Neural mechanisms preventing postpartum relapse to cocaine seeking in new mothers
Neural mechanisms preventing postpartum relapse to cocaine seeking in new mothers
批准号:
10614372
负责人:
Mariana Pereira Arboleya
金额:
$19.46万
依托单位国家:
美国
项目类别:
财政年份:
2022
资助国家:
美国
项目状态:
未结题
起止时间:
2022-05-01 至 2025-04-30
关键词:
AbstinenceAddressAffectAnimal ModelBehaviorBehavioralBirthCanine AdenovirusesChildChild CareChild DevelopmentChild HealthChild RearingClinical ResearchCocaineCocaine DependenceCoupledDecision MakingDopamineDrug CombinationsDrug ModelingsDrug usageDrug userEnterobacteria phage P1 Cre recombinaseExhibitsExtinctionGoalsHealthHealth BenefitHumanIncentivesInfantInfant DevelopmentInjectionsInterventionKnowledgeMaternal BehaviorMedialMediatingMethodsModelingMothersMotivationNeurobiologyNeuronsNucleus AccumbensPathway interactionsPerinatalPharmaceutical PreparationsPostpartum PeriodPostpartum WomenPreoptic AreasProcessRattusRelapseResistanceRewardsRoleSiteSocietiesStimulusStructureTechnologyTestingTherapeutic InterventionTimeVentral Tegmental AreaViralWomanWorkclinically significantcocaine relapsecocaine relapse preventioncocaine seekingcocaine useconditioned place preferencedesigner receptors exclusively activated by designer drugsdrug relapseeffective interventioneffective therapyexecutive functionexperimental groupexperimental studygenetic approachgenetic manipulationineffective therapiesmaternal cocaine usemotivated behaviorneuralneuroadaptationneurobiological mechanismneuromechanismnoveloffspringpharmacologicpre-clinicalpreventpuprelapse preventionresponsereward circuitrytoolvirus Cre recombinase
中文摘要
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。
英文摘要
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.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Postpartum Depression and Parenting: Role of mPOA circuits in maternal sensitivity
-
批准号:10726256
-
项目类别:
-
资助金额:$41.82万
-
财政年份:2023
-
负责人:Mariana Pereira Arboleya
-
依托单位:
Neural mechanisms preventing postpartum relapse to cocaine seeking in new mothers
-
批准号:10354553
-
项目类别:
-
资助金额:$23.48万
-
财政年份:2022
-
负责人:Mariana Pereira Arboleya
-
依托单位:
Dopamine/Adenosine interaction in depression: Therapeutic role of A2A antagonism
-
批准号:8359164
-
项目类别:
-
资助金额:$7.75万
-
财政年份:2012
-
负责人:Mariana Pereira Arboleya
-
依托单位:
Dopamine/Adenpsine interaction in depression: Therapeutic role of A2A antagonism
-
批准号:8501613
-
项目类别:
-
资助金额:$7.35万
-
财政年份:2012
-
负责人:Mariana Pereira Arboleya
-
依托单位:
Cocaine disruption of maternal motivation: preference for pups vs. cocaine
-
批准号:7781520
-
项目类别:
-
资助金额:$3.86万
-
财政年份:2009
-
负责人:Mariana Pereira Arboleya
-
依托单位:
Cocaine disruption of maternal motivation: preference for pups vs. cocaine
-
批准号:7921991
-
项目类别:
-
资助金额:$3.82万
-
财政年份:2009
-
负责人:Mariana Pereira Arboleya
-
依托单位:
海外基金