scholarly journals Pulsation changes link to impaired glymphatic function in a mouse model of vascular cognitive impairment

2021 ◽  
Author(s):  
Mosi Li ◽  
Akihiro Kitamura ◽  
Joshua Beverley ◽  
Juraj Koudelka ◽  
Jessica Duncombe ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Carotid Stenosis ◽  
Molecular Layer ◽  
Amyloid Β ◽  
Vascular Cognitive Impairment ◽  
Spatial Learning And Memory ◽  
Pial Arteries ◽  
Two Photon Microscopy ◽  
Two Photon ◽  
Dorsolateral Cortex

Large vessel disease and carotid stenosis are key mechanisms contributing to vascular cognitive impairment (VCI) and dementia. Our previous work, and that of others, using rodent models, demonstrated that bilateral common carotid stenosis (BCAS) leads to cognitive impairment via gradual deterioration of the glial-vascular unit and accumulation of amyloid-β (Aβ) protein. Since brain-wide drainage pathways (glymphatic) for waste clearance, including Aβ removal, have been implicated in the pathophysiology of VCI via glial mechanisms, we hypothesized that glymphatic function would be impaired in a BCAS model and exacerbated in the presence of Aβ. Male wild-type and Tg-SwDI (model of microvascular amyloid) mice were subjected to BCAS or sham surgery which led to a reduction in cerebral perfusion and impaired spatial learning and memory. After 3 months survival, glymphatic function was evaluated by cerebrospinal fluid (CSF) fluorescent tracer influx. We demonstrated that BCAS caused a marked regional reduction of CSF tracer influx in the dorsolateral cortex and CA1-DG molecular layer. In parallel to these changes increased reactive astrogliosis was observed post-BCAS. To further investigate the mechanisms that may lead to these changes, we measured the pulsation of cortical vessels using two-photon microscopy. BCAS impaired vascular pulsation in pial arteries in WT and Tg-SwDI mice. Since our findings show that BCAS may influence VCI by impaired glymphatic drainage and reduced vascular pulsation we propose that these additional targets need to be considered when treating VCI.

scholarly journals Impaired Glymphatic Function and Pulsation Alterations in a Mouse Model of Vascular Cognitive Impairment

2022 ◽  
Vol 13 ◽  
Author(s):  
Mosi Li ◽  
Akihiro Kitamura ◽  
Joshua Beverley ◽  
Juraj Koudelka ◽  
Jessica Duncombe ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Carotid Stenosis ◽  
Molecular Layer ◽  
Amyloid Β ◽  
Vascular Cognitive Impairment ◽  
Wild Type ◽  
Fluorescent Tracer ◽  
Pial Arteries ◽  
Dorsolateral Cortex ◽  
Large Vessel Disease

Large vessel disease and carotid stenosis are key mechanisms contributing to vascular cognitive impairment (VCI) and dementia. Our previous work, and that of others, using rodent models, demonstrated that bilateral common carotid stenosis (BCAS) leads to cognitive impairment via gradual deterioration of the neuro-glial-vascular unit and accumulation of amyloid-β (Aβ) protein. Since brain-wide drainage pathways (glymphatic) for waste clearance, including Aβ removal, have been implicated in the pathophysiology of VCI via glial mechanisms, we hypothesized that glymphatic function would be impaired in a BCAS model and exacerbated in the presence of Aβ. Male wild-type and Tg-SwDI (model of microvascular amyloid) mice were subjected to BCAS or sham surgery which led to a reduction in cerebral perfusion and impaired spatial learning acquisition and cognitive flexibility. After 3 months survival, glymphatic function was evaluated by cerebrospinal fluid (CSF) fluorescent tracer influx. We demonstrated that BCAS caused a marked regional reduction of CSF tracer influx in the dorsolateral cortex and CA1-DG molecular layer. In parallel to these changes increased reactive astrogliosis was observed post-BCAS. To further investigate the mechanisms that may lead to these changes, we measured the pulsation of cortical vessels. BCAS impaired vascular pulsation in pial arteries in WT and Tg-SwDI mice. Our findings show that BCAS influences VCI and that this is paralleled by impaired glymphatic drainage and reduced vascular pulsation. We propose that these additional targets need to be considered when treating VCI.

