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

• 批准号: 10588333
• 负责人: Paul Leon Brown
• 金额: $ 22.17万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/10588333
• 关键词: Acute; Behavior; Brain; Castration; Cell Nucleus; Cells; Chronic; Cues; Data; Development; Disease; Dopamine; Electrophysiology (science); Estradiol; Estrogen Receptors; Estrogen Replacements; Estrogens; Exhibits; Exposure to; Female; Fire - disasters; Fostering; Gonadal Hormones; Gonadal Steroid Hormones; Habenula; Hormones; Knowledge; Laboratories; Lateral; Learning; Literature; Mediating; Mental Depression; Mental disorders; Midbrain structure; Motivation; Nature; Neurologic; Neurons; Parkinson Disease; Pathway interactions; Pattern; Permeability; Play; Predisposition; Prevalence; Property; Rattus; Research; Rewards; Rodent; Role; Schizophrenia; Severities; Sex Differences; Steroids; Substance abuse problem; Symptoms; Testing; Testosterone; With laterality; Woman; Work; addiction; chronic pain; cohort; common symptom; comorbidity; design; dopaminergic neuron; experimental study; hormone regulation; in vivo; male; men; motivated behavior; neurophysiology; novel; patch clamp; response; sex; symptomatology; therapy development

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 几种神经系统和心理健康障碍，包括加法，抑郁，慢性疼痛和帕金森氏症 疾病，患病率，严重性或症状表现有明显的性别差异，这可以是 当考虑合并症时，进一步的放大器。因此，性是何时要考虑的重要变量 开发潜在的治疗。这种疾病常见的症状包括动机的变化 由异常动机，显着环境线索的处理和奖励学习产生的行为。 中脑多巴胺（DA）神经元的功能改变是与动机行为变化相关的核心 使用这些符号，此外，DA神经元活性由循环的性腺激素调节。这 外侧Habenula（LHB）也是DA细胞发射的重要调节剂，并且与这些相同 疾病。尽管如此，很少的工作已经调查了性和性腺激素对LHB功能的作用。我们的 初步数据显示LHB功能的性别差异明显，LHB的抑制作用较少 在雌性大鼠的DA细胞上，LHB在雌性大鼠中表现出更正常的发射方式。基于 这些新颖而令人兴奋的发现以及以前的文献，我们假设性腺恐怖调节了 LHB活性及其调节中脑神经元活性的能力。确定循环性腺的作用 在LHB诱导的中脑DA神经元的抑制作用中，骑马词（特定目标1）我们将比较雌性大鼠 （完整，卵巢切除或用雌激素替代的卵巢切除）和雄性大鼠（完整，cast割或 用体内电生理方法cast割睾丸激素的替代）。我们预测 雌性大鼠的抑制性LHB刺激对DA发射的抑制作用将变得更强 否定先前观察到的性别差异。我们进一步预测表型性别差异将是 通过雌二醇替换在雌性大鼠中恢复。确定循环性腺激素在 LHB发射率和模式（特定目的2）我们将比较一组单独的大鼠与同一组 使用离体电生理方法的名称。我们预测全细胞贴片钳记录 LHB神经元将以较少的定期模式发射，并增加对超极化诱导的敏感性 与完整的对应物相比，性腺切除术后雌性大鼠爆炸。我们进一步预测 在雌二醇替代的雌性大鼠中将恢复表型发射模式。我们有差距 关于LHB和性腺恐怖的相互作用的知识；提出的实验是针对的 开始填补这一空白。这些实验具有提供基于大脑电路的机制的潜力 在几种神经系统和心理健康障碍中通过性别区分症状学，导致更精确 在治疗开发中。