Dissecting Lateral Hypothalamic Input to Midbrain Neurons and its Role in Social Defeat Stress

 描述(申请人提供)：严重抑郁障碍(MDD)是一种慢性和危及生命的疾病，困扰着美国超过10%的成年人口。然而，近40%的MDD患者对治疗耐药。缺乏普遍有效的抗抑郁药物治疗可能是因为我们对负责调节抑郁的大脑区域了解不够充分。对抑郁症的临床前动物模型和人类患者的脑成像的研究表明，抑郁症患者的大脑中皮质边缘腹侧被盖区(VTA)奖赏回路一直未得到充分研究。最近的研究表明，VTA过度活动在慢性社会失败应激中调节抑郁相关行为的易感性，这是一种公认的抑郁症动物模型。在神经回路水平上，应激导致VTA的病理改变的机制还需要进一步的研究。我们对下丘脑外侧核(LHVTA)的初步研究表明，LHVTA的过度活动介导了易感性。利用光遗传学的光刺激来模拟黄体生成素-VTA神经元放电活动的增加，这种方法可以通过行为动物的光敏通道增加神经元的活动，从而诱导抑郁样行为。此外，我们的初步工作表明，促黄体生成素释放的下丘脑泌素(食欲素)是一种调节奖赏、觉醒和觉醒的神经肽，可能介导VTA神经元对社会失败应激的反应。在这项研究中，我将使用体内和体外电生理学和光遗传学的方法来研究在Lh-VTA光刺激诱导的VTA神经元亚群中是否存在病理生理变化，以及在社会失败应激中下丘脑肌醇如何调节VTA神经元亚群。这些研究将深入了解黄体生成素-VTA神经回路在抑郁症中的作用，并揭示抗抑郁药物开发的新靶点。

 DESCRIPTION (provided by applicant): Major depressive disorder (MDD) is a chronic and life-threatening illness, afflicting over 10% of the adult population in the United States. However nearly 40% of MDD patients are treatment resistant. The lack of universally effective antidepressant treatments may be due to our incomplete understanding of the brain regions responsible for mediating depression. Studies with preclinical animal models of depression and brain imaging of human patients have implicated the mesocorticolimbic ventral tegmental area (VTA) reward circuitry, which has been understudied in depression. Recent studies have implicated VTA hyperactivity in mediating susceptibility to depression-related behaviors in chronic social defeat stress, a well-established animal model of depression. Further research is required to fully characterize the mechanisms by which stress induces pathological alterations in the VTA at the level of neural circuitry. Our preliminary studies focusing on the lateral hypothalamus (LH) input to the VTA (LH-VTA) indicate that LH-VTA hyperactivity mediates susceptibility. Mimicking the increase in firing activity of LH-VTA neurons by the use of photostimulation with optogenetics, an approach that can increase neuronal activity through light-sensitive channels in behaving animals, induces depression-like behaviors. In addition, our preliminary work indicates that LH-released hypocretin (orexin), a neuropeptide known to regulate reward, arousal and wakefulness, may mediate the VTA neuron responses to social defeat stress. In this proposal, I will use in vivo and in vitro electrophysiology and optogenetic approaches to investigate whether there are pathophysiological alterations in VTA neuron subpopulations induced by LH-VTA photostimulation, as well as how hypocretin regulates VTA neuron subpopulations in social defeat stress. These studies will provide insight into the role of LH-VTA neural circuitry in depression and reveal novel targets for antidepressant development.