Neuronal Activity Topography Parameters as a Marker for Differentiating Vascular Cognitive Impairment in Carotid Stenosis

2014 ◽  
Vol 23 (9) ◽  
pp. 2384-2390 ◽  
Author(s):  
Takashi Shibata ◽  
Toshimitu Musha ◽  
Michiya Kubo ◽  
Yukio Horie ◽  
Takashi Asahi ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Carotid Stenosis ◽  
Neuronal Activity ◽  
Vascular Cognitive Impairment

scholarly journals Chronic cerebral hypoperfusion: a key mechanism leading to vascular cognitive impairment and dementia. Closing the translational gap between rodent models and human vascular cognitive impairment and dementia

2017 ◽  
Vol 131 (19) ◽  
pp. 2451-2468 ◽  
Author(s):  
Jessica Duncombe ◽  
Akihiro Kitamura ◽  
Yoshiki Hase ◽  
Masafumi Ihara ◽  
Raj N. Kalaria ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
White Matter ◽  
Small Vessel Disease ◽  
Amyloid Β ◽  
Vascular Cognitive Impairment ◽  
Chronic Cerebral Hypoperfusion ◽  
Cerebral Hypoperfusion ◽  
Pathophysiological Mechanism ◽  
Rodent Models ◽  
Recent Refinement

Increasing evidence suggests that vascular risk factors contribute to neurodegeneration, cognitive impairment and dementia. While there is considerable overlap between features of vascular cognitive impairment and dementia (VCID) and Alzheimer’s disease (AD), it appears that cerebral hypoperfusion is the common underlying pathophysiological mechanism which is a major contributor to cognitive decline and degenerative processes leading to dementia. Sustained cerebral hypoperfusion is suggested to be the cause of white matter attenuation, a key feature common to both AD and dementia associated with cerebral small vessel disease (SVD). White matter changes increase the risk for stroke, dementia and disability. A major gap has been the lack of mechanistic insights into the evolution and progress of VCID. However, this gap is closing with the recent refinement of rodent models which replicate chronic cerebral hypoperfusion. In this review, we discuss the relevance and advantages of these models in elucidating the pathogenesis of VCID and explore the interplay between hypoperfusion and the deposition of amyloid β (Aβ) protein, as it relates to AD. We use examples of our recent investigations to illustrate the utility of the model in preclinical testing of candidate drugs and lifestyle factors. We propose that the use of such models is necessary for tackling the urgently needed translational gap from preclinical models to clinical treatments.

scholarly journals Molecular layer interneurons in the cerebellum encode for valence in associative learning

2019 ◽  
Author(s):  
Ming Ma ◽  
Gregory L. Futia ◽  
Fabio M. Simoes De Souza ◽  
Baris N. Ozbay ◽  
Isabel Llano ◽  
...  
Keyword(s):  
Associative Learning ◽  
Molecular Layer ◽  
Differential Response ◽  
Water Reward ◽  
Sugar Water ◽  
Two Photon Microscopy ◽  
Two Photon ◽  
Time Out ◽  
Cerebellar Molecular Layer

We used two-photon microscopy to study the role of ensembles of cerebellar molecular layer interneurons (MLIs) in a go-no go task where mice obtain a sugar water reward if they lick a spout in the presence of the rewarded odorant and avoid a time out when they refrain from licking for the unrewarded odorant. In naïve animals the MLI responses did not differ between the odorants. With learning, the rewarded odorant elicited a large increase in MLI calcium responses, and the identity of the odorant could be decoded from the differential response. Importantly, MLIs switched odorant responses when the valence of the stimuli was reversed. Finally, mice took a longer time to refrain from licking in the presence of the unrewarded odorant and had difficulty becoming proficient when MLIs were inhibited by chemogenetic intervention. Our findings support a role for MLIs in learning valence in the cerebellum.

