Neuronal signaling mechanisms of stress-induced anhedonia in the lateral habenula

摘要： 重度抑郁症（抑郁症）每年影响美国超过1600万成年人，是第二大抑郁症。 残疾的主要原因。目前的药物很大程度上是偶然发现的，而且作用不具特异性， 除了效果不佳之外，还会导致不必要的副作用。我们认为，更好地了解 潜在的病理学，例如由于压力导致的奖励处理缺陷，将导致更具体的， 有效的治疗。这项研究的目的是确定压力如何影响外侧缰核的活动 - 一个编码奖励的大脑区域，对压力敏感，并与抑郁症有关-以及如何改变 外侧缰活动导致小鼠的奖赏反应性降低。尽管研究发现压力 诱导外侧缰的可塑性，压力如何影响体内活动和外侧缰的奖励编码， 对缰的了解很少。该领域的主导模型是，压力导致大脑中的紧张性过度活跃。 外侧缰，这有助于抑郁症。然而，我们最近发现，急性应激严重 改变外侧缰中的阶段性奖励信号，改变活动的减少（正常奖励反应） 惩罚性反应（punishment like response）我们的假设是压力不仅会增加紧张性活动 在外侧缰，但也改变了奖励的相位信号，这降低了奖励反应。我们将 使用慢性脑深部成像和侧脑室电生理记录在小鼠中测试这一假设。 在奖励消费期间，应激前后的缰活动。我们的假设预测， 和慢性应激改变了外侧缰中奖励的阶段性信号， 奖励行为。我们将测试相位性外侧缰奖赏信号对奖赏的因果影响 在奖励消费期间，通过扰动外侧缰活动来提高小鼠的反应性。我们的假设预测 在奖赏消费过程中，对外侧缰核活动的阶段性抑制将逆转有害影响， 奖励反应的压力。相反，我们预测，增加时相性外侧缰核活动， 奖励消费将模仿压力对奖励反应性的影响。我们还将确定压力是否 增加外侧缰的紧张性活动，以及紧张性活动的变化是否有助于 奖励反应性降低。这项研究意义重大，因为它明确了压力影响 奖励处理，并将其定位到大脑中与抑郁有关的区域。验证我们的 这一假说将把未来的工作重点放在表征这些活动和奖励的分子机制上 信号转换，它们在改变决策中的作用，以及识别 参与的外侧缰，可能导致新的疗法，提高奖励反应， 萧条

ABSTRACT: Major depressive disorder (depression) affects over 16 million adults in the U.S. per year and is the second leading cause of disability. Current medications were discovered largely by serendipity and act non-specifically, leading to unwanted side effects in addition to suboptimal effectiveness. We believe that a better understanding of the underlying pathologies, such as deficits in reward processing due to stress, will lead to more specific, effective treatments. The objective of this grant is to determine how stress affects activity in the lateral habenula – a brain region that encodes reward, is sensitive to stress, and is implicated in depression – and how altered lateral habenula activity leads to diminished reward responsivity in mice. Although studies have found that stress induces plasticity in the lateral habenula, how stress affects in vivo activity and reward encoding in the lateral habenula is poorly understood. The dominant model in the field is that stress causes tonic hyperactivity in the lateral habenula, which contributes to depression. However, we recently discovered that acute stress severely alters phasic reward signaling in the lateral habenula, changing decreases in activity (normal reward response) into increases in activity (punishment-like response). Our hypothesis is that stress not only increases tonic activity in the lateral habenula, but also alters phasic signaling of reward, which decreases reward responsivity. We will test this hypothesis in mice using chronic, deep-brain imaging and electrophysiological recording of lateral habenula activity during reward consumption, before and after stress. Our hypothesis predicts that both acute and chronic stress alter phasic signaling of reward in the lateral habenula as animals become less responsive to reward behaviorally. We will test for causal effects of phasic lateral habenula reward signals on reward responsivity in mice by perturbing lateral habenula activity during reward consumption. Our hypothesis predicts that phasic inhibition of lateral habenula activity during reward consumption will reverse the deleterious effects of stress on reward responsivity. Conversely, we predict that increasing phasic lateral habenula activity during reward consumption will mimic the effects of stress on reward responsivity. We will also determine if stress increases tonic activity in the lateral habenula and whether changes in tonic activity contribute to aspects of reduced reward responsivity. This study is significant because it specifies a mechanism by which stress affects reward processing and localizes it to a region of the brain that is implicated in depression. Validation of our hypothesis will focus future efforts on characterization of the molecular mechanisms of these activity and reward signaling transformations, their role in altered decision-making, and identification of the inputs/outputs of the lateral habenula that are involved, potentially leading to new therapies that improve reward responsivity in depression.