Nicotinic & dopaminergic mechanisms regulating in vivo plasticity

描述(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。烟碱、胆碱和多巴胺能神经递质系统导致许多患者无法进入工作大军和完全社交。例如，这些神经递质系统是导致精神分裂症和阿尔茨海默氏症的主要因素，据估计，在美国，这两种疾病每年分别造成620亿美元和1000亿美元的损失。归根结底，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靶点，以减少认知障碍、增强记忆力、导致遗忘(例如在创伤后应激障碍中)或防止遗忘(例如在痴呆症中)。我们的初步结果表明，胆碱能活动在体内剂量依赖性地诱导与小鼠学习空间任务或新对象相关的海马区长时程突触增强。早期的工作表明，体内突触可塑性的诱导需要局部解除兴奋回路的抑制，并结合来自中脑的传入多巴胺信号。这一结果与以下观点一致：进入海马体的多巴胺信号降低了作为学习基础的突触可塑性的门槛。在拟议的研究中，我们将研究尼古丁/多巴胺能影响的基础，并将调查以下工作假设：多巴胺信号降低阈值并调节学习背后的突触可塑性的大小。此外，多巴胺信号增强了环境事件之间的学习联系，因为多巴胺导致了更宽的突触可塑性诱导时间窗口。多巴胺通常有助于有效地学习受环境线索激励的适当行为反应。然而，工作假说也有助于解释在疾病中发现的多巴胺信号失衡时出现的认知功能障碍，在这些疾病中，不适当的感觉门控、注意力和学习会产生适应不良行为。一种应用于野生型和有策略准备的突变小鼠的多学科方法将跨越神经整合水平，以了解行为任务执行的突触机制。当小鼠运行行为任务时，内源性胆碱能和多巴胺能信号将得到控制，并将实时测量体内突触的可塑性。在体内结果的指导下，脑片 将从这些相关的神经区域切开，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描绘的机制将为开发减轻认知障碍的治疗策略提供靶点。未来的研究将使用这个小鼠模型平台来检查针对特定机制的治疗干预。

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.