Role of the prefrontal cortex in serotonergic modulation of interval timing

描述（由申请人提供）：啮齿动物和人类均有证据表明，多巴胺能系统调节间隔时间，这是一种在精神分裂症患者中显示异常的行为。这个K 01职业发展应用程序寻求支持一个项目，使用小鼠模型来阐明内源性5-羟色胺（5-HT）和致幻药物调节间隔时间的神经和受体机制。鉴于最近恢复了对致幻剂的人体研究，以及有报告表明致幻剂可能具有临床疗效，迫切需要对这些药物的作用有更全面的了解。所使用的具体范例是离散试验间隔计时任务，其中训练啮齿动物区分短刺激持续时间和长刺激持续时间。主要培训目标是为申请人：（1）发展专业知识， 在小鼠中使用操作程序;（2）开发跨物种操作任务以评估小鼠的间隔时间;（3）获得使用光遗传学技术控制位点特异性5-HT释放的专业知识。该项目有三个具体目标。目的1是在申请人开发的用于小鼠的离散试验任务中表征5-羟色胺激动剂和致幻剂对间隔时间的影响。该任务将通过测试5-HT激动剂（包括致幻剂psilocin和2，5-二甲氧基-4-碘苯丙胺，它们作为5-HT 2A激动剂）是否破坏小鼠的间隔计时行为来验证，正如大鼠的有限研究所表明的那样。目的2将检验5-HT在前额叶皮层（PFC）中特异性调节间隔时间的假设。PFC是间隔计时的关键神经基质，5-HT受体激活对PFC神经元的活动有深远的影响。使用基于病毒表达策略的光遗传学技术来选择性地激活从中缝背核到PFC的多巴胺能投射，该目的的研究将测试以下假设：选择性地增加PFC中的5-HT释放将破坏小鼠中的间隔定时，并且PFC中的5-HT释放破坏间隔定时的能力依赖于5-HT 2A受体。目的3将检验代谢型谷氨酸受体（mGluR 2/3）调节外源性给予的5-HT激动剂和内源性释放的5-HT对间隔时间的影响的假设。mGluR 2/3激动剂在功能上拮抗PFC中的5-HT 2A受体效应，并且可能在精神分裂症中具有抗精神病功效。这些研究解决了受体相互作用的新机制，对理解多巴胺能和多巴胺能系统之间的相互作用具有重要意义，并可能揭示精神病的病理生理学，从而有助于确定治疗精神分裂症的新药物。

DESCRIPTION (provided by applicant): There is evidence from both rodents and humans that the serotonergic system regulates interval timing, a behavior that has been shown to be abnormal in patients with schizophrenia. This K01 Career Development application seeks support for a project that uses a mouse model to elucidate the neural and receptor mechanisms underlying the modulation of interval timing by both endogenous serotonin (5-HT) and hallucinogenic drugs. In light of the recent resumption of human studies with hallucinogens, and reports indicating that hallucinogens may possess clinical efficacy, a more complete understanding of the action of these drugs is urgently needed. The specific paradigm used is a discrete-trials interval timing task where rodents are trained to distinguish between short and long stimulus durations. The main training goals are for the applicant to: (1) develop expertise in the use of operant procedures in mice; (2) develop a cross-species operant task to assess interval timing in mice; and (3) gain expertise in the use of optogenetic techniques to control site-specific 5-HT release. The project has three specific aims. Aim 1 is to characterize the effects of serotonin agonists and hallucinogens on interval timing in a discrete-trials task that te applicant has developed for use in mice. The task will be validated by testing whether 5-HT agonists (including the hallucinogens psilocin and 2,5-dimethoxy-4-iodoamphetamine, which act as 5-HT2A agonists) disrupt interval timing behavior in mice, as indicated by limited studies in rats. Aim 2 will test the hypothesis that 5-HT acts specifically in the prefrontal cortex (PFC) to modulate interval timing. The PFC is a critical neural substrate for interval timing, and 5-HT receptor activation has profound effects on the activity of PFC neurons. Using optogenetic techniques based on a viral expression strategy to selectively activate serotonergic projections from the dorsal raphe nucleus to the PFC, studies in this aim will test the hypotheses that selectively increasing 5-HT release in PFC will disrupt interval timing in mice, and that the abiliy of 5-HT release in the PFC to disrupt interval timing is dependent on the 5-HT2A receptor. Aim 3 will test the hypothesis that metabotropic glutamate receptors (mGluR2/3) modulate the effects of both exogenously administered 5-HT agonists and endogenously released 5-HT on interval timing. mGluR2/3 agonists functionally antagonize 5-HT2A receptor effects in the PFC, and may possess antipsychotic efficacy in schizophrenia. These studies address novel mechanisms of receptor interactions that have important implications for understanding the interplay between serotonergic and glutamatergic systems and may shed light on the pathophysiology of psychosis and thereby aid in identifying novel pharmacotherapeutic agents for the treatment of schizophrenia.