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

项目摘要 几种神经和精神健康障碍，包括成瘾、抑郁、慢性疼痛和帕金森氏症 疾病，在患病率、严重性或症状表现上有显著的性别差异，这可能是 当考虑到共同发病时，进一步放大。因此，在什么时候，性是一个需要考虑的重要变量 开发潜在的治疗方法。在这些障碍的共同症状中，有动机的变化 由异常动机、显著环境线索的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改变的中心 此外，DA神经元的活动受循环性腺激素的调节。这个 外侧缰核(LHb)也是DA细胞放电的重要调节器，并与这些 精神错乱。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。我们的 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LHb相比，LHb在雌性大鼠表现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的活性及其调节中脑神经元活动的能力。确定性腺循环中的作用 激素在LHb诱导的中脑DA神经元抑制中的作用(特定目标1)我们将比较雌性大鼠 (完整的，去卵巢的，或去卵巢加雌激素替代的)和雄性大鼠(完整，去势，或 使用体内电生理方法进行睾丸激素替代去势)。我们预测， 刺激LHb对雌性大鼠去性腺后DA放电的抑制作用更强， 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 雌性大鼠经雌二醇替代后恢复正常。为了确定循环性腺激素在 LHB的放电频率和模式(特定目标2)我们将比较同一组大鼠的不同队列 使用体外电生理方法的命名。我们预测记录的全细胞膜片钳 LHB神经元将以不太规则的模式放电，并增加对超极化诱导的敏感性 雌性大鼠性腺切除后的爆发式放电与完整的雌性大鼠相比。我们进一步预测， 雌激素替代后，雌性大鼠的表型放电模式将会恢复。我们有一条鸿沟 关于LHb和性腺激素相互作用的知识；拟议的实验旨在 开始填补这一空白。这些实验有可能提供一种基于大脑回路的机制 在几种神经和精神健康疾病中按性别区分症状，导致更精确 在治疗发展中。

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.