In the past decade, our understanding of the organizations among human brain networks has been revolutionized by the emerging technique of resting-state functional magnetic resonance imaging (rsfMRI). rsfMRI can be used to measure resting-state functional connectivity (RSFC) in the absence of any external stimulation. By utilizing this technique, vital neuropathological relevance of RSFC has been repeatedly demonstrated in numerous neurological, neuropsychiatric and neurodegenerative disorders, suggesting that RSFC might serve as a sensitive biomarker for aiding diagnosis and evaluation of treatment for human brain diorders. Unfortunately, the full potential of RSFC methods is limited by a critical gap in animal RSFC research, mainly challenged by the confounding effects of anesthesia used in animal experiments on RSFC. Lack of preclinical RSFC data has considerably hindered our understanding of the basal large-scale functional brain networks in animals. More importantly, since animal models have been comprehensively used to investigate the neurobiology of brain diseases and develop new therapies, inability of imaging RSFC in animals has tremendously impeded the application of RSFC methods to studying neuropathology. Therefore, to avoid the confounder of anesthesia and bridge the gap of RSFC research in animals, it is essential to image RSFC in awake animals. In our laboratory, we have """"""""surmounted a technical obstacle to imaging neural networks in rodents"""""""" (NIDA Notes, June 2012) and established a rsfMRI approach that allows RSFC in animals to be acquired at the awake condition. Based on this approach, we have demonstrated the feasibility of measuring individual neural circuitries, the intrinsic organization of the whole-brain networks, as well as brain network reconfigurations at different neurophysiological conditions in awake rats. These pilot data have prepared us for further characterizing RSFC in the awake rat brain. Importantly, we will be able to construct the RSFC-based rat brain connectome. In addition, since RSFC measurement in animals makes it feasible to investigate its detailed cellular and molecular mechanisms by taking advantage of well-established invasive preclinical tools, we will explore a potential neurochemical mechanism underlying RSFC. These research objectives will be achieved through three specific aims:
In Aim 1, we will systematically characterize RSFC to test its reliability and gain the knowledge of basal neural networks in the awake rat brain.
In Aim 2, we will construct and evaluate the rat brain connectome by using graph analysis to understand the rat brain organization. Also in an Exploratory Aim, we will examine the relationship between the serotonin system and RSFC, which has been suggested to be critical in the neurochemical mechanism of RSFC. The proposed work is innovative, because it will utilize a novel neuroimaging technique (RSFC in awake animals) to investigate large-scale neural networks in rodents. The impact of this research is highly significant because it will bridge the gap in RSFC research and open a new avenue to studying various animal models of brain disorders.

Public Health Relevance

Resting-state functional connectivity (RSFC) has been implicated in numerous neurological, psychiatric and neurodegenerative disorders. The paucity of information on the RSFC research in animals, due to the confounding effects of anesthesia used in animal experiments, has highlighted a critical gap to further understanding these brain disorders using animal models. The proposed research will bridge this gap by systemically characterizing RSFC in awake animals and constructing the RSFC-based rat brain connectome. In addition, the neurochemical mechanism underlying RSFC will be explored in the rat.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Babcock, Debra J
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Pennsylvania State University
Biomedical Engineering
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University Park
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Ma, Zilu; Ma, Yuncong; Zhang, Nanyin (2018) Development of brain-wide connectivity architecture in awake rats. Neuroimage 176:380-389
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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:
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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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