Estrogen modulation of the lateral habenula and its ability to inhibit midbrain dopamine neurons

雌激素对外侧缰核的调节及其抑制中脑多巴胺神经元的能力

基本信息

  • 批准号:
    10588333
  • 负责人:
  • 金额:
    $ 22.17万
  • 依托单位:
  • 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:
    2023-01-20 至 2024-12-31
  • 项目状态:
    已结题

项目摘要

Project Summary Several neurological and mental health disorders, including addiction, depression, chronic pain, and Parkinson’s disease, have notable sex differences in their prevalence, severity, or symptom presentation, which can be further amplified when co-morbidity is considered. Consequently, sex is an important variable to consider when developing potential treatment. Amongst the symptoms common to such disorders are changes in motivated behavior resulting from abnormal motivation, processing of salient environmental cues, and reward learning. Altered function of midbrain dopamine (DA) neurons are central to the changes in motivated behavior associated with these symptoms and, in addition, DA neuronal activity is modulated by circulating gonadal hormones. The lateral habenula (LHb) is also a significant regulator of DA cell firing and has been implicated in these same disorders. Despite this, little work has investigated the role of sex and gonadal hormones on LHb function. Our preliminary data have shown clear sex differences in LHb function, with the LHb having less inhibitory control over DA cells in female rats and with the LHb displaying a more regular firing pattern in female rats. Based on these novel and exciting findings, as well as previous literature, we hypothesize that gonadal hormones modulate both LHb activity and its ability to regulate midbrain neuronal activity. To determine the role circulating gonadal hormones play in LHb-induced inhibition of midbrain DA neurons (Specific Aim 1) we will compare female rats (intact, ovariectomized, or ovariectomized with estrogen replacement) and male rats (intact, castrated, or castrated with testosterone replacement) using an in vivo electrophysiological approach. We predict that the inhibitory effect of LHb stimulation on DA firing will become stronger in female rats following gonadectomy, negating the previously observed sex difference. We further predict that the phenotypical sex difference will be reinstated in female rats by estradiol replacement. To determine the role circulating gonadal hormones play in LHb firing rate and pattern (Specific Aim 2) we will compare a separate cohort of rats with the same group designations using an ex vivo electrophysiological approach. We predict that whole-cell patch-clamp recorded LHb neurons will fire in a less regular pattern and have increased susceptibility to hyperpolarization-induced burst firing in female rats following gonadectomy compared to their intact counterparts. We further predict that the phenotypical firing patterns will be reinstated in female rats with estradiol replacement. There is a gap in our knowledge regarding the interaction of the LHb and gonadal hormones; the proposed experiments are intended to begin to fill that gap. These experiments have the potential to provide a brain circuit-based mechanism of differing symptomatology by sex in several neurological and mental health disorders, leading to more precision in treatment development.
项目摘要 几种神经和精神健康疾病,包括成瘾,抑郁症,慢性疼痛和帕金森氏症 疾病,在患病率、严重程度或症状表现方面存在显著的性别差异,这可能是 当考虑到合并症时进一步放大。因此,性别是一个需要考虑的重要变量, 开发潜在的治疗方法。在这些疾病的共同症状中, 异常动机导致的行为,对显著环境线索的处理,以及奖励学习。 中脑多巴胺(DA)神经元的功能改变是与动机行为相关的变化的中心。 此外,DA神经元的活动受到循环性腺激素的调节。的 外侧缰核(LHb)也是DA细胞放电的重要调节器,并与这些相同的 紊乱尽管如此,很少有研究性和性腺激素对LHb功能的作用。我们 初步数据显示,LHb功能存在明显的性别差异,LHb具有较少的抑制控制作用 在雌性大鼠中,LHb显示出更规则的放电模式。基于 这些新的和令人兴奋的发现,以及以前的文献,我们假设性腺激素调节, LHb活性及其调节中脑神经元活性的能力。为了确定循环性腺的作用 激素在LHb诱导的中脑DA神经元抑制中的作用(具体目标1),我们将比较雌性大鼠 (完整、卵巢切除或卵巢切除伴雌激素替代)和雄性大鼠(完整、去势或卵巢切除伴雌激素替代) 用睾酮替代物阉割)。我们预测 雌性大鼠去性腺后,刺激LHb对DA放电的抑制作用增强, 否定了之前观察到的性别差异。我们进一步预测,表型性别差异将是 雌性大鼠通过雌二醇替代恢复。为了确定循环性腺激素在 LHb放电率和模式(特定目标2)我们将比较同一组的单独大鼠队列 使用离体电生理学方法进行命名。我们预测全细胞膜片钳记录 LHb神经元将以不太规则的模式发射,并且对超极化诱导的敏感性增加。 雌性大鼠性腺切除术后的爆发放电与其完整的对应物相比。我们进一步预测, 雌鼠的表型放电模式将在雌二醇替代后恢复。在我们的世界里, 关于LHb和性腺激素相互作用的知识;拟议的实验旨在 to开始to start开始to fill填补that gap空白.这些实验有可能提供一种基于脑回路的机制, 在几种神经和精神健康疾病中按性别区分神经病学, 在治疗发展中。

项目成果

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Paul Leon Brown其他文献

Paul Leon Brown的其他文献

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{{ truncateString('Paul Leon Brown', 18)}}的其他基金

A novel habenulo-mesencephalic circuit in aversive signaling
厌恶信号中一种新型的缰核中脑回路
  • 批准号:
    8505470
  • 财政年份:
    2011
  • 资助金额:
    $ 22.17万
  • 项目类别:
A novel habenulo-mesencephalic circuit in aversive signaling
厌恶信号中一种新型的缰核中脑回路
  • 批准号:
    8400570
  • 财政年份:
    2011
  • 资助金额:
    $ 22.17万
  • 项目类别:
A novel habenulo-mesencephalic circuit in aversive signaling
厌恶信号中一种新型的缰核中脑回路
  • 批准号:
    8202085
  • 财政年份:
    2011
  • 资助金额:
    $ 22.17万
  • 项目类别:

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