Aberrant Blink Reflex Motor Learning in a Rat Model of Parkinsons Disease

帕金森病大鼠模型中异常的眨眼反射运动学习

• 批准号: 8633481
• 负责人: Jaime A Kaminer
• 金额: $ 0.72万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2014-07-25
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8633481
• 关键词: Affect; Animal Model; Attenuated; Basal Ganglia; Behavioral; Blinking; Brain Stem; Case Study; Cell Death; Cells; Complex; Corpus striatum structure; Data; Deep Brain Stimulation; Disease; Dopamine; Dopaminergic Cell; Electrodes; Exhibits; Frequencies; Functional disorder; Impairment; Investigation; Lead; Learning; Learning Disturbances; Lesion; Long-Term Depression; Long-Term Potentiation; Modeling; Motor; Nerve Degeneration; Neurobehavioral Manifestations; Neurons; Output; Oxidopamine; Parkinson Disease; Patients; Pattern; Play; Process; Protocols documentation; Rattus; Reflex action; Research Personnel; Role; Stimulus; Structure of subthalamic nucleus; Substantia nigra structure; Symptoms; Techniques; Testing; Therapeutic; Therapeutic Effect; Trigeminal System; Trigeminal nerve structure; base; behavior test; blink reflexes; common treatment; dopaminergic neuron; improved; in vivo; insight; motor learning; neuromechanism; neuron loss; nigrostriatal pathway; pars compacta; prepulse inhibition; relating to nervous system; research study

DESCRIPTION (provided by applicant): The dopaminergic cell loss in the substantia nigra pars compacta (SNc) that causes Parkinson's disease (PD) creates a complex array of motor and cognitive symptoms. Although alterations in corticostriatal interactions play a major role in PD symptomatology, brainstem abnormalities also contribute significantly to PD symptoms. One circuit that has been especially useful in characterizing these brainstem disturbances is the trigeminal reflex blink. PD patients and animal models of PD exhibit hyperexcitable reflex blinks, a lack of blink habituation, and decreased long term potentiation (LTP) -like plasticity of the blik reflex. The reduced ability to potentiate blink circuits could result from saturation of this hyperexcitable circuit or it could indicate a general impairment of brainstem motor learning that may create many of the brainstem disorders in PD. In order to determine PD's effects on the motor learning capability of trigeminal reflex blink circuit, it is critical to investigate the capcity for long term depression (LTD)-like plasticity. The proposed studies will utilize behavioral and in vivo electrophysiological techniques to characterize the neural mechanisms underlying motor learning in the trigeminal reflex blink circuit in a 6-OHDA lesioned rat model of PD. Specific Aim 1 investigates the hypothesis that dopamine cell loss in the nigrostriatal pathway disrupts motor learning of trigeminal blink reflex circuit utilizing previously established LTD and LTP inducing protocols involving the presentation of high frequency stimulation to the supraorbital branch of the trigeminal nerve. These data will demonstrate the degree of disruption for short-term plasticity and long term learning of reflex blinking caused by PD. Specific Aim 2 examines the hypothesis that the deficient brainstem motor learning in PD results from dysfunctional patterns of substantia nigra pars reticulata (SNr) activity using multi-electrode recordings of the SNr in alert, behaving control and 6-OHDA rats during the learning paradigm. If the hypothesis is correct, SNr discharge in 6-OHDA lesioned rats will be much more irregular and synchronized than in control rats. Specific Aim 3 will test the hypothesis that the disruptions in brainstem motor learning result from an alteration in the pattern of SNr output rather than simply an increase in discharge frequency. Deep brain stimulation of the subthalamic nucleus (STN DBS) utilizing regular (130 Hz) or irregular (mean frequency 130 Hz) stimulation will be applied to 6-OHDA lesioned rats while they undergo the motor learning protocol. The ability of regular, but not irregular STN DBS to attenuate PD blink disturbances would support the hypothesis that DBS achieves its therapeutic effect through regularizing abnormal firing patterns of basal ganglia neurons. Overall, these experiments will elucidate the neural basis of diminished brainstem motor learning in PD and provide insight into the therapeutic mechanism of DBS in the treatment of PD that may lead to more effective use of this important PD treatment.

描述（由申请人提供）：导致帕金森病（PD）的黑质丘脑部（SNc）多巴胺能细胞损失产生一系列复杂的运动和认知症状。虽然皮质-纹状体相互作用的改变在PD发病中起着重要作用，但脑干异常也对PD症状有显著影响。在描述这些脑干障碍时特别有用的一个回路是三叉神经反射眨眼。PD患者和PD动物模型表现出过度兴奋性反射性眨眼，缺乏眨眼习惯性，以及blik反射的长时程增强（LTP）样可塑性降低。增强眨眼回路的能力降低可能是由于这种过度兴奋回路的饱和，或者它可能表明脑干运动学习的一般损伤，这可能导致PD中的许多脑干疾病。为了确定PD对三叉神经反射眨眼回路运动学习能力的影响，研究长时程抑郁（LTD）样可塑性的能力至关重要。拟议的研究将利用行为和 在6-OHDA损伤的PD大鼠模型中，采用体内电生理技术来表征三叉神经反射眨眼回路中运动学习的神经机制。具体目标1研究了黑质纹状体通路中的多巴胺细胞损失破坏三叉神经眨眼反射回路的运动学习的假设，该假设利用先前建立的LTD和LTP诱导方案，涉及向三叉神经的眶上分支提供高频刺激。这些数据将证明PD引起的反射性眨眼的短期可塑性和长期学习的破坏程度。具体目标2研究了以下假设：PD中脑干运动学习缺陷是由黑质网状部（SNr）活动的功能障碍模式引起的，使用多电极记录了学习范式期间警觉、行为控制和6-OHDA大鼠的SNr。如果假设是正确的，在6-OHDA损毁大鼠的SNr放电将更加不规则和同步化比对照组大鼠。具体目标3将检验以下假设：脑干运动学习的中断是由于SNr输出模式的改变，而不仅仅是放电频率的增加。在6-OHDA损伤的大鼠进行运动学习方案时，将利用规则（130 Hz）或不规则（平均频率130 Hz）刺激对丘脑底核进行深部脑刺激（DBS）。规则的，但不是不规则的DBS，以减轻PD眨眼干扰的能力将支持DBS通过规则化基底神经节神经元的异常放电模式来实现其治疗效果的假设。总体而言，这些实验将阐明帕金森病脑干运动学习能力减弱的神经基础，并深入了解DBS治疗帕金森病的治疗机制，这可能会导致更有效地使用这种重要的帕金森病治疗。