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广泛的神经精神障碍相关的不同行为是必不可少的。STR在享乐过程中的重要作用与抑郁障碍、焦虑障碍、物质滥用障碍和酒精中毒有关。虽然许多人关注STR的多巴胺能神经支配的功能意义，但对5-羟色胺系统对STR功能的调节知之甚少。已知但知之甚少的5-羟色胺系统操作对STR功能和享乐过程的影响突显了这一问题的重要性。这在一定程度上是由于5-羟色胺能神经传递的复杂性；5-羟色胺的作用至少由14种不同的5-羟色胺受体亚型介导。多条证据表明，5-HT2C受体(5HT2CR)亚型在调节快感状态和STR功能的5-羟色胺能调节中起着特别重要的作用。因此，我们发现，缺乏功能性5HT2CRs的突变小鼠表现出不同的神经化学、生理和行为表型，表明STR功能受到干扰，动机行为发生变化。尽管公认5HT2CRs在5-羟色胺能调节STR功能中的重要性，但很难辨别哪些神经回路对这些影响负有最大责任。5HT2CRs在多种细胞类型的多种基底节结构中的广泛表达，以及5HT2CR功能的药理探针特异性的局限性，阻碍了这一领域的研究进展。为了应对这一挑战，我们将结合诱导特定细胞类型的遗传操作的方法和高分辨率行为评估技术来确定中缝背侧纹状体投射对享乐状态的5-羟色胺能调节的贡献。我们将确定5HT2CRs在两个主要纹状体回路中表达的功能意义：直接途径和间接途径。

 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.