Limbic pallidal circuits linked to apathy in Parkinson’s disease during subthalamic deep brain stimulation

项目概要/摘要 帕金森病（Parkinson's disease，PD）是一种神经退行性疾病，表现为运动性和非运动性 干扰.丘脑底核深部脑刺激术（DBS）是治疗心脏病的有效方法。 PD的运动特征。相比之下，非运动症状通常不会改善，甚至可能恶化， DBS电极放置在小脑的运动亚区，但脱靶激活边缘和 关联电路，以及DBS后电路活动的适应性变化，可能导致非运动不良反应。 方面的影响.我们的研究计划的长期目标是i）确定可用于预测的生物标志物 当DBS可能导致情绪和认知障碍时，以及ii）改善DBS刺激范例以减少 非运动副作用。冷漠是PD的一种普遍的非运动症状，经常在治疗后出现。 DBS严重损害生活质量。因此，目前的R21研究将集中在冷漠。因此 研究的总体目标是确定冷漠的机制和解剖学基础， PD大鼠模型中的STN-DBS。高选择性光遗传学刺激方法将用于分离 已知调节冷漠的情感输出的贡献;即，腹侧苍白球的多巴胺能传出神经 （副总统）。本研究的中心假设是：i）在大鼠模型中，STN-DBS治疗期间的冷漠样行为 反映了下游边缘结构的神经可塑性，调节动机，和ii）激活的神经元， 在PD大鼠模型中，VP能传出足以介导冷漠样行为和回路 变化具体目标1将评估类失语症和运动性失语症的时间发展和持续性。 慢性光遗传STN-DBS中的行为。具体目标2将评估是否选择性激活 在STN-DBS期间，脑电刺激性STN-VP投射足以产生冷漠样行为。 综合行为评估将包括PD样运动和冷漠特征。电路后果 将通过测量死后神经元活动的标记来揭示。该研究具有创新性 因为这些研究将结合联合收割机已建立的技术来破译一种目前尚未描述的致病回路 这可能是与STN-DBS相关的非运动行为的基础。该研究对结果具有重要意义 i）确定特定的神经元投射到VP在PD样行为中的作用， ii）表明STN-VP回路作为DBS期间冷漠的生物标志物的潜力，以及iii）形成 为未来NIH资助的项目奠定了基础，这些项目将导致设计新的DBS协议，以改善结果。

PROJECT SUMMARY/ABSTARCT Parkinson’s disease (PD) is a neurodegenerative disease that presents both motor and non-motor disturbances. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is efficacious in treating cardinal motor features of PD. In contrast, non-motor symptoms typically do not improve and may even worsen with DBS. Electrode placement in the STN is targeted to the motor subregion, but off-target activation of limbic and associative circuits, and the resultant adaptations in circuit activity after DBS, likely lead to non-motor adverse effects. The long-term goals of our Research Program are to i) identify biomarkers that can be used to predict when DBS may result in disorders of mood and cognition, and ii) improve DBS stimulation paradigms to reduce non-motor adverse effects. Apathy is a prevalent non-motor symptom of PD that frequently worsens after STN- DBS to significantly impair quality of life. Thus, the current R21 Study will focus on apathy. Accordingly, the overall objective of the Study is to determine the mechanism(s) and anatomical substrate(s) of apathy after STN-DBS in a rat model of PD. Highly selective optogenetic stimulation approaches will be used to isolate the contribution of STN outputs known to regulate apathy; i.e., STN glutamatergic efferents to the ventral pallidum (VP). The Study central hypotheses are that i) apathy-like behaviors during STN-DBS treatments in a rat model of PD reflect neuroplasticity in downstream limbic structures that regulate motivation, and ii) activation of STN- VP glutamatergic efferents in a rat model of PD is sufficient to mediate apathy-like behaviors and circuit changes. Specific Aim 1 will assess the temporal development and persistence of apathy-like and motor behaviors in chronic optogenetic STN-DBS. Specific Aim 2 will assess whether selective activation of glutamatergic STN-VP projections during STN-DBS is sufficient to produce apathy-like behaviors. Comprehensive behavioral assessments will include PD-like motor and apathy profiles. Circuit consequences will be revealed by measuring post mortem markers of neuronal activity. The proposed research is innovative as these studies will combine established techniques to decipher a currently undescribed pathogenic circuit that likely underpins non-motor behaviors associated with STN-DBS. The research is significant for outcomes are expected to i) determine the role of specific STN glutamatergic projections to the VP in PD-like behaviors, ii) indicate the potential of STN-VP circuits to serve as biomarkers for apathy during DBS, and iii) form the basis for future NIH-funded projects that will lead to the design of novel DBS protocols that improve outcomes.