Striatal Circuits In The Serotonergic Modulation Of Hedonic States

 描述（由申请人提供）：纹状体通路对于调节与各种神经精神疾病相关的各种行为至关重要。STR在快乐过程中的重要作用与抑郁症、焦虑症、物质滥用障碍和酗酒有关。虽然很多注意力都集中在STR的多巴胺能神经支配的功能意义，少得多是已知的STR功能的5-羟色胺系统的调节。这个问题的重要性是突出的已知的，但知之甚少的影响5-羟色胺系统的操作STR功能和享乐过程。这部分归因于5-羟色胺能神经传递的复杂性; 5-羟色胺的作用由至少14种不同的5-羟色胺受体亚型介导。多种证据表明，5-HT 2C受体（5 HT 2CR）亚型在介导快感状态和STR功能的多巴胺能调节中起着特别突出的作用。因此，我们发现一系列缺乏功能性5 HT 2CRs的突变小鼠显示出不同的神经化学、生理和行为表型，表明STR功能受到干扰和动机行为发生改变。尽管5 HT 2CRs在STR功能的多巴胺能调节中的重要性已被公认，但很难辨别出那些最负责这些效应的神经回路。在这一领域的进展已被5 HT 2CR在多种基底神经节结构中的多种细胞类型中的广泛表达以及5 HT 2CR功能的药理学探针的特异性的限制所阻碍。为了应对这一挑战，我们将结合联合收割机的方法，诱导细胞类型特异性的遗传操作与高分辨率的行为评估技术，以确定中缝背核纹状体预测的贡献，对神经递质调节享乐状态。我们将确定在两个主要的纹状体电路：直接和间接途径表达的5 HT 2CRs的功能意义。

 DESCRIPTION (provided by applicant): Striatal pathways are essential to the regulation of diverse behaviors relevant to a wide array of neuropsychiatric disorders. Important roles for the STR in hedonic processes are relevant to depressive disorders, anxiety disorders, substance abuse disorders and alcoholism. Whereas much attention has focused on the functional significance of the dopaminergic innervation of the STR, much less is known about the regulation of STR function by serotonin systems. The importance of this issue is highlighted by the known, yet poorly understood impact of serotonin system manipulations on both STR function and hedonic processes. This is in part attributable to the complexity of serotonergic neurotransmission; the actions of serotonin are mediated by at least 14 distinct serotonin receptor subtypes. Multiple lines of evidence indicate that the 5- HT2C receptor (5HT2CR) subtype plays a particularly prominent role in mediating the serotonergic regulation of both hedonic states and STR function. Accordingly, we had found that a line of mutant mice lacking functional 5HT2CRs displayed diverse neurochemical, physiological and behavioral phenotypes indicative of perturbed STR function and alterations in motivated behavior. Despite the acknowledged prominence of 5HT2CRs in the serotonergic modulation of STR function, it has been very difficult to discern those neural circuits most responsible for these effects. Progress i this area has been hindered by the widespread expression of 5HT2CRs in multiple cell types in multiple basal ganglia structures, and by limitations in the specificity of pharmacological probes of 5HT2CR function. To address this challenge, we will combine methods for the induction of cell type-specific genetic manipulations with high-resolution behavioral assessment technology to determine the contribution of dorsal raphe striatal projections to the serotonergic regulation o hedonic states. We will determine the functional significance of 5HT2CRs expressed in two principal striatal circuits: the direct and indirect pathways.