In cerebrovascular disorders, such as Alzheimer?s Disease and stroke, the ability to maintain normal cerebral blood flow is compromised. Neurovascular coupling (NVC), the temporal relationship between neural activity and cerebral blood flow, is thought to be disrupted in these conditions resulting in cerebral hypoperfusion and cognitive dysfunction. As nitric oxide (NO) mediates vasodilation, the neurons that release (NO) are good candidates as a major regulator of cerebral blood flow (CBF). We recently developed a new genetic tool? NK1R-creER knockin mouse? that allows us to target and manipulate a specific subset of NO-generating neurons (nNOS Type 1 neurons), and thus test the involvement of these cells in neurovascular coupling for the first time. Here, we propose to test the specific hypothesis that nNOS Type 1 neurons receive excitatory pyramidal input and mediate vasodilation.
Aim 1 will investigate whether NK1R-creER cortical interneurons receive excitatory pyramidal input using immunohistochemical approaches.
Aim 2 will investigate whether pyramidal neurons form functional synapses onto NK1R-creER cortical interneurons using optogenetic approaches and slice electrophysiology. Lastly, Aim 3 will test whether NK1R-creER interneuron activity is necessary and sufficient to increase cerebral blood flow in vivo using laser Doppler flowmetry. Together, these experiments will investigate the circuits coupling neural activity and hemodynamics. This insight into NVC is fundamental to our understanding of the pathogenesis of common cerebrovascular diseases and the advancement of pharmacotherapeutics targeting cerebral perfusion.

Public Health Relevance

Neurovascular coupling (NVC) is the neural-evoked increase in cerebral blood flow that provides the proper metabolic requirements to activated brain areas, and is disrupted in cerebrovascular diseases, such as Alzheimer?s disease (AD) and stroke. This study aims to better understand the mechanism of NVC, focusing on a distinct, understudied population of cortical interneurons. A better understanding of NVC may provide a basis for therapeutic treatments aimed at improving cerebral microcirculation, potentially reducing the risk of stroke as well as the progression of AD and other cerebrovascular diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31NS106724-02
Application #
9667981
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Koenig, James I
Project Start
2018-03-01
Project End
2020-02-29
Budget Start
2019-03-01
Budget End
2020-02-29
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Neurosciences
Type
Schools of Arts and Sciences
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213