Hippocampus has lower oxygenation and weaker control of brain blood flow than cortex, due to microvascular differences

Shaw, Kira; Bell, L.; Boyd, Katie; Grijseels, Dorieke M; Clarke, Devin; Bonnar, Orla; Crombag, Hans S.; Hall, Catherine N.

doi:10.1101/835728

Cited by 10 publications

(11 citation statements)

References 55 publications

(62 reference statements)

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“…We previously demonstrated that inflammasomes contribute to neuronal cell death following ischemic stroke 7 , in part via NF-κB and MAPK signaling 34 . Our present data indicate that chronic cerebral hypoperfusion may also lead to increased expression and activation of NLRP and AIM2 inflammasome receptors in multiple brain areas, especially in the hippocampal region, which is known to be particularly vulnerable to injury following mild ischemia 45 . Cerebral hypoperfusion in the BCAS model used here is known to impact the hippocampus by mechanisms involving ionic imbalance, excitotoxicity, mitochondrial dysfunction and oxidative stress 46–48 .…”

Section: Discussionmentioning

confidence: 60%

AIM2 Inflammasome Mediates Hallmark Neuropathological Alterations and Cognitive Impairment in a Mouse Model of Vascular Dementia

Poh

Fann

Wong

et al. 2020

Preprint

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Chronic cerebral hypoperfusion is associated with vascular dementia (VaD). Cerebral hypoperfusion may initiate complex molecular and cellular inflammatory pathways that contribute to long term cognitive impairment and memory loss. Here we used a bilateral common carotid artery stenosis (BCAS) mouse model of VaD to investigate its effect on the innate immune response – particularly the inflammasome signaling pathway. Comprehensive analyses revealed that chronic cerebral hypoperfusion induces a complex temporal expression and activation of inflammasome components and their products (IL-1β and IL-18) in different brain regions, and promotes activation of apoptotic and pyroptotic cell death pathways. Glial cell activation, white matter lesion formation and hippocampal neuronal loss also occurred in a spatiotemporal manner. Moreover, in AIM2 knockout mice we observed attenuated inflammasome-mediated production of proinflammatory cytokines, apoptosis and pyroptosis, as well as resistance to chronic microglial activation, myelin breakdown, hippocampal neuronal loss, and behavioural and cognitive deficits following BCAS. Hence, we have demonstrated that activation of the AIM2 inflammasome substantially contributes to the pathophysiology of chronic cerebral hypoperfusion-induced brain injury and may therefore represent a promising therapeutic target for attenuating cognitive impairment in VaD.

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Section: Discussionmentioning

confidence: 60%

AIM2 Inflammasome Mediates Hallmark Neuropathological Alterations and Cognitive Impairment in a Mouse Model of Vascular Dementia

Poh

Fann

Wong

et al. 2020

Preprint

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“…The effect of vascular differences on BOLD would be expected to be particularly pronounced in cases in which the capillarization of a brain area is sparse like the hippocampus [75]. As an example of when this can be an issue in the hippocampus, Shaw et al [76] compared activation in the CA1 region of the hippocampus with the visual cortex in mice undergoing optogenetic stimulation of glutamatergic neurons. They coupled this stimulation with optical imaging of CBF, CBV and CMRO 2 .…”

Section: Why Does Regional Variability Arise? the Impact Of Regional mentioning

confidence: 99%

Regional variation in neurovascular coupling and why we still lack a Rosetta Stone

