In vivo functional brain mapping in a conditional mouse model of human tauopathy (taup301l) reveals reduced neural activity in memory formation structures

Pérez, Pablo D.; Hall, Gabrielle; Kimura, Tetsuya; Ren, Yan; Bailey, Rachel M.; Lewis, Jada; Febo, Marcelo; Sahara, Naruhiko

doi:10.1186/1750-1326-8-9

Cited by 38 publications

(42 citation statements)

References 41 publications

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“…Another study by Perez and colleagues observed neuronal dysfunction in the CA3 of five-month-old rTg4510 mice using MEMRI (Perez et al, 2013). Since tau pathology ensues well before five months in rTg4510 mice, it was reasonable to measure changes at earlier time points, which led us to identify MEMRI deficits as early as three months of age in rTg4510 mice (Fig.…”

Section: Discussionmentioning

confidence: 99%

Identification of changes in neuronal function as a consequence of aging and tauopathic neurodegeneration using a novel and sensitive magnetic resonance imaging approach

Fontaine

Ingram

Cloyd

et al. 2017

Neurobiology of Aging

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Tauopathies, the most common of which is Alzheimer’s disease (AD), constitute the most crippling neurodegenerative threat to our aging population. Tauopathic patients have significant cognitive decline accompanied by irreversible and severe brain atrophy, and it is thought that neuronal dysfunction begins years before diagnosis. Our current understanding of tauopathies has yielded promising therapeutic interventions but have all failed in clinical trials. This is partly due to the inability to identify and intervene in an effective therapeutic window early in the disease process. A major challenge that contributes to the definition of an early therapeutic window is limited technologies. To address these challenges, we modified and adapted a manganese-enhanced magnetic resonance imaging (MEMRI) approach to provide sensitive and quantitative power to detect changes in broad neuronal function in aging mice. Considering that tau tangle burden correlates well with cognitive impairment in Alzheimer’s patients, we performed our MEMRI approach in a time course of aging mice and an accelerated mouse model of tauopathy. We measured significant changes in broad neuronal function as a consequence of age and, in transgenic mice, before the deposition of bona fide tangles. This MEMRI approach represents the first diagnostic measure of neuronal dysfunction in mice. Successful translation of this technology in the clinic could serve as a sensitive diagnostic tool for the definition of effective therapeutic windows.

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Section: Discussionmentioning

confidence: 99%

Identification of changes in neuronal function as a consequence of aging and tauopathic neurodegeneration using a novel and sensitive magnetic resonance imaging approach

Fontaine

Ingram

Cloyd

et al. 2017

Neurobiology of Aging

View full text Add to dashboard Cite

show abstract

“…Despite such potential limitations, significant attempts have been made, in recent years, to use MEMRI in studies of the pathobiology of neurodegenerative diseases utilizing relevant animal models (Bertrand et al 2013; Perez et al 2013; Drobyshevsky et al 2012; Haenold et al 2012; Morken et al 2013; Saito et al 2012; Wideroe et al 2012; Bouilleret et al 2011; Chan et al 2011; Kim et al 2011; Smith et al 2011; Soria et al 2011; Tang et al 2011; Wideroe et al 2011; Inoue et al 2010; Kawai et al 2010; van Meer et al 2010). Nonetheless and paramount to the successful application of MEMRI is not simply the ability to deliver Mn 2+ to the site of interest or of disease but in determining the cell types and cellular mechanisms that engage the ion and produce the signal enhancement observed.…”

Section: Introductionmentioning

confidence: 99%

Improved Visualization of Neuronal Injury Following Glial Activation by Manganese Enhanced MRI

Bade

Zhou

Epstein

et al. 2013

J Neuroimmune Pharmacol

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Research directed at anatomical, integrative and functional activities of the central nervous system (CNS) can be realized through bioimaging. A wealth of data now demonstrates the utility of magnetic resonance imaging (MRI) towards unraveling complex neural connectivity operative in health and disease. A means to improve MRI sensitivity is through contrast agents and notably manganese (Mn2+). The Mn2+ ions enter neurons through voltage-gated calcium channels and unlike other contrast agents such as gadolinium, iron oxide, iron platinum and imaging proteins, provide unique insights into brain physiology. Nonetheless, a critical question that remains is the brain target cells serving as sources for the signal of Mn2+ enhanced MRI (MEMRI). To this end, we investigated MEMRI’s abilities to detect glial (astrocyte and microglia) and neuronal activation signals following treatment with known inflammatory inducing agents. The idea is to distinguish between gliosis (glial activation) and neuronal injury for the MEMRI signal and as such use the agent as a marker for neural activity in inflammatory and degenerative disease. We now demonstrate that glial inflammation facilitates Mn2+ neuronal ion uptake. Glial Mn2+ content was not linked to its activation. MEMRI performed on mice injected intracranially with lipopolysaccharide was associated with increased neuronal activity. These results support the notion that MEMRI reflects neuronal excitotoxicity and impairment that can occur through a range of insults including neuroinflammation. We conclude that the MEMRI signal enhancement is induced by inflammation stimulating neuronal Mn2+ uptake.

