Role of the prefrontal cortex in serotonergic modulation of interval timing

描述（由申请人提供）：啮齿动物和人类都有证据表明，血清素能系统调节间隔时间，这种行为在精神分裂症患者中被证明是不正常的。本K01职业发展申请寻求对一个项目的支持，该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。鉴于最近对致幻剂的人体研究的恢复，以及表明致幻剂可能具有临床疗效的报告，迫切需要更全面地了解这些药物的作用。使用的具体范例是一个离散试验间隔计时任务，其中训练啮齿动物区分短和长刺激持续时间。申请人的主要培训目标是：(1)发展专业知识

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.