Neural mechanisms preventing postpartum relapse to cocaine seeking in new mothers

项目摘要 产后妇女再次使用可卡因是一个严重的健康问题，影响母亲的 照顾她的孩子，对母亲和孩子都会产生终身的影响。有一扇机会之窗 用于产后早期治疗，因为新妈妈的可卡因使用量显著减少 与育儿相关的相互竞争的动机。不幸的是，很少有女性保持禁欲和复发 在孩子出生后的前6个月内吸食可卡因。到目前为止，人们对此知之甚少 母亲的动机可以防止新生的可卡因复吸的神经生物学机制 母亲们。目前的建议建立在我过去几年的工作基础上。我们之前在老鼠身上所做的工作 表明在独特的产后早期，新妈妈也减少了寻求可卡因的次数，并且 内侧视前区(MPOA)的药理学失活，这是一种协调母亲 行为，导致母亲对可卡因条件刺激的选择增加，同时出现幼崽/可卡因 选择条件性位置偏好(CPP)任务。这项提议的目的是描绘神经 新妈妈对可卡因复发的暂时性抵抗的潜在过程。为了实现这一目标，我们 将使用一种新的适应灭绝-恢复CPP的药物复发动物模型和一种途径- 确定投射到下缘皮质(IL)的mPOA神经元作用的特殊化学发生方法 腹侧被盖区(VTA)在防止戒断的新妈妈恢复寻找可卡因中的作用 老鼠。这两个结构都接收来自mPOA的直接输入，并且都是中介电路的关键节点 奖励和反应分配，其中IL有助于刺激识别和执行功能，以及 VTA通过向伏隔核投射多巴胺来调节行为策略。这些实验 在AIM 1中，将使用依赖CRE的抑制性(HM4Di)或兴奋性(HM3Dq)设计器的组合注射 受体被特制药物(DREADD)AAV激活进入mPOA，通过逆行转导 CAV2-Cre病毒导入IL评价mPOAàIL途径功能的必要性和充分性 恢复新妈妈的可卡因寻觅。AIM 2中的实验将确定单突触的作用 MPOA向VTA(mPOAàVTA)的投射在防止先前熄灭的可卡因恢复中的作用 在新妈妈身上寻找行为。该AIM还将使用GI-或GQ-DREADS与CAV2-CRE相结合，以 可卡因CPP恢复过程中选择性地操纵mPOAàVTA通路这些因素的影响 还将研究mPOAàIL和mPOAàVTA对母体行为的化学遗传操作。 考虑到母亲使用可卡因对母亲和儿童健康的影响，它具有重大的临床意义。 了解神经生物学对这种复发抵抗状态的作用具有重要意义。这项提议将 产生关于促进禁欲的自然神经适应的关键新知识，并可能揭示出新的 治疗可卡因成瘾的潜在治疗干预的目标。

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.