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

 描述（由申请人提供）：重度抑郁症（MDD）是一种慢性和危及生命的疾病，困扰着美国10%以上的成年人口。然而，近40%的MDD患者对治疗耐药。缺乏普遍有效的抗抑郁治疗可能是由于我们对负责调解抑郁症的大脑区域的不完全理解。抑郁症的临床前动物模型和人类患者的脑成像研究涉及中皮质边缘腹侧被盖区（VTA）的奖励回路，这在抑郁症中研究不足。最近的研究表明，在慢性社会失败压力（一种成熟的抑郁症动物模型）中，腹侧被盖区过度活跃介导了抑郁症相关行为的易感性。需要进一步的研究，以充分表征应激诱导腹侧被盖区在神经回路水平的病理改变的机制。我们的初步研究集中在外侧下丘脑（LH）输入的VTA（LH-VTA）表明，LH-VTA活动过度介导的易感性。通过使用光遗传学的光刺激来模拟LH-VTA神经元的放电活动的增加，这是一种可以通过行为动物中的光敏通道增加神经元活动的方法，诱导抑郁样行为。此外，我们的初步工作表明，LH释放的下丘脑泌素（orexin），一种已知调节奖赏，唤醒和觉醒的神经肽，可能介导VTA神经元对社会失败应激的反应。在这个建议中，我将使用在体内和体外的电生理学和光遗传学的方法来研究是否有病理生理学改变，在腹侧被盖区神经元亚群诱导LH-VTA光刺激，以及下丘脑泌素如何调节腹侧被盖区神经元亚群在社会失败的压力。这些研究将深入了解LH-VTA神经回路在抑郁症中的作用，并揭示抗抑郁药开发的新靶点。

 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.