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）：抑郁症是精神疾病中最普遍的抑郁症，比任何其他精神疾病都会引起更高的发病率和死亡率。但是，这种疾病的神经生物学基础尚不清楚。 Anhedonia是无法从环境中获得愉悦的一种主要特征。我们专注于Anhedonia的神经生物学基础，该基础也存在于精神分裂症，躁郁症，药物戒断和帕金森氏病，从而与研究领域的标准方法一致。多巴胺（DA）系统与Anhedonia经典相关，并被建议在抑郁症中发挥作用。但是，缺乏有关这种关联的直接实验证据。功能成像研究表明，在抑郁症患者中，杏仁核的25区（与啮齿动物额叶前额叶皮层同源）之间的多动症之间有关联。我们在初步研究中发现，额叶前额叶皮层的激活降低了DA神经元活性状态，这可以通过基底外侧杏仁核的失活而逆转。此外，在抑郁症动物模型中，我们发现DA神经元活性状态也有所下降，而基底外侧杏仁核也可以逆转。这些数据与一个模型一致，在该模型中，ILPFC抑郁诱导的多动症驱动DA神经元反应性的杏仁核依赖性下调，从而导致Anhedonia。此外，在临床上发现氯胺酮可以引起快速抗抑郁剂反应，既逆转DA神经元活性的降低又逆转了无助的无助性行为的无助状态。这可能会导致人们对抑郁症治疗的新型机制和其他疾病的重大作用。但是，为此，我们将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神经元活性状态的电路。 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基底外侧杏仁核激活减弱了DA神经元活性模式，3）评估这些系统参与抑郁症和抗抗激元的动物模型，以及4）评估氯胺酮如何逆转减轻的DA神经元活动和Anhedonia在动物模型中。这将使用集成的以系统为导向的方法来完成，该方法集中在体内电生理学，光遗传学和行为上。通过更好地了解可能是抑郁症和其他疾病中抗抗衰果的途径，我们将有更好的位置，可以鉴定出具有新颖和特定机制的药物，这些药物可能会减轻这种残酷的疾病。