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.
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.
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