Ekstrom

2020

Phil. Trans. R. Soc. B

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Functional magnetic resonance imaging (fMRI) is the dominant tool in cognitive neuroscience although its relation to underlying neural activity, particularly in the human brain, remains largely unknown. A major research goal, therefore, has been to uncover a ‘Rosetta Stone’ providing direct translation between the blood oxygen level-dependent (BOLD) signal, the local field potential and single-neuron activity. Here, I evaluate the proposal that BOLD signal changes equate to changes in gamma-band activity, which in turn may partially relate to the spiking activity of neurons. While there is some support for this idea in sensory cortices, findings in deeper brain structures like the hippocampus instead suggest both regional and frequency-wise differences. Relatedly, I consider four important factors in linking fMRI to neural activity: interpretation of correlations between these signals, regional variability in local vasculature, distributed neural coding schemes and varying fMRI signal quality. Novel analytic fMRI techniques, such as multivariate pattern analysis (MVPA), employ the distributed patterns of voxels across a brain region to make inferences about information content rather than whether a small number of voxels go up or down relative to baseline in response to a stimulus. Although unlikely to provide a Rosetta Stone, MVPA, therefore, may represent one possible means forward for better linking BOLD signal changes to the information coded by underlying neural activity. This article is part of the theme issue ‘Key relationships between non-invasive functional neuroimaging and the underlying neuronal activity’.

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“…It remains unclear why the capillary thrombosis is mainly located in the cortex, instead of the striatum and hippocampus. It has been documented that the topological distribution of the capillary network is different throughout the brain to match the regional metabolism ( Shaw et al, 2019 ; Zhang et al, 2019 ). The vascular network shows distinct distribution and density in the cortex, hippocampus and striatum.…”

Section: Discussionmentioning

confidence: 99%

Stem Cell Factor in Combination With Granulocyte Colony-Stimulating Factor Protects the Brain From Capillary Thrombosis-Induced Ischemic Neuron Loss in a Mouse Model of CADASIL

Ping

Qiu

Gonzalez-Toledo

et al. 2021

Front. Cell Dev. Biol.

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Cerebral autosomal dominant arteriopathy with subcortical infarct and leukoencephalopathy (CADASIL) is a Notch3 mutation-induced cerebral small vessel disease, leading to recurrent ischemic stroke and vascular dementia. There is currently no treatment that can stop or delay CADASIL progression. We have demonstrated the efficacy of treatment with combined stem cell factor (SCF) and granulocyte colony-stimulating factor (G-CSF) (SCF+G-CSF) in reducing cerebral small vessel thrombosis in a TgNotch3R90C mouse model of CADASIL. However, it remains unknown whether SCF+G-CSF treatment protects neurons from microvascular thrombosis-induced ischemic damage. Using bone marrow transplantation to track thrombosis, we observed that capillary thrombosis was widely distributed in the cortex, striatum and hippocampus of 22-month-old TgNotch3R90C mice. However, the capillary thrombosis mainly occurred in the cortex. Neuron loss was seen in the area next to the thrombotic capillaries, and severe neuron loss was found in the areas adjacent to the thrombotic capillaries with bifurcations. SCF+G-CSF repeated treatment significantly attenuated neuron loss in the areas next to the thrombotic capillaries in the cortex of the 22-month-old TgNotch3R90C mice. Neuron loss caused by capillary thrombosis in the cerebral cortex may play a crucial role in the pathogenesis of CADASIL. SCF+G-CSF treatment ameliorates the capillary thrombosis-induced ischemic neuron loss in TgNotch3R90C mice. This study provides new insight into the understanding of CADASIL progression and therapeutic potential of SCF+G-CSF in neuroprotection under microvascular ischemia in CADASIL.

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Hippocampus has lower oxygenation and weaker control of brain blood flow than cortex, due to microvascular differences

Cited by 10 publications

References 55 publications

AIM2 Inflammasome Mediates Hallmark Neuropathological Alterations and Cognitive Impairment in a Mouse Model of Vascular Dementia

AIM2 Inflammasome Mediates Hallmark Neuropathological Alterations and Cognitive Impairment in a Mouse Model of Vascular Dementia

Regional variation in neurovascular coupling and why we still lack a Rosetta Stone

Stem Cell Factor in Combination With Granulocyte Colony-Stimulating Factor Protects the Brain From Capillary Thrombosis-Induced Ischemic Neuron Loss in a Mouse Model of CADASIL

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