Synaptic Transmission, Plasticity and Integration in the Subthalamic Nucleus

丘脑底核出现相关的低频(30赫兹)节律性神经元活动。 US(STN)对于帕金森病(PD)的症状性表达至关重要。GABA能突触输入 来自外部苍白球和谷氨酰胺的来自皮质和丘脑的突触输入是至关重要的 用于正常和病理的STN活性模式。将由此检验的主要假设 研究表明，帕金森病中多巴胺的丢失导致了STN内异常的突触传递，这 (部分)是病态放电模式的基础。这一假说将通过电生理学进行检验。 脑片记录STN神经元，相关光镜和电子显微镜及双光子成像。 多巴胺的影响将通过比较突触传递和整合在i) 多巴胺受体激动剂/拮抗剂的存在和不存在以及2)正常和多巴胺耗竭的患者 动物。 该项目有三个具体目标。具体目标一：测量短期可塑性和影响 GABA能和谷氨酸能突触传递及其多巴胺受体激动剂和 对抗者。具体目标2：确定长期支持的节前和/或节后活动模式 孤束核内GABA能和谷氨酸能突触传递的可塑性具体目标3：比较 GABA能和谷氨酸能突触在STNin对照动物和实验中的操作和影响 帕金森病的心理模型。 这个项目所产生的知识将进一步加深我们对病理基础因素的理解 在STN中的活动，并帮助合理开发治疗方法，以改善症状和内部 通过改变STN活性来阻断帕金森病的进展。 层级描述：丘脑底核(STN)神经细胞病理活动的取消会导致 帕金森氏症(PD)症状的显著改善。这个项目将检验这一假说 这种病理性的STN活动(部分)是由帕金森病患者的STN神经细胞的异常输入驱动的。通过澄清 异常活动背后的机制，本研究将指导治疗的合理发展 这通过使STN活性正常化来改善症状并中断PD的进展。

The emergence ofcorrelated, low-frequency (< 30 Hz), rhythmicactivity ofneurons in the subthalamicnucle- us (STN) is critical for the symptomatic expression of Parkinson's disease (PD). GABAergic synaptic inputs from the external globus pallidusand glutamatergicsynaptic inputs from the cortex and thalamus are critical for the normal and pathological patterning ofSTNactivity. The principal hypothesis that will be tested bythis research is that the loss of dopamine in PD leads to abnormal synaptic transmission within the STN, which (in part) underlies the pathological firing pattern. This hypothesis will be tested using electrophysiological recording of STN neurons in brain slices, correlated light and electron microscopy and 2-photon imaging. The influence of dopamine will be assessed by comparison of synaptic transmission and integration in i) the presence and absence of dopamine receptor agonists/antagonists and 2) in normal and dopamine-depleted animals. There are three specific aims of the project. Specific Aim i: Measure the short-term plasticity and impactof GABAergic and glutamatergic synaptictansmission and their modulationby dopamine receptor agonists and antagonists. Specific Aim2: Determine the pre- and/or postynaptic activity patterns that underlielong-term plasticity of GABAergicand glutamatergic synaptic transmission in the STN. Specific Aim 3: Compare the operation and influence of GABAergic and glutamatergic synapses in the STNin control animalsand experi- mental models of PD. The knowledgegenerated bythis project will further our understandingofthe factors underlying pathological activity in the STNand assist the rational development oftherapies that ameliorate the symptoms and inter- rupt the progression of PD by modification of STN activity. Lay Description: Abolition of pathological activity of nerve cells in the subthalamic nucleus (STN) leads to a profound improvement in the symptoms of Parkinson's disease (PD). This project will test the hypothesis that pathological STNactivity is driven (in part) by abnormal inputs to STNnerve cells in PD. By elucidating the mechanisms underlyingabnormal activity, this research will guidethe rational development of therapies that ameliorate the symptoms and interrupt the progression ofPDthroughthe normalizationof STNactivity.