Sex differences in stress inoculation of addiction-like phenotypes

成瘾样表型应激接种的性别差异

基本信息

批准号：
10757580
负责人：
Debra A Bangasser
金额：
$ 47.3万
依托单位：
GEORGIA STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10757580
关键词：
Adult Adverse event Affect Animal Model Beds 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 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 programs promote resilience pup resilience response reward circuitry sex tool transcriptome transcriptome sequencing transmission process

项目摘要

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上升，经济和人为成本令人震惊。尚不清楚为什么只一部分接受阿片类药物发展依赖的人，促使人们努力了解促进的因素滥用阿片类药物的脆弱性。但是，识别促进底物弹性的因素也至关重要使用障碍（SUD）。生命早期的经验可以改变疾病后来发展的风险/韧性。为了例如，没有压倒性的早期生活压力会产生“接种效应”，从而促进成年后的韧性发展。在这里，我们使用早期逆境，有限的床上用品和嵌套（LBN）模型，以评估这种操纵如何影响成年后的成瘾表型。在磅在幼崽生命的第一周，大坝及其幼崽暴露于低资源环境，这会引起幼犬的压力。我们发现LBN会反对雄性反对成瘾的行为，因此成年男性暴露于LBN的大鼠自助剂较少的吗啡，比成年男性更少动机服用吗啡在正常的，充分采购的筑巢环境中升起。冲动选择是SUD的危险因素，也是评估，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。该建议将决定LBN如何进一步改变类似添加的行为，并改变生理学以及伏隔核（NAC）的转录组，该区域严重介导了药物摄入和冲动。 AIM 1将检验以下假设：LBN会改变吗啡自我的剂量反应曲线在男性的右边行政。这个目标还将确定LBN是否减少了冲动选择和男性冲动行动。与我们的初步数据一致，女性LBN的行为变化 AIM 2将检验以下假设：LBN降低了NAC中的谷氨酸能传播男性，但不是女性，这种作用将促进吗啡的增强有效性。先前的工作已经证明，早期的生活经验可以通过表观遗传修饰来重新编程大脑持续变化基因表达和神经元信号传导。那是AIM 3将确定针对性的变化 LBN引起的NAC中的基因表达和参与染色质重塑事件。我们的初步数据表明，LBN降低了男性几种谷氨酸信号基因的表达。某些组蛋白在这些基因中暗示了脱乙酰基酶（HDACS），从组蛋白尾部去除乙酰基的酶更改。我们将通过操纵NAC中的功能来测试这些HDAC的行为相关性并确定它们是否介导与成瘾相关的行为的弹性。总的来说，该提议将揭示了LBN可以通过这些机制接种雄性对成瘾样表型的机制。值得注意的是，我们的团队研究者的独特位置可以评估LBN诱导的从行为水平到分子水平的变化。此外，LBN效应的性别特异性将使我们通过比较性别来确定新目标这促进了对SUD的韧性，这可能导致发展更好的疗法以减少阿片类药物滥用。