Striatal astrocytic mechanisms underlying the development of compulsive drug seeking habits

药物成瘾是一种慢性、复发性的脑部疾病，困扰着英国和国际上的许多人，给健康、社会和刑事司法系统带来了巨大的负担。随着美国，英国和欧盟阿片类药物使用和相关死亡的增加，了解神经生物学机制从未如此紧迫，这些机制使一些人易于从受控的，娱乐性的海洛因使用转向持久的，强迫性的，药物成瘾的特征寻求行为。只有这样，我们才能开发出新的治疗方法，帮助打破这些适应不良的强迫性药物寻求习惯，或防止其在高危人群中的发展。值得注意的是，尽管已经了解了成瘾物质如何通过对大脑神经元的特定作用产生愉悦或奖励效应，但仍不清楚为什么目前使用海洛因等药物的人中只有一小部分人随后成瘾。最近的发现有助于理解，在长期的药物暴露史中，控制药物寻求行为的大脑回路如何发生转变，从所谓的奖励系统到背外侧（DLS）多巴胺依赖的习惯系统。这些转变被认为依赖于药物对这些回路中涉及多巴胺相关机制的神经元的劫持。因此，研究几乎完全集中在这些回路的神经元内发生的细胞和分子机制上，试图阐明成瘾的生物学基础。然而，暴露于滥用药物也会触发星形胶质细胞的细胞和分子适应，迄今为止，星形胶质细胞仅被认为在大脑中起支持作用，因为它们为神经元提供燃料并维持大脑稳态。由于星形胶质细胞形成了自己的网络，或合胞体，跨越大脑的广泛领域，它们在功能上处于独特的位置，可以桥接异常的神经元回路，否则这些回路是独立的。因此，本研究项目旨在了解星形胶质细胞及其合胞体的贡献，从腹侧纹状体的DLS在海洛因寻求控制时，它成为习惯性的，最终强迫性的功能过渡。利用我们在大鼠中强迫性海洛因寻求习惯的新行为模型，我们将首先进行交叉-截面研究，旨在确定在强迫性海洛因寻求习惯的发展过程中，纹状体星形胶质细胞合胞体跨纹状体功能域的功能募集的时空分布，并确定这种功能募集的分子相关性。因果地建立DLS星形胶质细胞在DLS-多巴胺依赖的海洛因寻求习惯的表达中的作用，以及它们在面对惩罚时的适应不良的持久性。为此，我们将结合联合收割机对DLS星形胶质细胞的病毒介导的操作和DLS内多巴胺受体拮抗剂的输注，以确定是否Hm 4Di介导的激活或膜钙泵影响了已确立的海洛因寻求对DLS多巴胺机制的依赖。介导的抑制星形胶质细胞的活动，以及这些操作是否影响的倾向，坚持寻求海洛因，尽管惩罚。该项目是因果地确定中脑核中星形胶质细胞在aDLS依赖多巴胺的海洛因寻求习惯和强迫性海洛因寻求的发展中的作用。为此，我们将使用类似于目标2的策略，我们将测量在海洛因自我给药的整个历史中腹侧纹状体星形胶质细胞的慢性激活或抑制对出现的DLS-多巴胺依赖性海洛因寻求习惯及其在面对惩罚时的适应不良持久性的影响。

Drug addiction is a chronic, relapsing, brain disorder that afflicts many people in the UK and internationally, placing enormous burdens on health, social and criminal justice systems. With the increase in opiates use and associated deaths in the USA, the UK and the EU, it has never been more urgent to understand the neurobiological mechanisms that confer some individuals the vulnerability to switch from controlled, recreational, heroin use to the persistent, compulsive, drug-seeking behaviour that characterises addiction. Only then we will be in a position to develop new treatments that help break these maladaptive compulsive drug-seeking habits or prevent their development in at-risk populations. Remarkably, despite understanding how addictive substances produce their pleasurable or rewarding effects through specific actions on neurons in the brain, it remains unclear why only a subset of individuals currently using drugs such as heroin subsequently become addicted. Recent discoveries have helped understand how, over the course of a prolonged history of drug exposure, a transition occurs in the brain circuits that control drug-seeking behaviour, from the so-called reward system to the dorsolateral (DLS) dopamine-dependent habit system. These transitions have been considered to depend on the hijacking by drugs of the neurons involved in dopamine-related mechanisms in these circuits. Thus, research has almost exclusively focused on the cellular and molecular mechanisms occurring within the neurons of these circuits in trying to elucidate the biological basis of addiction. However, exposure to drugs of abuse also triggers cellular and molecular adaptations in astrocytes, the cells hitherto considered only to have a supporting role in the brain, in that they provide neurons with fuel and maintain brain homeostasis. Because astrocytes form a network of their own, or syncytium, that spans broad territories of the brain, they are in a unique position functionally to bridge aberrantly neuronal circuits that are otherwise independent. Thus, the present research project seeks to understand the contribution of astrocytes and their syncytium to the functional transition from the ventral striatum to the DLS in the control over heroin seeking when it becomes habitual and eventually compulsive. Capitalizing on our novel behavioural models of compulsive heroin seeking habits in the rat we will first carry a cross-sectional study aiming to determine the spatiotemporal profile of the functional recruitment of the striatal astrocytic syncytium across functional domains of the striatum over the course of the development of compulsive heroin seeking habits and identify molecular correlates of this functional recruitment.The second objective of this project is to causally establish the role of DLS astrocytes in the expression of DLS-dopamine dependent heroin seeking habits and their maladaptive persistence in the face of punishment. For this, we will combine viral-mediated manipulations of DLS astrocytes with intra DLS infusions of dopamine receptor antagonists in order to determine whether the reliance of well-established heroin seeking on DLS dopamine mechanisms is influenced by Hm4Di-mediated activation or membrane calcium pump-mediated inhibition of astrocyte activity and whether these manipulations influence the tendency to persist in seeking heroin despite punishment.The third objective of this project is to causally establish the role of astrocytes in the nucleus accumbens in the development of aDLS dopamine-dependent heroin seeking habits and compulsive heroin seeking. For this, we will use a strategy similar to that laid out for objective 2, and we will measure the influence of chronic activation or inhibition of ventral striatal astrocytes throughout the entire history of heroin self-administration on the emergence of DLS-dopamine dependent heroin seeking habits and their maladaptive persistence in the face of punishment.