Disfunction of the prefrontal cortex (PFC), plays a crucial role in compulsive cocaine use and addiction. The role of glia in addition to that of neurons and vascular networks in cocaine-induced PFC dysfunction remains elusive. In the completing R01, we showed that the neurotoxic effects of cocaine were associated with persistent decreases in cerebral blood flow (CBF) and an elevation in intracellular calcium in cortex; however, we did not assess the role of glia versus that of neurons on the CBF decreases. This renewal application, Calcium-related neurotoxicity of cocaine, will assess the effects of acute and chronic cocaine on astrocytic Ca2+ and its role on the CBF deficits and neuronal Ca2+ increases in PFC and their association with cocaine intake in an animal model of compulsive-like cocaine self-administration. Specifically, we will apply multimodality optical imaging (MOI) in combination with genetically-encoded Ca2+ indicators to capture activities in neurons (jRGECO1a) and astrocytes (GCaMP6f) and ultrahigh- resolution optical coherence angiography and Doppler tomography (ODT) for quantitative imaging of 3D CBF networks in PFC of GFAP cre mice (Aim 1). We will apply chemogenetics with Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) to manipulate astrocytic Ca2+ accumulation while assessing its consequences on acute and chronic cocaine?s vascular and neuronal effects and cocaine intake (Aim 2, Aim 3). These studies will be valuable for understanding how astrocyte and neuronal networks in the PFC interact and mediate the associated local neurovascular responses to cocaine and how they contribute to compulsive-like drug consumption, providing knowledge to guide development of novel addiction interventions.
This proposal will apply a novel multimodality optical imaging platform that, when combined with genetically encoded Ca2+ fluorescence indicators of astrocyte and neuronal activities and chemogenetics for astrocytic Ca2+ manipulation, will allow us to assess the effects of cocaine in astrocytes and their role in modulating neuronal and vascular responses to cocaine in the prefrontal cortex (PFC) and their association with cocaine self-administration with repeated exposures. This proposal will also assess the efficacy of astrocytic Ca2+ modulation as an interventional strategy aimed at restoring PFC function and reducing cocaine use.
Showing the most recent 10 out of 23 publications
