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

描述(申请人提供)：双相情感障碍(BD)是一种终生严重的精神疾病，影响多达2%的人口。BD的独特之处在于，患者会在狂躁的极端状态(欣快感、冲动等)之间切换。变得抑郁(镇静、绝望等)穷 治疗方案会导致较高的自杀率。缺乏选择的部分原因是我们对引起BD情绪状态切换的电路了解有限。识别这一回路需要分享BD患者生物学变化的动物模型。目前，还没有与这种转变的原因相关的模型动物。多巴胺(DA)活性升高会导致躁狂发作。多巴胺转运体(DAT)起减少突触DA的作用。与BD相关的DAT基因多态性降低了DAT的功能性表达(50%)，并限制了DA的清除。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。除了自然环境，环境还可以触发开关，例如，随着白天变长，躁狂发作最常见，而抑郁发作发生在较短的白天。类似地，处于高和低活动诱导光周期(夏季和冬季)的正常大鼠分别转换为适度的躁狂和抑郁行为。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中，在接受光输入的大脑区域(下丘脑)，DA升高，而生长抑素(SST)减少。短活动光周期的情况正好相反。这里测试的总体假设是，小鼠DAT表达减少会导致光周期改变导致极端行为开关的易感性。特定目标1将测试DAT表达50%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。这些行为将通过与“情绪”相关的行为学测试，以及在老鼠和人类身上使用的注意力、冒险、探索和感觉运动门控测试来衡量。《特定目标2》将绘制大脑回路图，假想是这些行为极端变化的基础。工作模型是，50%的DAT表达会导致神经化学环境的变化，从而在改变光周期期间实现更高的DA和SST表达。因此，假设：A)长活动光周期将提高下丘脑DA，上调DA D2受体的表达和纹状体DA，从而导致躁狂样行为；B)短活动光周期将提高下丘脑SST和促肾上腺皮质激素释放因子的水平，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两极之间潜在的转换电路。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，由于使用的动物认知和行为任务与人类相似，为这一回路开发的任何治疗方法都将有更多的机会在临床上发挥作用，从而帮助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.