Regional heterogeneity of the mural and vascular network in the adult mouse brain and associated vulnerability and anatomical remodeling in aging
Restricted (Penn State Only)
- Author:
- Bennett, Hannah
- Graduate Program:
- Neuroscience
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- November 21, 2022
- Committee Members:
- Patrick Drew, Outside Unit & Field Member
Anirban Paul, Major Field Member
Kirsteen Browning, Major Field Member
Yongsoo Kim, Chair & Dissertation Advisor
Alistair Barber, Program Head/Chair - Keywords:
- brain
pericyte
vascular
aging
serial two photon tomography
light sheet fluorescent microscopy
iDISCO
mural
mouse - Abstract:
- Mounting evidence indicates that neurovascular degradation contributes to both normal aging processes and neurodegenerative diseases. Mural cells, including both vascular smooth muscle cells (vSMCs) and pericytes, are critical components of the vasculature that dynamically regulate blood flow. In addition, pericytes have been implicated in the pathophysiology of age-related diseases, such as Alzheimer’s disease and Diabetes mellitus. Despite the links between mural cells, cerebrovascular dysfunction, and aging, it remains unclear how mural populations across various brain regions are differently impacted in response to aging. Here, we utilize mesoscale brain-wide mapping methods to fully represent the mural and vascular networks of the adult and aging mouse brain, as well as brain clearing and immunolabeling methods to interrogate mural and vascular changes during aging within the same brain. We show that the adult mouse brain has high densities of vasculature and capillary pericytes in primary motor sensory cortices compared with association cortices. In fact, this vascular distribution shows significant positive and negative correlations with energy-demanding parvalbumin+ and vasomotor nNOS+ neurons, respectively. Additionally, thalamo-striatal areas that are connected to primary motor sensory cortices also show high densities of vasculature and pericytes, suggesting dense energy support for motor sensory processing areas. Our results in the aging brain reveal that normal aging is associated with reduced vascular and capillary pericyte density in the basal forebrain, deep cortical layers, as well as subtle decreases in regions we previously identified to have lower baseline densities in the adult mouse brain, such as regions of the hippocampal formation. Interestingly, our results indicate that aging is associated with an increase in pericyte density in layer 4, and a decrease in both vascular and capillary pericyte density in layer 6, which are cortical layers that are not normally accessible by other imaging methods. Moreover, in C57Bl/6J mice, we found that normal aging is associated with decreases in capillary pericyte density in isocortical layer 6 and the entorhinal cortex, as well as striking geometric and structural changes in vascular smooth muscle, particularly in the penetrating arterioles of the supplementary somatosensory cortex. This work suggests that mural populations and cerebrovasculature are heavily impacted by normal aging alone, yet the effects vary vastly across brain regions.