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Projection-specific gene expression in resilience to chronic stress

慢性应激恢复能力中的投射特异性基因表达

基本信息

批准号：
10683942
负责人：
Michelle Suzanne Mazei-Robison
金额：
$ 60.94万
依托单位：
MICHIGAN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-08 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10683942
关键词：
Affect Affinity Chromatography Amygdaloid structure Androgen Receptor Anhedonia Anxiety Automobile Driving Behavior Behavior assessment Behavioral Behavioral Assay Binding Biological Brain Cell physiology Chronic stress Cytosol DNA Data Female Fright Functional disorder Funding Gene Expression Gene Targeting Genetic Glutamates Hippocampus Individual Knock-out Major Depressive Disorder Mental Health Mental disorders Molecular Mood Disorders Mus National Institute of Mental Health Neurobiology Neurons Nuclear Nucleus Accumbens Patients Pharmacology Process Receptor Signaling Research Ribosomes Role Sex Differences Signal Transduction Stress System Techniques Testosterone Therapeutic Intervention Transgenic Mice Translating Viral Viral Vector Woman Work antagonist brain circuitry chromatin immunoprecipitation designer receptors exclusively activated by designer drugs emotion regulation experience health disparity hedonic innovation interest male men novel novel therapeutic intervention patient subsets pharmacologic promote resilience public health relevance receptor function resilience response sex sexual disparity stress resilience therapeutic target tool treatment strategy

项目摘要

SUMMARY Stressful and traumatic experiences can contribute to mood disorders in some individuals while others are resilient to this process, and pharmacological tools for treating major depression (MDD) are effective on only a subset of patients. Moreover, MDD affects women nearly twice as often as men, but the neurobiological underpinnings of this discrepancy are unclear. Over the past five years of the current funded project, we demonstrated that lower excitability of ventral hippocampal glutamatergic projections to nucleus accumbens (vHPC-NAc) drives increased resilience to stress-induced anhedonia in male mice compared to females, and that this effect is caused directly by testosterone in males. However, the mechanisms by which testosterone regulates excitability of the vHPC-NAc remain unknown. Testosterone produces many of its effects through activation of the androgen receptor (AR) which can alter cell function through signaling cascades in the cytosol or through directly binding to DNA and altering gene expression. We have shown that vHPC-NAc neurons produce AR and respond to AR antagonists, and our preliminary data show that eliminating AR in vHPC-NAc neurons increases excitability. This leads to our overarching hypothesis for years 6-10: that testosterone activation of ARs in vHPC-NAc decreases excitability through changes in gene expression to drive behavioral resilience to stress. This is significant, as identification of AR targets/mechanisms driving resilience may generate novel therapeutic strategies that would be particularly beneficial in females, an unmet need due to the sexual disparity in mood disorders. We will address this using three specific aims: 1) Uncover the mechanisms of testosterone-driven reduction in vHPC-NAc excitability using novel transgenic mice and classical pharmacology; 2) Uncover the mechanisms of testosterone-driven resilience to stress using novel mouse lines and a circuit- specific intersection dual viral vector approach; and 3) Determine circuit-specific gene expression driven by sex, testosterone, and the androgen receptor using translating ribosome affinity purification. Given the established role of vHPC circuitry in emotional regulation, the gene expression studies proposed here will meaningfully impact basic psychiatric research and may elucidate novel treatment strategies for psychiatric disorders that could be particularly beneficial to female patients. Moreover, our understanding of basal sex differences in brain circuitry is lacking, so this work will inform not only stress studies, but will increase understanding of sex as a biological variable in all behaviors that engage vHPC circuitry.

总结压力和创伤性经历会导致某些人的情绪障碍，而另一些人则会适应这一过程，和治疗抑郁症（MDD）的药物工具是有效的，只有一个患者的子集。此外，MDD影响女性的频率几乎是男性的两倍，但神经生物学这种差异的依据尚不清楚。在过去五年的资助项目中，我们表明腹侧海马神经元投射到延髓核的兴奋性降低，与雌性小鼠相比，vHPC-NAc在雄性小鼠中驱动对应激诱导的快感缺失的恢复力增加，这种效应是由男性体内的睾丸激素直接引起的。然而，睾丸激素调节vHPC-NAc的兴奋性仍然未知。Tehran产生了许多影响，通过雄激素受体（AR）的激活，可通过胞质溶胶中的信号级联改变细胞功能或通过直接结合DNA并改变基因表达。我们已经证明vHPC-NAc神经元产生AR并对AR拮抗剂产生反应，我们的初步数据表明，在vHPC-NAc中消除AR 神经元增加兴奋性。这就引出了我们对6-10年级的总体假设： vHPC-NAc中AR的激活通过基因表达的变化降低兴奋性，抗压能力这是重要的，因为识别AR目标/驱动弹性的机制可以产生新的治疗策略，这将是特别有益的女性，一个未满足的需求，由于性情绪障碍的差异。我们将使用三个具体目标来解决这个问题：1）揭示使用新型转基因小鼠和经典药理学，睾酮驱动的vHPC-NAc兴奋性降低; 2)使用新型鼠标线和电路揭示睾丸激素驱动的压力恢复机制- 特异性交叉双病毒载体方法;和3）确定由性别驱动电路特异性基因表达，睾酮和雄激素受体。鉴于既定的 vHPC电路在情绪调节中的作用，这里提出的基因表达研究将有意义影响基础精神病学研究，并可能阐明精神疾病的新治疗策略，对女性患者尤其有益。此外，我们对大脑中基础性别差异的理解因此，这项工作不仅将为压力研究提供信息，而且将增加对性作为一种参与vHPC电路的所有行为中的生物变量。

项目成果

期刊论文数量（18）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Commentary: Untangling the structural and enzymatic roles of CaMKII at the synapse.

评论：阐明 CaMKII 在突触中的结构和酶作用。

DOI：
10.1016/j.ceca.2023.102813
发表时间：
2023
期刊：
Cell calcium
影响因子：
4
作者：
Anderson,Daniela;Robison,AJ
通讯作者：
Robison,AJ

Sex differences in the traumatic stress response: the role of adult gonadal hormones.

DOI：
10.1186/s13293-018-0192-8
发表时间：
2018-07-13
期刊：
Biology of sex differences
影响因子：
7.9
作者：
Pooley AE;Benjamin RC;Sreedhar S;Eagle AL;Robison AJ;Mazei-Robison MS;Breedlove SM;Jordan CL
通讯作者：
Jordan CL

Light modulates hippocampal function and spatial learning in a diurnal rodent species: A study using male nile grass rat (Arvicanthis niloticus).