SEROTONIN REGULATION OF BASAL GANGLIA NEUROPEPTIDES

这项研究将确定5-羟色胺传递在 基底节神经肽基因表达的调控。 具体地说，我们将检验如下假设：5-羟色胺传递 提供对神经肽nMRA表达的调节控制 基底节通过多种受体亚型。虽然这项规定 可能仅在正常情况下对基因表达进行轻微调整 在成人大脑的状况下，5-羟色胺可能会产生更大的影响 在发育过程中，对多巴胺耗竭的反应，或在 谷氨酸诱导的兴奋性毒性损伤。以下具体目标将 确定： 1.5-羟色胺受体介导的基因表达调控 正常成人基底节。多种5-羟色胺受体亚型可能 差异影响基底节的基因表达。北方 将利用分析和原位杂交方法来确定 哪些5-羟色胺受体与转录调控有关 前速激肽原和前脑啡肽原基因在纹状体中表达。 2.5-羟色胺对大鼠基底神经节基因表达的影响 发展。传入前脑的5-羟色胺在 发育，并已被假设在大脑中发挥形态发生作用 成熟。在胚胎和出生后早期，5-羟色胺 传播将被改变，特定的受体亚型将被 发现影响神经肽基因表达发展的因素 基底节的模式。 3.5-羟色胺对基底神经节基因表达的影响 多巴胺传递。5-羟色胺可能增加其对基础状态的影响 多巴胺改变对神经节基因表达的影响 神经传递。因此，实验将确定 5-羟色胺及其受体在神经肽基因表达调控中的作用 在对新生儿和新生儿进行多巴胺神经传递操作后 成年人的大脑。 4.谷氨酸过程中影响基因表达的5-羟色胺机制 神经传递与基底节的兴奋毒性损伤。5-羟色胺 可能调节谷氨酸兴奋性神经递质在脑内的作用 基底节以及介导谷氨酸受体诱导 兴奋性毒性。实验将确定5-羟色胺如何促进 异常时基底节基因表达的调节 谷氨酸受体刺激。 这些研究的完成将增加我们对如何 5-羟色胺传递影响正常人群的基因表达模式 发育中的和成年的基底节；以及对 多巴胺和谷氨酸的神经传递。这样的信息将会增加 我们对5-羟色胺作为基底神经节主要传入调节因子的认识 作用并导致以5-羟色胺为基础的疗法的发展 治疗基底节疾病。

This research will determine the role of serotonin transmission in the regulation of neuropeptide gene expression in the basal ganglia. Specifically, we will test hypothesis that: Serotonin transmission provides regulatory control over neuropeptide nMRA expression within the basal ganglia via multiple receptor subtypes. Although this regulation may only provide slight adjustments to gene expression under normal conditions in the adult brain, serotonin may exert larger influences during development, in response to dopamine depletion, or during glutamate-induced excitotoxic damage. The following specific aims will determine: 1. Serotonin Receptor-Mediated Regulation of Gene Expression in the Normal Adult Basal Ganglia. Multiple serotonin receptors subtypes may differentially influence gene expression in the basal ganglia. Northern analysis and in situ hybridization methods will be utilized to determine which serotonin receptors are linked to transcriptional regulation of preprotachykinin and preproenkephalin genes expressed in the striatum. 2. Serotonin Influences on Basal Ganglia Gene Expression during Development. Serotonin afferent to the forebrain appear early during development and have been postulated to play a morphogenic role in brain maturation. During embryonic and early postnatal time periods, serotonin transmission will be altered and specific receptors subtypes will be identified that influence the development of neuropeptide gene expression patterns in the basal ganglia. 3. Serotonin Influences on Basal Ganglia Gene Expression during Altered Dopamine Transmission. Serotonin may increase its influence on basal ganglia gene expression in response to altered dopamine neurotransmission. Therefore, experiments will determine the role of serotonin and its receptors in regulating neuropeptide gene expression following manipulation of dopamine neurotransmission in both neonatal and adult brains. 4. Serotonin Mechanisms That Affect Gene Expression during Glutamate Neurotransmission and Excitotoxic Damage of the Basal Ganglia. Serotonin may modulate the effects of glutamate excitatory neurotransmission in the basal ganglia, as well as mediate glutamate receptor induced excitotoxicity. Experiments will determine how serotonin contributes to the regulation of basal ganglia gene expression following abnormal glutamate receptor stimulation. Completion of these studies will increase our understanding of how serotonin transmission influences gene expression patterns in the normal developing and adult basal ganglia; as well as in response to changes in dopamine and glutamate neurotransmission. Such information will increase our awareness of serotonin as a major afferent regulator of basal ganglia function and lead to the development of serotonin-based therapies to treat basal ganglia disease.