In vivo Single Cell Optical Ablation of Brain Pericytes

Nielson, Cara D.; Berthiaume, Andrée-Anne; Bonney, Stephanie; Shih, Andy Y.

doi:10.3389/fnins.2022.900761

Cited by 5 publications

(4 citation statements)

References 34 publications

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“…Pericyte ablations were conducted with focused two-photon line-scan to specifically target individual pericyte somata. 10, 63 This approach is effective only for pericyte ablation in the upper ∼200 µm of cerebral cortex. The ablative scan was performed at 725 nm.…”

Section: Methodsmentioning

confidence: 99%

Pericyte remodeling is deficient in the aged brain and contributes to impaired capillary flow and structure

Berthiaume

Schmid

Stamenković

et al. 2022

Preprint

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Deterioration of brain capillary flow and architecture is a hallmark of aging and dementia. It remains unclear how loss of brain pericytes in these conditions contributes to capillary dysfunction. We conducted cause-and-effect studies by optically ablating pericytes in adult and aged mice in vivo. Focal pericyte loss induced capillary dilation without blood-brain barrier disruption. These abnormal dilations were exacerbated in the aged brain, and resulted in increased flow heterogeneity in capillary networks. A subset of affected capillaries reduced in perfusion due to flow steal. Some capillaries stalled in flow and regressed, leading to loss of capillary connectivity. Remodeling of neighboring pericytes restored endothelial coverage and vascular tone within days. Pericyte remodeling was slower in the aged brain, resulting in regions of persistent capillary dilation. These findings link pericyte loss to disruption of capillary flow and structure. They also identify pericyte remodeling as a therapeutic target to preserve capillary flow dynamics.

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Section: Methodsmentioning

confidence: 99%

Pericyte remodeling is deficient in the aged brain and contributes to impaired capillary flow and structure

Berthiaume

Schmid

Stamenković

et al. 2022

Preprint

Self Cite

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“…Chronic blockage of capillary blood flow may lead to neurodegeneration in the surrounding area and loss of functional hyperemic responses in upstream PAs. More recent work indicates that optical ablation of even a single pericyte causes capillary remodeling and reductions in flow that are more severe in elderly mice [239,240].…”

Section: Capillary Rarefactionmentioning

confidence: 99%

Cerebrovascular Dysfunction in Alzheimer’s Disease and Transgenic Rodent Models

Fang,

Fan,

Roman

2024

J Exp Neurol

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Alzheimer’s Disease (AD) and Alzheimer’s Disease-Related Dementia (ADRD) are the primary causes of dementia that has a devastating effect on the quality of life and is a tremendous economic burden on the healthcare system. The accumulation of extracellular beta-amyloid (Aβ) plaques and intracellular hyperphosphorylated tau-containing neurofibrillary tangles (NFTs) in the brain are the hallmarks of AD. They are also thought to be the underlying cause of inflammation, neurodegeneration, brain atrophy, and cognitive impairments that accompany AD. The discovery of APP, PS1, and PS2 mutations that increase Aβ production in families with early onset familial AD led to the development of numerous transgenic rodent models of AD. These models have provided new insight into the role of Aβ in AD; however, they do not fully replicate AD pathology in patients. Familial AD patients with mutations that elevate the production of Aβ represent only a small fraction of dementia patients. In contrast, those with late-onset sporadic AD constitute the majority of cases. This observation, along with the failure of previous clinical trials targeting Aβ or Tau and the modest success of recent trials using Aβ monoclonal antibodies, has led to a reappraisal of the view that Aβ accumulation is the sole factor in the pathogenesis of AD. More recent studies have established that cerebral vascular dysfunction is one of the earliest changes seen in AD, and 67% of the candidate genes linked to AD are expressed in the cerebral vasculature. Thus, there is an increasing appreciation of the vascular contribution to AD, and the National Institute on Aging (NIA) and the Alzheimer’s Disease Foundation recently prioritized it as a focused research area. This review summarizes the strengths and limitations of the most commonly used transgenic AD animal models and current views about the contribution of Aβ accumulation versus cerebrovascular dysfunction in the pathogenesis of AD.

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“…The recent development of more neuroscientific techniques and advanced animal models have shown promise on revealing the distinct role of pericytes in brain function and dysfunction [70]. Some in vivo dyes were found to only be taken up by certain cell populations within the brain, such as NeuroTrace 500/525 in pericytes [71], and have demonstrated some success in the specific investigation of capillary pericytes.…”

Section: Limitations Of Study and Future Directionsmentioning

confidence: 99%

Dynamic changes in structure and function of brain mural cells around chronically implanted microelectrodes

Wellman,

Forrest,

Douglas

et al. 2024

Preprint

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1.0ABSTRACTIntegration of neural interfaces with minimal tissue disruption in the brain is ideal to develop robust tools that can address essential neuroscience questions and combat neurological disorders. However, implantation of intracortical devices provokes severe tissue inflammation within the brain, which requires a high metabolic demand to support a complex series of cellular events mediating tissue degeneration and wound healing. Pericytes, peri-vascular cells involved in blood-brain barrier maintenance, vascular permeability, waste clearance, and angiogenesis, have recently been implicated as potential perpetuators of neurodegeneration in brain injury and disease. While the intimate relationship between pericytes and the cortical microvasculature have been explored in other disease states, their behavior following microelectrode implantation, which is responsible for direct blood vessel disruption and dysfunction, is currently unknown. Using two-photon microscopy we observed dynamic changes in the structure and function of pericytes during implantation of a microelectrode array over a 4-week implantation period. Pericytes respond to electrode insertion through transient increases in intracellular calcium and underlying constriction of capillary vessels. Within days following the initial insertion, we observed an influx of new, proliferating pericytes which contribute to new blood vessel formation. Additionally, we discovered a potentially novel population of reactive immune cells in close proximity to the electrode-tissue interface actively engaging in encapsulation of the microelectrode array. Finally, we determined that intracellular pericyte calcium can be modulated by intracortical microstimulation in an amplitude- and frequency-dependent manner. This study provides a new perspective on the complex biological sequelae occurring the electrode-tissue interface and will foster new avenues of potential research consideration and lead to development of more advanced therapeutic interventions towards improving the biocompatibility of neural electrode technology.

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In vivo Single Cell Optical Ablation of Brain Pericytes

Cited by 5 publications

References 34 publications

Pericyte remodeling is deficient in the aged brain and contributes to impaired capillary flow and structure

Pericyte remodeling is deficient in the aged brain and contributes to impaired capillary flow and structure

Cerebrovascular Dysfunction in Alzheimer’s Disease and Transgenic Rodent Models

Dynamic changes in structure and function of brain mural cells around chronically implanted microelectrodes

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