and astrocytes in wild-type and hemizygous TgF344-AD (Tg) rats, an animal model of AD pathology. We assessed the brain-wide functional output of this manipulation usingin vivoSingle Photon Emission Computed Tomography to measure cerebral blood flow and D2/3receptor binding. We also assessed the effects of the chemogenetic manipulations on astrocytic and microglial capacity to surround and phagocytize Aβ both locally and in the striatum. Our results show that acute and chronic neuronal and astrocytic stimulation induces widespread effects on the brain regional activation pattern, notably with an inhibition of striatal activation. In the TgF344-AD rats, both these effects were blunted. Chemogenetic stimulation in the hippocampus increased microglial density and its capacity to limit AD pathology, whereas these effects were absent in the striatum perhaps as a consequence of the altered connectivity between the hippocampus and the striatum. Our work suggests that hippocampal AD pathology may alter mesostriatal signalling and induce widespread alterations of brain activity. Neuronal and astrocytic activation may induce a protective, Aβ-limiting phenotype of microglia, which surrounds Aβ plaques and limits Αβ concentration more efficiently.

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Intensity-Dependent Gamma Electrical Stimulation Regulates Microglial Activation, Reduces Beta-Amyloid Load, and Facilitates Memory in a Mouse Model of Alzheimer's Disease

Cited by 3 publications

References 57 publications

Transcriptomic analysis of rat brain response to alternating current electrical stimulation: unveiling insights via single‐nucleus RNA sequencing

Transcriptomic analysis of rat brain response to alternating current electrical stimulation: unveiling insights via single‐nucleus RNA sequencing

Gamma neuromodulation improves episodic memory and its associated network in amnestic mild cognitive impairment: a pilot study

Impairment of hippocampal astrocyte-mediated striatal dopamine release and locomotion in Alzheimer’s disease

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