Circuit-based Study of Depression/Anhedonia in Rats

大鼠抑郁/快感缺失的回路研究

• 批准号: 9043194
• 负责人: ANTHONY A GRACE
• 金额: $ 37.77万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9043194
• 关键词: Address; Affect; Affective; Amphetamines; Amygdaloid structure; Anhedonia; Animal Model; Area; Attenuated; Behavior; Behavioral; Bipolar Disorder; Cell Nucleus; Chronic; Complex; Data; Diagnostic; Dimensions; Disease; Dopamine; Down-Regulation; Electrophysiology (science); Emotional; Environment; Exhibits; Female; Functional Imaging; Functional disorder; Globus Pallidus; Habenula; Health; Hippocampus (Brain); Homologous Gene; Human; Hyperactive behavior; Image; Ketamine; Kynurenic Acid; Lead; Learned Helplessness; Link; Longevity; Major Depressive Disorder; Measures; Medial; Mediating; Mental Depression; Mental disorders; Microinjections; Modeling; Morbidity - disease rate; Neural Pathways; Neurobiology; Neurons; Neurotransmitters; Parkinson Disease; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Play; Population; Positioning Attribute; Prefrontal Cortex; Primates; Rattus; Regulation; Research Domain Criteria; Rewards; Rodent; Role; Schizophrenia; Stimulus; Stress; Suicide; Symptoms; System; Tegmentum Mesencephali; Temporal Lobe; Testing; Therapeutic; Time; Ventral Tegmental Area; Work; analog; antidepressant effect; attenuation; base; behavioral response; depression model; dopamine system; dopaminergic neuron; drug development; drug withdrawal; in vivo; insight; male; mortality; novel; novel therapeutics; optogenetics; pleasure; productivity loss; research study; response; restoration; stressor

DESCRIPTION (provided by applicant): Depression is the most prevalent of the psychiatric disorders, causing higher morbidity and mortality than any other psychiatric disorder. Nonetheless, the neurobiological underpinnings of this disorder are not known. Anhedonia, an inability to derive pleasure from the environment, is a major feature of depression. We focus on the neurobiological basis of anhedonia, which is also present in schizophrenia, bipolar disorder, drug withdrawal, and Parkinson's disease, thereby being consistent with the Research Domain Criteria approach. The dopamine (DA) system has been classically associated with anhedonia, and has been suggested to play a role in depression; however, direct experimental evidence for this association is lacking. Functional imaging studies have shown an association between hyperactivity in area 25 (homologous to rodent infralimbic prefrontal cortex) and hyper-excitability of the amygdala in patients with depression. We have found in our preliminary studies that activation of the infralimbic prefrontal cortex decreases DA neuron activity states, which can be reversed by inactivation of the basolateral amygdala. Moreover, in animal models of depression we found that there is also a decrease in DA neuron activity states that also can be reversed by inactivation of the basolateral amygdala. These data are consistent with a model in which depression-induced hyperactivity of the ilPFC drives an amygdala-dependent down-regulation of DA neuron responsivity, leading to anhedonia. Moreover, ketamine, which has been found clinically to elicit rapid anti-depressant responses, reverses both the decrease in DA neuron activity and the helplessness state specifically in rats showing learned helplessness behavior. This could lead to insights into novel mechanisms of treatment for depression and other disorders in which anhedonia plays a major role. However, to do this we will need a better understanding of the circuitry involved, in particular the circuit by which the basolateral amygdala down-modulates DA neuron activity states. To address our overarching hypothesis, which is in disorders with a negative affective state, hyperactivity within the ilPFC causes an overdrive of the BLA, resulting in an attenuation of VTA DA neuron activity and anhedonia, we will perform experiments to address the following Specific Aims: 1) To examine how infralimbic prefrontal cortical activation affects DA neuron activity states, 2) To examine the pathways through which basolateral amygdala activation attenuates DA neuron activity patterns, 3) To evaluate the involvement of these systems in animal models of depression and anhedonia, and 4) to evaluate how ketamine can reverse the attenuated DA neuron activity and anhedonia in animal models. This will be done using an integrated systems-oriented approach focused on in vivo electrophysiology, optogenetics and behavior. By providing a better understanding of pathways that may underlie anhedonia in depression and other disorders, we will be in a better position to identify drugs with novel and specific mechanisms that may alleviate this crippling disorder.

描述（由申请人提供）：抑郁症是最普遍的精神障碍，其发病率和死亡率高于任何其他精神障碍。尽管如此，这种疾病的神经生物学基础尚不清楚。快感缺乏，即无法从环境中获得快乐，是抑郁症的一个主要特征。我们关注快感缺乏的神经生物学基础，它也存在于精神分裂症、双相情感障碍、药物戒断和帕金森病中，因此与研究领域标准方法一致。多巴胺（DA）系统一直被认为与快感缺乏有关，并被认为在抑郁症中发挥作用；然而，这种关联缺乏直接的实验证据。功能成像研究显示抑郁症患者的25区（与啮齿动物边缘下前额叶皮层相对应）的过度活跃与杏仁核的过度兴奋性之间存在关联。我们在初步研究中发现，边缘下前额叶皮层的激活降低了DA神经元的活动状态，这可以通过基底外侧杏仁核的失活来逆转。此外，在抑郁症的动物模型中，我们发现DA神经元活动状态的减少也可以通过基底外侧杏仁核的失活来逆转。这些数据与抑郁诱导的ilPFC过度活跃驱动杏仁核依赖性DA神经元反应性下调的模型一致，从而导致快感缺乏。此外，临床上发现氯胺酮能引起快速的抗抑郁反应，逆转DA神经元活性下降和无助状态，特别是在表现习得性无助行为的大鼠中。这可能会导致对治疗抑郁症和其他快感缺乏起主要作用的疾病的新机制的见解。然而，要做到这一点，我们需要更好地了解所涉及的电路，特别是基底外侧杏仁核下调DA神经元活动状态的电路。为了解决我们的总体假设，即在消极情感状态的疾病中，ilPFC的过度活跃导致BLA的过度驱动，导致VTA DA神经元活动的衰减和快感缺乏症，我们将进行实验来解决以下具体目标：1)研究边缘下前额叶皮层激活如何影响DA神经元活动状态，2)研究基底外侧杏仁核激活减弱DA神经元活动模式的途径，3)评估这些系统在抑郁症和快感缺乏动物模型中的参与程度，4)评估氯胺酮如何逆转DA神经元活动减弱和快感缺乏动物模型。这将使用集中在体内电生理学、光遗传学和行为的综合系统导向方法来完成。通过更好地了解抑郁症和其他疾病中快感缺乏的潜在途径，我们将能够更好地识别出具有新颖和特定机制的药物，这些药物可能会减轻这种严重的疾病。