Nicotinic & dopaminergic mechanisms regulating in vivo plasticity

描述（由申请人提供）：与疾病和衰老相关的认知功能障碍和衰退是严重的健康问题。尼古丁胆碱能和多巴胺能神经递质系统的损害，阻止许多患者进入劳动力和充分的社会化。例如，这些神经递质系统是精神分裂症和阿尔茨海默氏痴呆症的主要原因，据估计，在美国，精神分裂症和阿尔茨海默氏痴呆症每年分别花费> 620亿美元和> 1000亿美元。最终，减少认知障碍的治疗方法必须影响相关的神经回路。识别关键的神经通路、神经递质和机制将为治疗方法提供合理的目标，以减少认知障碍、增强记忆、引起遗忘（例如创伤后应激障碍）或防止遗忘（例如痴呆症）。 我们的初步结果表明，胆碱能活性剂量依赖性地诱导在体海马长时程突触增强与小鼠学习空间任务或新的对象。早期的研究表明，体内突触可塑性的诱导需要兴奋性回路的局部去抑制，再加上来自中脑的传入多巴胺信号。这一结果与多巴胺信号进入海马体降低了作为学习基础的突触可塑性阈值的观点一致。在拟议的研究中，我们将研究烟碱/多巴胺能影响的基础，并将研究以下工作假设：多巴胺信号降低阈值，并调节突触可塑性的大小。此外，多巴胺信号增强了环境事件之间的学习关联，因为多巴胺导致更宽的时间窗口用于诱导突触可塑性。多巴胺通常有助于有效学习由环境线索激发的适当行为反应。然而，工作假设也有助于解释在疾病中发现的多巴胺信号失衡期间出现的认知功能障碍，这些疾病中不适当的感觉门控，注意力和学习会产生适应不良的行为。 应用于野生型和战略准备的突变小鼠的多学科方法将跨越神经整合水平，以了解行为任务表现的突触机制。当小鼠进行行为任务时，内源性胆碱能和多巴胺能信号将被控制，并且体内突触可塑性将被真实的测量。在体内结果的指导下，脑切片 将从这些相同的相关神经区域切下，以了解控制突触可塑性和学习的机制。这些关键神经回路中的机制将为开发减少认知障碍的治疗策略提供目标。未来的研究将使用该小鼠模型平台检查针对特征机制的治疗干预。

DESCRIPTION (provided by applicant): Cognitive dysfunction and decline associated with disease and aging are serious health problems. Nicotinic cholinergic and dopaminergic neurotransmitter systems contribute to the impairments that prevent many patients from entering the work force and fully socializing. For example, these neurotransmitter systems are major contributes to schizophrenia and Alzheimer's dementia, which are estimated to cost > $62 billion and > $100 billion a year respectively in the United States. Ultimately, therapeutic approaches to decrease cognitive impairments must influence pertinent neural circuits. Identifying critical neural pathways, neurotransmitters, and mechanisms will provide rational targets for therapeutic approaches to decrease cognitive impairments, produce memory enhancement, cause forgetting (e.g. in post traumatic stress disorder), or prevent forgetting (e.g. in dementia). Our preliminary results show that cholinergic activity dose-dependently induces in vivo hippocampal long-term synaptic potentiation correlated with mice learning spatial tasks or novel objects. The earlier work showed that induction of in vivo synaptic plasticity requires local disinhibition of excitatory circuits coupled with an afferent dopamine signal arriving from the midbrain. The results are consistent with the view that dopamine signals into the hippocampus lower the threshold for synaptic plasticity that underlies learning. In the proposed studies, we will examine the basis for the nicotinic/dopaminergic influences, and will investigate the following working hypothesis: The dopamine signal lowers the threshold and regulates the magnitude of synaptic plasticity underlying learning. Furthermore, the dopamine signal enhances learning associations among environmental events because dopamine causes a broader timing window for the induction of synaptic plasticity. Dopamine normally contributes to the efficient learning of appropriate behavioral responses motivated by environmental cues. The working hypothesis, however, also helps to explain the cognitive dysfunctions that arise during dopamine signaling imbalances found in diseases where inappropriate sensory gating, attention, and learning produce maladaptive behavior. A multidisciplinary approach applied to wild-type and strategically prepared mutant mice will cross neural levels of integration to understand the synaptic mechanisms underlying performance of behavioral tasks. While mice run behavioral tasks, endogenous cholinergic and dopaminergic signals will be controlled and in vivo synaptic plasticity will be measured in real time. Guided by the in vivo results, brain slices will be cut from these same pertinent neural areas to understand the mechanisms that control synaptic plasticity and learning. The delineated mechanisms within these critical neural circuits will provide targets for developing therapeutic strategies that diminish cognitive impairments. Future research will examine therapeutic interventions targeted to the characterized mechanisms using this mouse model platform.