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“…It is commonly assumed that NFT-bearing neurons exhibit deficits in synaptic integration and eventually lead to neurodegeneration (11,12). However, the actual functional properties of NFT-bearing neurons in intact neural circuits have not been explored previously (13).…”

mentioning

confidence: 99%

Neurofibrillary tangle-bearing neurons are functionally integrated in cortical circuits in vivo

Kuchibhotla

Wegmann

Kopeikina

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

179

136

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Alzheimer's disease (AD) is pathologically characterized by the deposition of extracellular amyloid-β plaques and intracellular aggregation of tau protein in neurofibrillary tangles (NFTs) (1, 2). Progression of NFT pathology is closely correlated with both increased neurodegeneration and cognitive decline in AD (3) and other tauopathies, such as frontotemporal dementia (4,5). The assumption that mislocalization of tau into the somatodendritic compartment (6) and accumulation of fibrillar aggregates in NFTs mediates neurodegeneration underlies most current therapeutic strategies aimed at preventing NFT formation or disrupting existing NFTs (7,8). Although several disease-associated mutations cause both aggregation of tau and neurodegeneration, whether NFTs per se contribute to neuronal and network dysfunction in vivo is unknown (9). Here we used awake in vivo two-photon calcium imaging to monitor neuronal function in adult rTg4510 mice that overexpress a human mutant form of tau (P301L) and develop cortical NFTs by the age of 7-8 mo (10). Unexpectedly, NFT-bearing neurons in the visual cortex appeared to be completely functionally intact, to be capable of integrating dendritic inputs and effectively encoding orientation and direction selectivity, and to have a stable baseline resting calcium level. These results suggest a reevaluation of the common assumption that insoluble tau aggregates are sufficient to disrupt neuronal function.paired helical filaments | tau pathology | neuronal networks N eurofibrillary tangles (NFTs) containing aggregated tau protein (1) have long been considered key players in the progressive neural dysfunction and neurodegeneration observed in Alzheimer's disease (AD) (2, 3) and other tauopathies (4, 5). It is commonly assumed that NFT-bearing neurons exhibit deficits in synaptic integration and eventually lead to neurodegeneration (11,12). However, the actual functional properties of NFT-bearing neurons in intact neural circuits have not been explored previously (13). We addressed this question directly using awake in vivo two-photon calcium imaging in a mouse model of NFT formation (rTg4510) by applying recently developed imaging approaches allowing for single-neuron-level and population-level assessment of neural activity in awake mice (14). Because two-photon calcium imaging allows for measurement of response properties in many neurons simultaneously, we were able to directly isolate the impact of NFT deposition in a neuronal microcircuit by evaluating population-level network dynamics and, more specifically, by differentiating the function of individual NFT-bearing and neighboring non-NFT-bearing neurons.To assess the functional properties of neurons in the visual cortex, we used a genetically encoded ratiometric calcium indicator, yellow cameleon 3.6 (YC3.6), packaged in an adenoassociated viral vector (15,16). To assess functional responses, we exploited the well-characterized functional architecture of visual cortex whereby neurons in mouse visual cortex modulate their activity d...

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In vivo functional brain mapping in a conditional mouse model of human tauopathy (taup301l) reveals reduced neural activity in memory formation structures

Cited by 38 publications

References 41 publications

Identification of changes in neuronal function as a consequence of aging and tauopathic neurodegeneration using a novel and sensitive magnetic resonance imaging approach

Identification of changes in neuronal function as a consequence of aging and tauopathic neurodegeneration using a novel and sensitive magnetic resonance imaging approach

Improved Visualization of Neuronal Injury Following Glial Activation by Manganese Enhanced MRI

Neurofibrillary tangle-bearing neurons are functionally integrated in cortical circuits in vivo

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