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呈上升趋势，造成的经济和人力成本令人震惊。目前还不清楚为什么只 服用阿片类药物的一部分人会产生依赖性，促使人们努力了解促进阿片类药物产生的因素 容易滥用阿片类药物。然而，找出促进物质弹性的因素也很重要。 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/恢复力。为了 例如，早期生活中的压力如果不是压倒性的，可以产生“接种”效应，促进 成年期复原力的发展。在这里，我们使用了早期生活逆境的老鼠模型，有限的床上用品和 嵌套（LBN）模型，以评估这种操作如何影响成年期的成瘾样表型。在LBN中， 母鼠及其幼崽在幼崽出生后的第一周就暴露在资源匮乏的环境中，这会导致 幼犬的压力。我们发现 LBN 可以让男性预防类似成瘾的行为，例如成年男性 与成年雄性相比，暴露于 LBN 的大鼠自我施用的吗啡较少，并且服用吗啡的积极性较低 在正常的、资源充足的筑巢环境中长大。冲动选择是 SUD 的一个危险因素，也是 评估发现，LBN 减少了男性的冲动选择。 LBN 对雌性大鼠的这些行为没有影响。 该提案将确定 LBN 如何进一步改变类似加法的行为，以及改变生理学 以及伏隔核（NAc）的转录组，该区域关键介导药物摄入和 冲动。目标 1 将检验 LBN 改变吗啡自我剂量反应曲线的假设 男性右侧给药。这个目标还将决定 LBN 是否会减少冲动选择和 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 预计不会。目标 2 将检验 LBN 减少 NAc 中谷氨酸传递的假设 男性，但不是女性，这种效应将提高吗啡增强功效的恢复力。之前的工作 已经证明，早期的生活经历可以通过表观遗传修饰对大脑进行重新编程，从而导致 基因表达和神经信号传导的持续变化。因此，目标 3 将识别性别特异性变化 LBN 引发的 NAc 中的基因表达和伴随的染色质重塑事件。我们的初步 数据显示，LBN 降低了雄性体内几种谷氨酸信号基因的表达。某些组蛋白 脱乙酰酶 (HDAC) 是一种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 NAc 内的功能来测试这些 HDAC 的行为相关性 并确定它们是否能调节对成瘾相关行为的恢复力。总的来说，该提案将 揭示了 LBN 可以让男性接种疫苗以对抗成瘾样表型的机制。值得注意的是，我们的团队 研究人员具有独特的优势来评估 LBN 引起的从行为到分子水平的变化。 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目标 提高对 SUD 的抵抗力，这可能会导致开发出更好的疗法来减少阿片类药物的滥用。