The medial prefrontal cortex (mPFC) plays a critical role in cocaine addiction. The mechanism underlying mPFC dysfunction in cocaine abusers are not well understood and could reflect disruption of cerebral blood flow (cocaine?s vascular effects) and/or disruption of dopaminergic modulation of the prefrontal cortex (cocaine?s neuronal effects). However, current neuroimaging tools cannot readily separate vascular from neuronal effects nor distinguish between cell specific (e.g., D1r vs D2r neuronal) responses to cocaine. This application, Optical platform to image neuronal and vascular effects of cocaine in awake rodents, proposes to develop an innovative and integrated optical imaging platform to address these challenges and demonstrate its value in addiction research. Specifically, we propose to develop a unique optical platform that enables simultaneous (1) fluorescence imaging of D1r/D2r-specific neuronal Ca2+ dynamics (marker of neuronal activity) taking advantage of cre transgenic mice and viral delivery of optically encoded Ca2+ indicator (GCaMP6f) to identify specific neuronal populations, and (2) 3D ultrahigh-resolution optical coherence Doppler tomography (1.3?m ?ODT) of micro cerebral blood flow (CBF) in deep layers of the mPFC (>1.4mm). We will demonstrate the value of this integrated approach to assess the vascular and neuronal responses in mPFC of awake animals to acute and chronic cocaine. Our recent optical tool advances and their use for studying the effects of cocaine in cerebrovascular networks and in neuronal function separately for D1r- and D2r- expressing neurons have laid a solid foundation for the proposed study of cocaine-induced mPFC dysfunction. Successful development of the proposed novel fluorescence-?ODT platform will not only provide new insights into cocaine-induced mechanism underlying mPFC dysfunction but also will be of value for studying neurovascular interactions and their disruption in animal models of various brain disorders.

Public Health Relevance

A fundamental scientific challenge is to understand the interaction between neuronal activity and hemodynamics. For drug addiction research this is relevant for the investigation of both neurobiological adaptations associated with addiction and of drug induced neurotoxicity. Here we propose to develop an integrated optical imaging platform, which will allow simultaneous measurement of neuronal activity and cerebral blood flow (CBF) at very high spatial and temporal resolutions and depth penetration. We will combine it with genetically encoded Ca2+ fluorescence indicator in D1/D2-cre transgenic mice to test its capability in elucidating the effects of acute and chronic cocaine in specific D1R vs D2R expressing neuronal types along with the associated CBF changes in prefrontal cortex.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21DA042597-02
Application #
9283547
Study Section
Special Emphasis Panel (ZDA1-SXM-M (13)S)
Program Officer
Pariyadath, Vani
Project Start
2016-06-01
Project End
2018-05-31
Budget Start
2017-06-01
Budget End
2018-05-31
Support Year
2
Fiscal Year
2017
Total Cost
$197,412
Indirect Cost
$72,412
Name
State University New York Stony Brook
Department
Biomedical Engineering
Type
Schools of Medicine
DUNS #
804878247
City
Stony Brook
State
NY
Country
United States
Zip Code
11794
Du, Congwu; Volkow, Nora D; You, Jiang et al. (2018) Cocaine-induced ischemia in prefrontal cortex is associated with escalation of cocaine intake in rodents. Mol Psychiatry :
Li, Ang; Zeng, Guang; Du, Congwu et al. (2018) Automated motion-artifact correction in an OCTA image using tensor voting approach. Appl Phys Lett 113:101102
Gu, Xiaochun; Chen, Wei; You, Jiang et al. (2018) Long-term optical imaging of neurovascular coupling in mouse cortex using GCaMP6f and intrinsic hemodynamic signals. Neuroimage 165:251-264
Allen, Craig P; Park, Kicheon; Li, Ang et al. (2018) Enhanced neuronal and blunted hemodynamic reactivity to cocaine in the prefrontal cortex following extended cocaine access: optical imaging study in anesthetized rats. Addict Biol :
Yin, Wei; Clare, Kevin; Zhang, Qiujia et al. (2017) Chronic cocaine induces HIF-VEGF pathway activation along with angiogenesis in the brain. PLoS One 12:e0175499
Li, Ang; You, Jiang; Du, Congwu et al. (2017) Automated segmentation and quantification of OCT angiography for tracking angiogenesis progression. Biomed Opt Express 8:5604-5616
You, Jiang; Li, Ang; Du, Congwu et al. (2017) Volumetric Doppler angle correction for ultrahigh-resolution optical coherence Doppler tomography. Appl Phys Lett 110:011102
You, Jiang; Volkow, Nora D; Park, Kicheon et al. (2017) Cerebrovascular adaptations to cocaine-induced transient ischemic attacks in the rodent brain. JCI Insight 2:e90809
Chen, Wei; Park, Kicheon; Volkow, Nora et al. (2016) Cocaine-Induced Abnormal Cerebral Hemodynamic Responses to Forepaw Stimulation Assessed by Integrated Multi-wavelength Spectroimaging and Laser Speckle Contrast Imaging. IEEE J Sel Top Quantum Electron 22:
Chen, W; Liu, P; Volkow, N D et al. (2016) Cocaine attenuates blood flow but not neuronal responses to stimulation while preserving neurovascular coupling for resting brain activity. Mol Psychiatry 21:1408-16

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