Dopaminergic plasticity underlying bonding and loss

项目摘要： 虽然强大和健康的社会关系对我们的健康和幸福有积极的贡献，但它们的损失是 对我们的身心健康有害。一夫一妻制的草原田鼠（Microtus ochrogaster）提供了一种 是研究社会联系和丧失的神经生物学的理想物种。先前的工作表明， 中脑核中的多巴胺（DA）受体是键形成和维持的关键介质。 具体而言，DA受体活化对于形成对交配伴侣的选择性联系是必不可少的， 随后对非合作伙伴的侵略，这表明DA在核中的功能作用， 随着关系的成熟，合作者会从伙伴关系转变为非伙伴攻击。其他工作 提示脑内DA系统的可塑性伴随着结合，包括DA受体的变化 表达和离体DA释放。然而，受体表达或释放能力的变化并不 充分解释DA的功能从伙伴关系到新型攻击的转变。da释放和 受体的激活需要是环境特异性的，以便显示出对受体的适当行为。 伴侣或新田鼠。因此，我的研究探讨了多巴胺能系统如何作为一个功能的变化， 在损失中的结合，包括伙伴和新田鼠之间释放的变化。 为此，我的论文利用了GRABDA和光纤测光，这两个工具是我在大草原开发的 田鼠，检测体内DA释放行为田鼠毫秒分辨率。我用这些工具来调查 社会联系和损失可能导致DA系统可塑性的三种方式，DA系统介导了这种转变 在结合行为中。在目标1中，我问是否存在结合诱导的DA释放的体内变化 容量我的初步工作表明，最初的债券形成和债券损失减少光遗传学 诱发延髓核DA释放。目标1将决定我观察到的结果是否 特别是由于异性伴侣的结合/损失，而不是来自其他实验条件， 普遍的社会孤立。在目标2中，我研究了DA释放是如何通过无限制的社交互动与一个 伴侣或新的田鼠在债券成熟和损失的变化。最后，在目标3中，我使用了一个社会操作语 范式，以区分DA释放期间的食欲和完善方面的相互作用， 合作伙伴或小说跨越结合和损失。总之，该提案使用了新颖的行为和技术 方法在草原田鼠，以提供深入了解多巴胺能动力学，有助于内- 个体的可塑性，使社会联系。

Project Summary: While strong and healthy social relationships positively contribute to our health and wellbeing, their loss is detrimental for our mental and physical health. Monogamous prairie voles (Microtus ochrogaster) provide an ideal species to examine the neurobiology of social bonding and loss. Prior work has shown that activation of dopamine (DA) receptors in the nucleus accumbens is a critical mediator of bond formation and maintenance. Specifically, DA receptor activation is essential for forming selective affiliation towards a mating partner and subsequent aggression towards non-partners, suggesting that the functional role of DA in the nucleus accumbens transitions from partner affiliation to non-partner aggression as the bond matures. Other work suggests plasticity of the accumbal DA system accompanies bonding, including changes in DA receptor expression and ex vivo DA release. However, changes in receptor expression or capacity for release do not fully explain the shift in the function of DA from partner affiliation to novel aggression. DA release and activation of receptors needs to be context specific in order to display the appropriate behavior towards the partner or novel voles. Thus, my research examines how the dopaminergic system changes as a function of bonding in loss, including changes in release between the partner and novel voles. To do so, my dissertation leverages GRABDA and fiber photometry, two tools that I developed in prairie voles, to detect in vivo DA release in behaving voles with millisecond resolution. I use these tools to investigate three ways in which social bonding and loss can cause plasticity in the DA system that mediates the transition in bonding behaviors. In Aim 1 I ask whether there are bonding induced in vivo changes in DA release capacity. My preliminary work shows that initial bond formation and bond loss decreases optogenetically evoked DA release in the nucleus accumbens. Aim 1 will determine whether my observed results are specifically due to bonding/loss from an opposite sex partner, not from other experimental conditions or general social isolation. In Aim 2, I examine how DA release elicited by unrestricted social interaction with a partner or novel vole changes during bond maturation and loss. Finally, in Aim 3, I use a social operant paradigm to distinguish DA release during the appetitive and consummatory aspects of interaction with a partner or novel across bonding and loss. In sum, this proposal uses novel behavioral and technical approaches in prairie voles to provide insights into the dopaminergic dynamics that contribute to within- individual plasticity that enables social bonding.