Calcium-related neurotoxicity of cocaine

前额叶皮层（PFC）的功能障碍在强迫性可卡因使用和成瘾中起着关键作用。 可卡因诱导PFC功能障碍中胶质细胞与神经元及血管网络的作用 仍然难以捉摸在完整的R 01中，我们发现可卡因的神经毒性作用与 脑血流量（CBF）持续下降，皮质细胞内钙升高; 然而，我们没有评估胶质细胞与神经元在CBF减少中的作用。此续订 一项名为“可卡因的钙相关神经毒性”的应用将评估急性和慢性可卡因的影响， 对星形胶质细胞Ca 2+及其在PFC中CBF缺陷和神经元Ca 2+增加及其相关性的作用 与可卡因摄入量在一个动物模型的强迫样可卡因自我管理。 具体来说，我们将应用多模态光学成像（MOI）结合基因编码的 用于捕获神经元（jRGECO 1a）和星形胶质细胞（GCaMP 6 f）中的活性的Ca 2+指示剂和用于捕获神经元（jRGECO 1a）和星形胶质细胞（GCaMP 6 f）中的活性的Ca 2+指示剂。 分辨率光学相干血管造影术和多普勒断层扫描（µODT），用于3D定量成像 GFAP cre小鼠PFC中的CBF网络（目的1）。我们将应用化学遗传学与设计师受体 由设计药物独家激活（DREADDs）以操纵星形胶质细胞Ca 2+积聚， 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 摄入量（目标2、目标3）。 这些研究对于了解PFC中星形胶质细胞和神经元网络的作用机制具有重要意义 相互作用和介导相关的局部神经血管反应可卡因，以及它们如何有助于 强迫性药物消费，提供知识，指导新成瘾的发展 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.