Changes in spontaneous and sensory evoked cerebral blood flow are extensively used to infer neural activity in the brain with functional magnetic resonance imaging (fMRI). However, the relationship of these hemodynamic changes to neural activity, the pathways by which neural activity controls blood flow, and the interaction between sensory-evoked and spontaneous activity are still poorly understood. To address these questions, we will use 2-photon laser-scanning microscopy (2PLSM) and intrinsic optical signal (IOS) to measure spontaneous and sensory evoked hemodynamics in the somatosensory cortex of awake, head-fixed mice. We will measure the relationship between both sensory evoked and spontaneous neural activity and the subsequent blood flow ('neurovascular coupling'). The signaling pathways that underlying this coupling will be dissected by measuring neural activity and blood flow in transgenic mice lacking muscarinic cholinergic receptors on either blood vessels or cortical neurons. This will allow us to disentangle the direct vasodilatory effects of acetylcholine from the indirect effects mediated via increases in neural excitability. Finally, we will determine how sensory evoked activity interacts with ongoing spontaneous activity in the brain. Quantifying how spontaneous and sensory-evoked neural activity couples to blood flow is critical for understanding the function of the healthy brain.

Public Health Relevance

Increases in blood flow are commonly used to non-invasively infer neural activity in the human brain, however it is not known if spontaneous fluctuations in blood flow reflect neural activity in the same way sensory evoked activity does, and by what pathways neurons increase cerebral blood flow. We will measure the relationship of cerebral blood flow increases to neural activity and their mechanistic basis in an animal model, which will provide insight into neurovascular disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS079737-02
Application #
8467071
Study Section
Medical Imaging Study Section (MEDI)
Program Officer
Gnadt, James W
Project Start
2012-05-15
Project End
2017-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
2
Fiscal Year
2013
Total Cost
$305,787
Indirect Cost
$94,693
Name
Pennsylvania State University
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
003403953
City
University Park
State
PA
Country
United States
Zip Code
16802
Gao, Yu-Rong; Drew, Patrick J (2016) Effects of Voluntary Locomotion and Calcitonin Gene-Related Peptide on the Dynamics of Single Dural Vessels in Awake Mice. J Neurosci 36:2503-16
Gao, Yu-Rong; Ma, Yuncong; Zhang, Qingguang et al. (2016) Time to wake up: Studying neurovascular coupling and brain-wide circuit function in the un-anesthetized animal. Neuroimage :
Shirey, Michael J; Smith, Jared B; Kudlik, D'Anne E et al. (2015) Brief anesthesia, but not voluntary locomotion, significantly alters cortical temperature. J Neurophysiol 114:309-22
Huo, Bing-Xing; Greene, Stephanie E; Drew, Patrick J (2015) Venous cerebral blood volume increase during voluntary locomotion reflects cardiovascular changes. Neuroimage 118:301-12
Gao, Yu-Rong; Greene, Stephanie E; Drew, Patrick J (2015) Mechanical restriction of intracortical vessel dilation by brain tissue sculpts the hemodynamic response. Neuroimage 115:162-76
Huo, Bing-Xing; Gao, Yu-Rong; Drew, Patrick J (2015) Quantitative separation of arterial and venous cerebral blood volume increases during voluntary locomotion. Neuroimage 105:369-79
Huo, Bing-Xing; Smith, Jared B; Drew, Patrick J (2014) Neurovascular coupling and decoupling in the cortex during voluntary locomotion. J Neurosci 34:10975-81
Letourneur, Annelise; Chen, Victoria; Waterman, Gar et al. (2014) A method for longitudinal, transcranial imaging of blood flow and remodeling of the cerebral vasculature in postnatal mice. Physiol Rep 2:
Gao, Yu-Rong; Drew, Patrick J (2014) Determination of vessel cross-sectional area by thresholding in Radon space. J Cereb Blood Flow Metab 34:1180-7