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.

项目概要 多种神经和精神健康疾病，包括成瘾、抑郁、慢性疼痛和帕金森病 疾病的患病率、严重程度或症状表现存在显着的性别差异，这可能是 当考虑测试合并症时，性别是一个需要考虑的重要变量。 开发潜在的治疗方法是此类疾病的常见症状之一。 由异常动机、显着环境线索处理和奖励学习引起的行为。 中脑多巴胺（DA）神经元功能的改变是相关动机行为变化的核心 伴随这些症状，此外，DA 神经元活动受到循环性腺激素的调节。 外侧缰核 (LHb) 也是 DA 细胞放电的重要调节者，并且与这些相同的事件有关 尽管如此，很少有人研究性激素和性腺激素对 LHb 功能的影响。 初步数据显示 LHb 功能存在明显的性别差异，LHb 的抑制控制较少 与雌性大鼠的 DA 细胞相比，并且 LHb 在雌性大鼠中表现出更规则的放电模式。 这些新颖而令人兴奋的发现以及之前的文献，我们追求性腺激素调节 LHb 活性及其调节中脑神经元活动的能力确定循环性腺的作用。 激素在 LHb 诱导的中脑 DA 神经元抑制中发挥作用（具体目标 1）我们将比较雌性大鼠 （完整的、切除卵巢的或切除卵巢并补充雌激素）和雄性大鼠（完整的、阉割的或 我们使用体内电生理学方法预测。 雌性大鼠性腺切除后，LHb 刺激对 DA 放电的抑制作用会更强， 否定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。 通过雌二醇替代恢复雌性大鼠体内循环性腺激素的作用。 LHb 放电率和模式（具体目标 2）我们将单独的一组大鼠与同一组进行比较 我们使用离体电生理学方法预测全细胞膜片钳记录。 LHb 神经元将以不太规则的模式放电，并且对超极化诱导的敏感性增加 与完整的骨骼相比，雌性大鼠在性腺切除后会出现爆发性放电。 通过雌二醇替代，雌性大鼠的典型放电模式将得到恢复，但我们的研究存在差距。 有关 LHb 和性腺激素相互作用的知识； 这些实验有可能提供一种基于脑回路的机制。 在几种神经系统和精神健康疾病中，不同性别的症状有所不同，从而提高精确度 在治疗开发中。