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

描述（由申请人提供）：双相情感障碍（BD）是一种终身严重精神疾病，影响高达2%的人口。BD的独特之处在于患者在极端躁狂状态（欣快症，冲动等）之间切换。抑郁（镇静，绝望等）。贫困 治疗选择导致自杀率很高。缺乏选择的部分原因是我们对导致BD情绪状态之间转换的电路的知识有限。识别这种电路需要模型动物，分享BD患者中看到的生物学变化。目前，没有与这种转换原因相关的模型动物。多巴胺（DA）活性升高可诱发躁狂发作。DA转运蛋白（DAT）用于减少突触DA。与BD相关的DAT多态性减少DAT的功能表达（50%）并限制DA清除。在BD中，DAT水平降低与状态无关。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，躁狂发作最常发生在白天变长时，而抑郁发作发生在白天变短时。同样，正常大鼠在高和低活动诱导光周期（夏季和冬季样）分别切换到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，DA升高，而生长抑素（SST）在大脑区域，接收光输入（下丘脑）减少。短活动光周期的情况正好相反。在此测试的总体假设是，小鼠中DAT表达的减少赋予了对由光周期改变引起的极端行为转换的易感性。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饲养时是否表现出躁狂样行为，以及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将映射大脑回路假设这些极端的行为变化的基础。工作模型是50%DAT表达引起神经化学环境的变化，从而在变化的光周期期间实现更高的DA和SST表达。因此，假设是：A）长活动光周期将升高下丘脑DA，升高纹状体中DA D2受体表达和DA，从而导致躁狂样行为;和B）短活动光周期将升高下丘脑SST和促肾上腺皮质激素释放因子水平，升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电路基础之间的极端两极的BD切换。这项研究应该有助于识别针对这种神经回路的新治疗方法。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，帮助BD患者。

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.