Circuit-based Study of Depression/Anhedonia in Rats

大鼠抑郁/快感缺失的回路研究

基本信息

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
项目类别：
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

项目摘要

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）：抑郁症是最常见的精神疾病，其发病率和死亡率高于任何其他精神疾病。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，这种基础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) 系统传统上与快感缺乏有关，并且被认为在抑郁症中发挥着作用。然而，缺乏这种关联的直接实验证据。功能成像研究表明，抑郁症患者 25 区（与啮齿类动物边缘下前额皮质同源）的过度活跃与杏仁核的过度兴奋之间存在关联。我们在初步研究中发现，边缘下前额叶皮层的激活会降低 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，在抑郁症动物模型中，我们发现 DA 神经元活动状态也有所下降，这也可以通过基底外侧杏仁核的失活来逆转。这些数据与抑郁症引起的 ilPFC 过度活跃驱动杏仁核依赖性 DA 神经元反应性下调，导致快感缺失的模型一致。此外，临床上发现氯胺酮可引起快速抗抑郁反应，可逆转 DA 神经元活动的减少和无助状态，特别是在表现出习得性无助行为的大鼠中。这可能会导致人们深入了解治疗抑郁症和其他以快感缺乏为主的疾病的新机制。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 内的过度活跃会导致 BLA 过度驱动，导致 VTA DA 神经元活动减弱和快感缺失，我们将进行实验来解决以下具体目标： 1) 检查边缘下前额皮质激活如何影响 DA 神经元活动状态，2) 检查基底外侧杏仁核激活的途径减弱 DA 神经元活动模式，3) 评估这些系统在抑郁和快感缺乏动物模型中的参与情况，4) 评估氯胺酮如何逆转动物模型中减弱的 DA 神经元活动和快感缺乏。这将使用专注于体内电生理学、光遗传学和行为的集成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具有新颖和特定机制的药物，可以缓解这种严重的疾病。