CA1 spatial coding as a predictor for vulnerability to compulsive alcohol seeking

强迫性饮酒和对酒精预测环境的选择--通常会导致再次饮酒--是酒精使用障碍(AUD)的特征。虽然人们对驱动这些病理行为的神经网络知之甚少，但那些支持通向奖励的导航可能是重要的。哺乳动物的目标导向导航依赖于使用背侧海马区产生的内部空间表征。最近的研究一致地表明，背侧海马体的活动正在驱动与可卡因相关的空间记忆。因此，很自然地认为，涉及背侧海马体的神经元网络在适应不良的酒精寻求中也扮演着基本的角色。然而，在实验室动物身上研究这些网络受到了许多技术限制的阻碍：无法跟踪活体受试者大量神经元的活动，个人行为分层不佳，以及缺乏精确控制特定大脑回路活动的工具。在这里，我们建议结合：(I)宽视场头戴式显微镜来成像小鼠背侧CA1区(DCA1)数百个锥体神经元的神经元活动，(Ii)遗传和化学发生工具来标记和操纵具有细胞类型和投影特异性的神经元网络，(Iii)一种新的行为任务和仪器(E-迷宫)来研究在空间规划、决策、导航和饮酒过程中DCAL的表征，以及(Iv)已建立的AUD动物模型。这些方法将使我们能够研究在饮酒过程中编码dCA1是否预测成瘾样行为表型的出现。

Compulsive alcohol seeking and choice of alcohol-predicting contexts - that often result in relapse to alcohol consumption - are hallmarks of alcohol use disorders (AUD). While the neuronal networks driving these pathological behaviors are poorly understood, those supporting navigation towards rewards are likely to be important. Goal-oriented navigation in mammals relies on the use of internal representations of space produced in the dorsal hippocampus. Consistently, recent work has shown that activity of the dorsal hippocampus is driving spatial memory related to cocaine. It is thus natural to suppose that neuronal networks involving the dorsal hippocampus, also play a fundamental role in maladaptive alcohol seeking. Yet, studying these networks in laboratory animals has been prevented by many technical limitations: impossibility to track activity of a large number of neurons of live subjects, poor behavioral stratification of individuals, as well as lack of tools to precisely control the activity of specific brain circuits. Here, we propose to combine: (i) wide field head mounted microscopes to image neuronal activity of hundreds of pyramidal neurons in the dorsal CA1 area (dCA1) of mice, (ii) genetic and chemogenetic tools to label and manipulate neuronal networks with cell-type and projection specificity, (iii) a novel behavioral task and apparatus (E-maze) to investigate the dCAl representations during spatial planning, decision, navigation and consumption of alcohol and (iv) an established animal model of AUD. These methods will enable us to study whether dCA1 coding during alcohol seeking predicts the emergence of addicted-like behavioral phenotypes.