39. Early diagnosis of vascular cognitive impairment with carotid stenosis using Neuronal Activity Topography (NAT)

2012 ◽  
Vol 123 (9) ◽  
pp. e96
Author(s):  
Takashi Shibata ◽  
Nobuhisa Matsumura ◽  
Yukio Horie ◽  
Nakamasa Hayashi ◽  
Naoya Kuwayama ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Early Diagnosis ◽  
Carotid Stenosis ◽  
Neuronal Activity ◽  
Vascular Cognitive Impairment

scholarly journals Microvascular basis for growth of small infarcts following occlusion of single penetrating arterioles in mouse cortex

2015 ◽  
Vol 36 (8) ◽  
pp. 1357-1373 ◽  
Author(s):  
Zachary J Taylor ◽  
Edward S Hui ◽  
Ashley N Watson ◽  
Xingju Nie ◽  
Rachael L Deardorff ◽  
...  
Keyword(s):  
Capillary Flow ◽  
Infarct Volume ◽  
Vascular Cognitive Impairment ◽  
Aging Brain ◽  
Hemodynamic Changes ◽  
Two Photon Microscopy ◽  
Two Photon ◽  
Mouse Cortex ◽  
Gradual Expansion

Small cerebral infarcts, i.e. microinfarcts, are common in the aging brain and linked to vascular cognitive impairment. However, little is known about the acute growth of these minute lesions and their effect on blood flow in surrounding tissues. We modeled microinfarcts in the mouse cortex by inducing photothrombotic clots in single penetrating arterioles. The resultant hemodynamic changes in tissues surrounding the occluded vessel were then studied using in vivo two-photon microscopy. We were able to generate a spectrum of infarct volumes by occluding arterioles that carried a range of blood fluxes. Those resulting from occlusion of high-flux penetrating arterioles (flux of 2 nL/s or higher) exhibited a radial outgrowth that encompassed unusually large tissue volumes. The gradual expansion of these infarcts was propagated by an evolving insufficiency in capillary flow that encroached on territories of neighboring penetrating arterioles, leading to the stagnation and recruitment of their perfusion domains into the final infarct volume. Our results suggest that local collapse of microvascular function contributes to tissue damage incurred by single penetrating arteriole occlusions in mice, and that a similar mechanism may add to pathophysiology induced by microinfarcts of the human brain.

scholarly journals Topological analyses in APP/PS1 mice reveal that astrocytes do not migrate to amyloid-β plaques

2015 ◽  
Vol 112 (51) ◽  
pp. 15556-15561 ◽  
Author(s):  
Elena Galea ◽  
Will Morrison ◽  
Eloise Hudry ◽  
Michal Arbel-Ornath ◽  
Brian J. Bacskai ◽  
...  
Keyword(s):  
Spatial Analysis ◽  
Hard Spheres ◽  
Amyloid Β ◽  
Confined Space ◽  
3D Images ◽  
Large Plaque ◽  
Two Photon Microscopy ◽  
Two Photon ◽  
Cortical Astrocyte ◽  
Quantitative Spatial Analysis

Although the clustering of GFAP immunopositive astrocytes around amyloid-β plaques in Alzheimer’s disease has led to the widespread assumption that plaques attract astrocytes, recent studies suggest that astrocytes stay put in injury. Here we reexamine astrocyte migration to plaques, using quantitative spatial analysis and computer modeling to investigate the topology of astrocytes in 3D images obtained by two-photon microscopy of living APP/PS1 mice and WT littermates. In WT mice, cortical astrocyte topology fits a model in which a liquid of hard spheres exclude each other in a confined space. Plaques do not disturb this arrangement except at very large plaque loads, but, locally, cause subtle outward shifts of the astrocytes located in three tiers around plaques. These data suggest that astrocytes respond to plaque-induced neuropil injury primarily by changing phenotype, and hence function, rather than location.

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