Sex differences in stress inoculation of addiction-like phenotypes

成瘾样表型应激接种的性别差异

• 批准号: 10392452
• 负责人: Debra A Bangasser
• 金额: $ 64.65万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-15 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10392452
• 关键词: Adult; Adverse event; Affect; Animal Model; Behavior; Behavioral; Brain; Data; Dependence; Development; Disease; Dose; Economics; Environment; Enzymes; Epigenetic Process; Ethics; Event; Exposure to; Female; Gene Expression; Genes; Genetic Transcription; Glutamates; HDAC1 gene; Histone Acetylation; Histone Deacetylase; Histone Deacetylase Inhibitor; Histones; Human; Impulsivity; Intake; Intervention; Lead; Life; Life Experience; Link; Measures; Mediating; Mental disorders; Metabolic; Modeling; Modification; Molecular; Morphine; Neurobiology; Neurons; Nucleus Accumbens; Opioid; Paper; Persons; Pharmaceutical Preparations; Phenotype; Physiological; Physiology; Positioning Attribute; Poverty; Probability; Psychological reinforcement; Rattus; Regulator Genes; Research Personnel; Resource-limited setting; Resources; Rewards; Risk; Risk Factors; Self Administration; Sex Differences; Specificity; Stress; Substance Use Disorder; Tail; Testing; Viral; Whole-Cell Recordings; Work; addiction; behavior test; behavioral phenotyping; chromatin remodeling; cost; design; discounting; early experience; early life adversity; early life stress; experience; glutamatergic signaling; histone modification; hypothalamic-pituitary-adrenal axis; innovation; male; neurotransmission; novel; opioid misuse; opioid use; opioid use disorder; overexpression; postnatal; postsynaptic; pre-clinical; pre-clinical research; presynaptic; pup; resilience; response; reward circuitry; sex; tool; transcriptome; transcriptome sequencing; transmission process

Opioid use disorder is on the rise and the economic and human cost is staggering. It remains unclear why only a subset of people who take opioids develop dependence, prompting efforts to understand factors that promote vulnerability to opioid misuse. However, it is also critical to identify factors that promote resilience to substance use disorder (SUD). Experiences early in life can alter risk/resilience for the later development of disorders. For example, early life stress that is not overwhelming can have an “inoculating” effect that promotes the development of resilience in adulthood. Here we use a rat model of early life adversity, the limited bedding and nesting (LBN) model, to assess how this manipulation affects addiction-like phenotypes in adulthood. In LBN, dams and their pups are exposed to a low resource environment during the pups first week of life, which induces stress in the pups. We found that LBN inoculates males against addiction-like behaviors, such that adult male rats exposed to LBN self-administer less morphine and are less motivated to take morphine than adult males raised in a normal, adequately resourced, nesting environment. Impulsive choice, a risk factor for SUD, was also assessed, and LBN reduced impulsive choice in males. LBN had no effect on these behaviors in female rats. This proposal will determine how LBN further alters addition-like behaviors, as well as changes the physiology and the transcriptome of the nucleus accumbens (NAc), a region that critically mediates drug intake and impulsivity. Aim 1 will test the hypothesis that LBN shifts the dose-response curve for morphine self- administration to the right in males. This aim will also determine if LBN reduces both impulsive choice and impulsive action in males. Consistent with our preliminary data, behavioral changes following LBN in females are not expected. Aim 2 will test the hypothesis that LBN reduces glutamatergic transmission in the NAc of males, but not females, an effect that would promote resilience to the reinforcing efficacy of morphine. Prior work has demonstrated that early life experience can reprogram the brain through epigenetic modifications that lead to persistent changes in gene expression and neuronal signaling. Thus, Aim 3 will identify sex-specific changes in gene expression and accompanying chromatin remodeling events in the NAc elicited by LBN. Our preliminary data reveal that LBN reduces the expression of several glutamate signaling genes in males. Certain histone deacetylases (HDACs), enzymes that remove acetyl groups from histone tails, are implicated in these gene changes. We will test the behavioral relevance of these HDACs by manipulating their function within the NAc and determining whether they mediate resilience to addiction-related behavior. Collectively, this proposal will reveal mechanisms by which LBN can inoculate males against addiction-like phenotypes. Notably, our team of investigators is uniquely positioned to assess LBN-induced changes from the behavioral to the molecular level. Moreover, the sex-specificity of the LBN effects will allow us to, by comparing the sexes, identify novel targets that promote resilience to SUD, which may lead to the development of better therapies to reduce opioid misuse.

阿片类药物使用障碍正在增加，经济和人力成本惊人。目前还不清楚为什么只有 服用阿片类药物的一部分人会产生依赖性，这促使人们努力了解促进阿片类药物依赖的因素。 滥用阿片类药物的脆弱性。然而，确定促进对实质性问题的复原力的因素也至关重要 使用障碍（SUD）。生命早期的经历可以改变疾病后期发展的风险/弹性。为 例如，早期生活中的压力，不是压倒性的，可以有一个“负”的影响，促进 在成年期发展韧性。在这里，我们使用了一个早期生活逆境的大鼠模型，有限的床上用品， 嵌套（LBN）模型，以评估这种操纵如何影响成年后的成瘾样表型。在黎巴嫩， 母鼠和它们的幼崽在出生后的第一周就暴露在低资源环境中， 幼崽的压力我们发现，LBN接种男性对成瘾样行为，如成年男性 暴露于LBN的大鼠自我施用的吗啡较少，并且比成年雄性大鼠更不愿意服用吗啡 在正常的、资源充足的筑巢环境中长大。冲动性选择是SUD的一个危险因素， 评估，LBN减少男性的冲动选择。LBN对雌性大鼠的这些行为没有影响。 这项提议将确定LBN如何进一步改变类似加法的行为，以及改变生理学 和转录组的核神经元（NAc），一个区域，关键介导的药物摄入， 冲动目的1将检验LBN移动吗啡自我调节的剂量-反应曲线的假设。 在男性中向右给药。这一目标也将决定LBN是否会减少冲动选择， 男性的冲动行为与我们的初步数据一致，女性LBN后的行为变化 是不期望的。目的2将检验LBN减少NAc中的神经递质传递的假设， 男性，但不是女性，这将促进恢复吗啡的增强功效的效果。先前工作 已经证明，早期的生活经验可以通过表观遗传修饰重新编程大脑， 基因表达和神经信号的持续变化。因此，目标3将确定性别特异性变化 在基因表达和伴随的染色质重塑事件在NAc引起的LBN。我们的初步 数据显示LBN降低了雄性中几种谷氨酸信号基因的表达。某些组蛋白 去乙酰基酶（HDAC），从组蛋白尾部去除乙酰基的酶，与这些基因有关 变化我们将通过操纵这些HDAC在NAc内的功能来测试它们的行为相关性 并确定它们是否介导成瘾相关行为的恢复力。总的来说，这项建议将 揭示LBN可以使男性抵抗成瘾样表型的机制。值得注意的是，我们的团队 研究人员处于独特的地位，以评估从行为到分子水平的LBN诱导的变化。 此外，LBN效应的性别特异性将使我们能够通过比较性别来识别新的靶点 促进对SUD的恢复力，这可能导致开发更好的治疗方法以减少阿片类药物滥用。