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) 是一种终生严重精神疾病，影响高达 2% 的人口。 BD 的独特之处在于，患者会在极端的躁狂状态（欣快感、冲动等）和抑郁状态（镇静、绝望等）之间切换。贫穷的治疗选择会导致高自杀率。缺乏选择的部分原因是我们对导致 BD 情绪状态之间切换的电路了解有限。识别这一回路需要模型动物具有在双相情感障碍患者中观察到的生物学变化。目前，尚不存在与这种转变原因相关的模型动物。多巴胺（DA）活性升高会诱发躁狂发作。 DA 转运蛋白 (DAT) 用于减少突触 DA。与 BD 相关的 DAT 多态性会降低 DAT 的功能表达 (50%) 并限制 DA 清除。在 BD 中，无论处于何种状态，DAT 水平都会降低。因此，减少 DAT 可能对抑郁情绪也很重要。除了自然之外，环境也可以触发开关，例如，随着白天变长，躁狂发作最常发生，而抑郁发作则在较短的白天发生。同样，处于高和低活动诱导光周期（类似夏季和冬季）的正常大鼠分别会转变为适度的躁狂和抑郁样行为。免疫细胞化学揭示了这些开关背后的一些神经化学。在长时间活动的光周期期间，接收光输入的大脑区域（下丘脑）中的 DA 升高，而生长抑素 (SST) 降低。对于短活动光周期，情况正好相反。这里测试的总体假设是，小鼠中 DAT 表达的减少使小鼠对光周期改变导致的极端行为转换更敏感。具体目标 1 将测试具有 50% DAT 表达的小鼠在长活动诱导光周期中是否表现出躁狂样行为，在短活动诱导光周期中是否表现出抑郁样行为。这些行为将使用与行为学相关的“情绪”测试以及在小鼠和人类中使用的注意力、冒险、探索和感觉运动门控测试来测量。具体目标 2 将绘制假设为这些极端行为变化背后的大脑回路。工作模型是 50% DAT 表达导致神经化学环境发生变化，从而在光周期变化期间实现更高的 DA 和 SST 表达。因此，假设：A）长活性光周期会升高下丘脑DA，提高DA D2受体表达和纹状体中的DA，从而导致躁狂样行为； B) 短活动光周期会提高下丘脑 SST 和促肾上腺皮质激素释放因子的水平，从而提高海马乙酰胆碱水平，从而产生抑郁样行为。这些研究将有助于阐明 BD 极端之间切换的电路。这项研究应该有助于识别针对这种神经回路的新疗法。此外，由于所使用的动物认知和行为任务与人类类似，因此为该回路开发的任何治疗方法都将有更大的机会在临床上发挥作用，从而帮助双相情感障碍患者。