Neural mechanisms preventing postpartum relapse to cocaine seeking in new mothers

项目摘要 产后妇女重新使用可卡因是一个严重的健康问题，影响母亲的能力， 照顾她的孩子，对母亲和孩子都有终身的影响。有一个机会之窗 对于产后早期的治疗，因为新母亲使用可卡因的情况大大减少， 与养育子女有关的竞争动机。不幸的是，很少有女性保持禁欲和复发， 可卡因使用超过第一个6个月后，他们的孩子出生。到目前为止，人们对它知之甚少。 神经生物学机制，母亲的动机可以防止复发可卡因寻求新的 妈妈们目前的建议是在我过去几年工作的基础上提出的。我们之前在老鼠身上的工作 表明，在独特的产后早期，新妈妈也减少了可卡因的寻求， 内侧视前区（mPOA）是一个重要的结构， 行为，结果增加了母亲选择可卡因条件的激励在一个并发的小狗/可卡因 选择条件位置偏好（CPP）这项建议的目的是描绘神经 新妈妈对可卡因复发的短暂抵抗的潜在过程。为了实现这一目标，我们 将使用一种新的适应药物复发的预防-恢复CPP动物模型和一种途径- 特异性化学发生学方法来确定mPOA神经元投射到边缘下皮层（IL）的作用 腹侧被盖区（VTA）在预防禁欲新母亲可卡因寻求恢复中的作用 大鼠这两种结构都从mPOA接收直接输入，并且是介导 奖励和反应分配，IL有助于刺激识别和执行功能， 腹侧被盖区通过多巴胺投射到延髓核调节行为策略。实验 在AIM 1中，将使用Cre依赖性抑制性（hM4Di）或兴奋性（hM3Dq）设计者的组合注射 受体专门激活的设计师药物（DREADD）AAV进入mPOA，与逆行转导 将CAV2-Cre病毒导入IL中，以评估mPOA à IL途径在 可卡因在新妈妈中的恢复。AIM 2的实验将确定单突触的作用， 对VTA的mPOA预测（mPOAàVTA），以防止以前被扑灭的可卡因死灰复燃 寻找新妈妈的行为该AIM还将使用Gi-或Gq-DREADD与CAV2-Cre组合， 在可卡因CPP恢复期间选择性地操纵mPOAàVTA通路。实体就雇员 还将研究mPOAàIL和mPOAàVTA化学遗传学操作对母体行为的影响。 考虑到母亲使用可卡因对母亲和儿童健康的后果， 了解导致这种耐复发状态的神经生物学具有重要意义。这项建议会 产生关于促进禁欲的自然神经适应的重要新知识，并可能揭示新的 作为治疗可卡因成瘾的潜在治疗干预的靶点。

Project Summary Relapse to cocaine use in postpartum women is a serious health problem that impacts the mother’s ability to care for her child, with life-long consequences for both the mother and child. There is a window of opportunity for treatment in the early postpartum period, as cocaine use in new mothers is significantly reduced by the competing motivation related to child rearing. Unfortunately, few women maintain abstinence and relapse to cocaine use beyond the first 6 months following their child’s birth. To date, little is known regarding the neurobiological mechanisms by which maternal motivation can prevent relapse to cocaine seeking in new mothers. The current proposal builds logically on my work from the past several years. Our prior work in rats demonstrates that during the unique early postpartum period, new mothers also reduce cocaine seeking, and that pharmacological inactivation of the medial preoptic area (mPOA), a critical structure orchestrating maternal behavior, results in increased maternal choice of cocaine-conditioned incentives in a concurrent pup/cocaine choice conditioned place preference (CPP) task. The objective of this proposal is to delineate the neural processes underlying the transient resistance to cocaine relapse in new mothers. To accomplish this goal, we will use a novel adaptation of the extinction-reinstatement CPP animal model of drug relapse and a pathway- specific chemogenetic approach to determine the role of mPOA neurons projecting to the infralimbic cortex (IL) and the ventral tegmental area (VTA) in preventing reinstatement of cocaine seeking in abstinent new mother rats. Both structures receive direct input from the mPOA and are critical nodes of the circuitry that mediates reward and response allocation, with the IL contributing to stimulus recognition and executive functions, and the VTA modulating the behavioral strategy via dopamine projections to the nucleus accumbens. The experiments in AIM 1 will use combined injections of a Cre-dependent inhibitory (hM4Di) or excitatory (hM3Dq) designer receptors exclusively activated by designer drugs (DREADD) AAV into the mPOA, with a retrograde transducing CAV2-Cre virus into the IL to assess the functional necessity and sufficiency of the mPOA à IL pathway on reinstatement of cocaine seeking in new mothers. Experiments in AIM 2 will determine the role of monosynaptic mPOA projections to the VTA (mPOAàVTA) in preventing reinstatement of previously extinguished cocaine seeking behavior in new mothers. This AIM will also use Gi- or Gq-DREADDs combined with CAV2-Cre to selectively manipulate mPOAàVTA pathway during reinstatement of cocaine CPP. The impact of these mPOAàIL and mPOAàVTA chemogenetic manipulations on maternal behavior will be also studied. Considering the consequences of maternal cocaine use on both mother and child health, it is of major clinical significance to understand the neurobiology contributing to this relapse-resistant state. This proposal will generate critical new knowledge of the natural neural adaptations that promote abstinence and may reveal novel targets for potential therapeutic intervention to treat cocaine addiction.