A model organism of brain circuitry and behavioral switching for bipolar disorder

双相情感障碍的脑电路和行为转换的模型生物

基本信息

批准号：
9095908
负责人：
Jared William Young
金额：
$ 42.32万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
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：
2014-07-01 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9095908
关键词：
Acetylcholine Affect Animal Model Animals Attention Automobile Driving Behavior Behavioral Biological Bipolar Disorder Brain Brain region Cell Nucleus Cell surface Characteristics Chemistry Chronic Clinic Cognitive Complementary DNA Complex Corpus striatum structure Corticotropin-Releasing Hormone Depressed mood Development Disease Dopamine Dopamine D2 Receptor Environment Etiology Euphoria Exhibits Generations Genetic Genetic Polymorphism Health Hippocampus (Brain)Hour Housing Human Hypersensitivity skin testing Hypothalamic structure Impulsivity Individual Knowledge Lead Learning Length Light Link Literature Lithium Maintenance Manic Maps Measures Mediating Mental Depression Modeling Molecular Abnormality Mood stabilizers Moods Mus Muscarinic Acetylcholine Receptor Nature Neurobiology Pathway interactions Patients Photoperiod Phototherapy Physostigmine Population Positron-Emission Tomography Predisposition Punishment Rattus Research Risk-Taking Rodent Scopolamine Sedation procedure Sleep Somatostatin Stress Suicide attempt Synapses Testing Time Tyrosine 3-Monooxygenase Validation Viral Work analog base behavior test brain circuitry cognitive testing day length depressive symptoms design dopamine transporter drug discovery esterase esterase inhibitor immunocytochemistry in vivo Model inattention migration neural circuit neurochemistry novel novel therapeutics prevent receptor expression relating to nervous system response severe mental illness suicide rate targeted treatment

项目摘要

DESCRIPTION (provided by applicant): Bipolar disorder (BD) is a lifelong severe mental illness affecting up to 2% of the population. BD is unique in that patients switch between extreme states of mania (euphoria, impulsivity, etc.) to depression (sedation, despair, etc.). Poor treatment options contribute to a high rate of suicide. The lack of options is partly due to our limited knowledge of circuitry causing switches between mood states in BD. Identifying this circuitry requires model animals that share biological changes seen in BD patients. Currently, no model animals related to the causes of this switch exist. Elevating dopamine (DA) activity can induce manic episodes. The DA transporter (DAT) serves to reduce synaptic DA. DAT polymorphisms associated with BD reduce the functional expression of DAT (50%) and limit DA clearance. In BD, DAT levels are reduced irrespective of state. Reduced DAT may therefore also be important for depressed moods. Beyond nature, the environment can trigger switches, e.g., mania episodes occur most often as days grow longer while depressive episodes occur in shorter days. Similarly, normal rats housed in high and low activity-inducing photoperiods (summer- and winter-like) switch into modest mania- and depressive-like behaviors respectively. Immunocytochemistry revealed some of the neural chemistry underlying these switches. During long-activity photoperiods, DA was elevated while somatostatin (SST) was reduced in the brain region that receives light input (the hypothalamus). The opposite was true for short-activity photoperiods. The overall hypothesis tested here is that reduced DAT expression in mice confers susceptibility to extreme behavioral switches resulting from altered photoperiods. Specific Aim 1 will test if mice with 50% DAT expression exhibit mania-like behaviors when housed in long activity-inducing photoperiods and depression-like behaviors in short activity-inducing photoperiods. These behaviors will be measured using ethologically relevant tests for 'mood' and by tests of attention, risk-taking, exploration, and sensorimotor gating that are used in both mice and humans. Specific Aim 2 will map the brain circuitry hypothesized to underlie these extreme changes in behavior. The working model is that 50% DAT expression causes changes in the neurochemical environment enabling higher DA and SST expression during changing photoperiods. Hence, the hypotheses are that: A) long-activity photoperiods will elevate hypothalamic DA, elevating DA D2 receptor expression and DA in the striatum, and thereby lead to mania-like behaviors; and B) short-activity photoperiods will elevate levels of hypothalamic SST and corticotropin releasing factor, elevating hippocampal acetylcholine levels, and thereby producing depression-like behaviors. These studies will help elucidate the circuitry underlying switching between the extreme poles of BD. This research should facilitate the identification of novel treatments targeted at this neural circuitry. Furthermore, because the animal cognitive and behavioral tasks used have human analogs, any treatments developed for this circuit will have an increased chance of working in the clinic, helping patients with BD.

描述（由申请人提供）：双相情感障碍（BD）是一种终生的严重精神疾病，影响多达2％的人口。 BD是独一无二的，因为患者在极端的躁狂状态（欣快感，冲动等）之间切换到抑郁症（镇静，绝望等）。贫穷的治疗方案有助于高自杀率。缺乏选择部分是由于我们对电路的了解有限，导致BD中情绪状态之间的切换。识别该电路需要模型的动物，这些动物具有在BD患者中看到的生物学变化。当前，没有与此开关原因有关的模型动物。抬高多巴胺（DA）活性会诱发躁狂发作。 DA转运蛋白（DAT）用于减少突触DA。与BD相关的DAT多态性降低了DAT的功能表达（50％），并限制了DA清除率。在BD中，无论状态如何，DAT级别都会降低。因此，减少的DAT对于沮丧的情绪也可能很重要。除了自然之外，环境还可以触发开关，例如，躁狂发作通常会随着天数增长而发生的，而抑郁发作则在较短的日子发生。同样，正常大鼠分别以高和低活性的光周期（夏季和冬季）分别转变为适度的狂热和抑郁样行为。免疫细胞化学揭示了这些开关的一些神经化学。在长期光周期期间，DA被升高，而在接受光输入（下丘脑）的大脑区域中，生长抑素（SST）降低。对于短活化光周期而言，情况恰恰相反。这里检验的总体假设是，小鼠中的DAT表达减少赋予对光周期改变的极端行为开关的敏感性。特定的目标1将测试50％DAT表达的小鼠在长期诱导的光周期和抑郁症状行为中，在短期诱导的短期诱导光周期中表现出躁狂样行为。这些行为将使用与“情绪”的伦理学相关测试以及在小鼠和人类中都使用的注意，冒险，探索和感觉运动门控的测试来衡量。特定的目标2将绘制假设的脑电路，以构成这些行为的极端变化的基础。工作模型是50％的DAT表达会导致神经化学环境的变化，从而在变化的光周期中实现了更高的DA和SST表达。因此，假设是：a）长期光周期将升高下丘脑DA，在纹状体中升高DA D2受体表达和DA，从而导致类似躁狂的行为； b）短活化光周期将升高下丘脑SST和皮质激素释放因子的水平，升高海马乙酰胆碱水平，从而产生抑郁症样行为。这些研究将有助于阐明BD极端极线之间的基础电路切换。这项研究应促进针对该神经回路的新型治疗方法的鉴定。此外，由于所使用的动物认知和行为任务具有人类类似物，因此为该电路开发的任何治疗方法都将增加在诊所工作的机会，帮助患有BD患者。