The brain is a highly inter-connected network system, with distributed brain regions orchestrating to maintain normal brain function and mediate complex behavior. It is becoming increasingly clear that altered brain network properties underlie mental illness, but the neural substrates causing these large-scale network changes remain unknown. A key hypothesis is the dysfunction of brain hub regions. Hubs are brain regions that have high degrees of connections with the rest of the brain network. Because of their central roles, dysfunction of hub nodes can change global integrative process, and has been hypothesized to be a direct cause of altered brain network function and pathophysiology of brain disorders. However, directly testing this hypothesis in humans is challenging, as selectively manipulating activity in a hub and dissecting its causal impact on brain networks is difficult. We will bridge this critical gap using cutting-edge tools to manipulate the activity of a hub, and monitor the impact of these manipulations on brain networks using resting state functional magnetic resonance imaging (rsfMRI) and behavior in an awake rat model. In the current grant cycle we have established the rsfMRI approach in awake rats, which allows us to reliably measure resting-state functional connectivity (RSFC) and characterize brain network properties in rats. We have built on our awake rat rsfMRI approach by incorporating Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), optogenetics, electrophysiology and animal behaviors. With these capacities, we can causally manipulate the activity in a hub brain region, and measure the corresponding brain-wide network reconfigurations. Using optogenetics, we can manipulate neural activity on the millisecond timescale, and using DREADDs, we can manipulate neural activity on the times scales of hours to days. Finally, concurrent electrophysiology-fMRI will allow us to directly relate brain network and behavioral changes to their neural basis. Our goal is to elucidate the causal impact of manipulating hub region activity on brain network organization, function and behavior in awake rats using rsfMRI, DREADDs, optogenetics and electrophysiology.
In Aim 1, we will document changes in network properties including the network topological organization and brain-wide RSFC dynamics induced by semi-acute suppression of a brain hub. With the cell- type specificity of DREADDs, we will examine the role of the balance of excitation and inhibition in a hub in brain network dynamics. To elucidate the relationship between activity of a network node and specific brain network function, in Aim 2 we will dissect the functional role of each node in the default mode network and related behaviors in rats.
In Aim 3, we will further determine the impact of chronic suppression of a hub on long-term network reorganization and behavior. Successful completion of the proposed research will elucidate the causal relationship between short-term and long-term dysfunction of a hub and brain network reconfigurations, which will help understand the neural substrates causing large-scale brain network changes.

Public Health Relevance

It has been hypothesized that dysfunction of brain hubs underlies brain network changes and neuro- pathophysiology of numerous brain disorders, but directly testing this hypothesis in humans is challenging. The proposed research will elucidate the causal impact of short-term and long-term suppression of a hub on brain network organization, function and behavior using an awake rodent model. Such knowledge will help reveal the neural substrates causing large-scale brain network changes, and provide insight into understanding the neuro- pathophysiology of brain disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS085200-06A1
Application #
9973295
Study Section
Emerging Imaging Technologies in Neuroscience Study Section (EITN)
Program Officer
Babcock, Debra J
Project Start
2013-09-01
Project End
2025-03-31
Budget Start
2020-05-15
Budget End
2021-03-31
Support Year
6
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Pennsylvania State University
Department
Biomedical Engineering
Type
Biomed Engr/Col Engr/Engr Sta
DUNS #
003403953
City
University Park
State
PA
Country
United States
Zip Code
16802
Ma, Zilu; Ma, Yuncong; Zhang, Nanyin (2018) Development of brain-wide connectivity architecture in awake rats. Neuroimage 176:380-389
Ma, Zhiwei; Perez, Pablo; Ma, Zilu et al. (2018) Functional atlas of the awake rat brain: A neuroimaging study of rat brain specialization and integration. Neuroimage 170:95-112
Dopfel, David; Zhang, Nanyin (2018) Mapping stress networks using functional magnetic resonance imaging in awake animals. Neurobiol Stress 9:251-263
Ma, Zhiwei; Zhang, Nanyin (2018) Temporal transitions of spontaneous brain activity. Elife 7:
Hamilton, Christina; Ma, Yuncong; Zhang, Nanyin (2017) Global reduction of information exchange during anesthetic-induced unconsciousness. Brain Struct Funct 222:3205-3216
Smith, Jared B; Liang, Zhifeng; Watson, Glenn D R et al. (2017) Interhemispheric resting-state functional connectivity of the claustrum in the awake and anesthetized states. Brain Struct Funct 222:2041-2058
Ma, Yuncong; Hamilton, Christina; Zhang, Nanyin (2017) Dynamic Connectivity Patterns in Conscious and Unconscious Brain. Brain Connect 7:1-12
Ma, Zhiwei; Zhang, Nanyin (2017) Cross-population myelination covariance of human cerebral cortex. Hum Brain Mapp 38:4730-4743
Lee, Athene K W; Gansler, David A; Zhang, Nanyin et al. (2017) Relationship of mindful awareness to neural processing of angry faces and impact of mindfulness training: A pilot investigation. Psychiatry Res Neuroimaging 264:22-28
Gao, Yu-Rong; Ma, Yuncong; Zhang, Qingguang et al. (2017) Time to wake up: Studying neurovascular coupling and brain-wide circuit function in the un-anesthetized animal. Neuroimage 153:382-398

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