Calcium-related neurotoxicity of cocaine

前额叶皮质功能障碍在可卡因的强迫性使用和成瘾中起着至关重要的作用。 除了神经元和血管网络外，神经胶质细胞在可卡因诱导的PFC功能障碍中的作用 仍然难以捉摸。在完成的R01中，我们表明可卡因的神经毒性作用与 脑血流量持续下降，皮质细胞内钙升高； 然而，我们没有评估神经胶质细胞与神经元在脑血流量下降中的作用。此次续订 应用“可卡因的钙相关神经毒性”将评估急性和慢性可卡因的影响。 PFC中星形胶质细胞钙离子及其在脑血流缺陷和神经元钙离子升高中的作用及其相互关系 在强迫性类可卡因自我给药的动物模型中摄取可卡因。 具体地说，我们将应用多模式光学成像(MOI)与遗传编码相结合 钙指示剂捕捉神经元(JRGECO1a)和星形胶质细胞(GCaMP6f)的活动，并超高... 用于三维定量成像的分辨率光学相干血管成像和多普勒层析成像 GFAP cre小鼠PFC内的CBF网络(目标1)。我们将把化学遗传学应用于设计受体 由特制药物(DREADD)独家激活，以操纵星形细胞钙蓄积，同时 评估其对急性和慢性可卡因的血管和神经效应以及可卡因的影响 摄入量(目标2、目标3)。 这些研究将有助于理解星形胶质细胞和神经元网络在前额叶皮质中的作用。 与可卡因相关的局部神经血管反应的相互作用和调节，以及它们如何参与 强迫型药物消费，提供知识指导新型成瘾发展 干预措施。

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 (µODT) 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.