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

摘要： 在美国，每年有1600多万成年人受到严重抑郁障碍(抑郁症)的影响，是全球第二大抑郁症 导致残疾的主要原因。目前的药物很大程度上是偶然发现的，作用不是特定的， 除了效果欠佳外，还会产生不良副作用。我们相信，更好的理解 潜在的病理，如由于压力导致的奖励处理缺陷，将导致更具体的， 有效的治疗方法。这项资助的目的是确定应力如何影响外侧缰核的活动。 -大脑中编码奖励的区域，对压力敏感，并与抑郁有关-以及如何改变 外侧缰核活动导致小鼠奖赏反应减弱。尽管研究发现，压力 诱导外侧缰核的可塑性，应激如何影响体内活动和外侧缰核的奖赏编码 缰核对此知之甚少。该领域的主要模型是，应激导致紧张性多动 外侧缰核，这是导致抑郁的原因。然而，我们最近发现，急性应激严重 改变外侧缰核的相奖赏信号，改变活动的减少(正常奖赏反应) 转化为活动的增加(类似惩罚的反应)。我们的假设是，压力不仅增加了补药的活性 但也改变了奖赏的时相信号，从而降低了奖赏响应性。我们会 在小鼠身上用慢性脑深部成像和电生理记录来验证这一假说。 在应激前后的奖赏消费中缰核的活动。我们的假设预测，两者都是急性的 慢性应激改变了外侧缰核中奖赏信号的相位信号，因为动物对 从行为上奖励。我们将检验外侧缰核奖赏信号对奖赏的因果效应。 小鼠在奖励消费过程中通过扰乱外侧缰核活动的反应性。我们的假设预测 在奖励消费期间对外侧缰核活动的阶段性抑制将逆转有害影响 对奖励责任感的压力。相反，我们预测在下一阶段，外侧缰核活动的增加 奖励消费将模仿压力对奖励响应性的影响。我们还将确定压力是否 增加外侧缰核的紧张性活动，以及紧张性活动的变化是否有助于 降低了奖励响应性。这项研究很有意义，因为它明确了压力影响的机制 奖赏处理，并将其定位于大脑中与抑郁有关的区域。验证我们的 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，它们在改变的决策制定中的作用，以及识别 参与的外侧缰核，可能导致新的治疗方法，提高奖励反应性 抑郁症。

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.