Mechanisms Underlying TAAR1-induced Wakefulness and REM Sleep Suppression

TAAR1 诱导觉醒和快速眼动睡眠抑制的机制

• 批准号: 10408062
• 负责人: Thomas S Kilduff
• 金额: $ 62.99万
• 依托单位: SRI INTERNATIONAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10408062
• 关键词: Address; Agonist; Amines; Amygdaloid structure; Anti-Anxiety Agents; Antidepressive Agents; Antipsychotic Agents; Arousal; Attenuated; Biological Psychiatry; Brain region; Cataplexy; Cells; Clinical Trials; Dopamine; Dopamine D1 Receptor; Dopamine D2 Receptor; Dose; Electroencephalography; Frequencies; G-Protein-Coupled Receptors; GTP-Binding Protein alpha Subunits, Gs; Glutamates; Hour; Human; Knock-out; Knockout Mice; Laboratories; LacZ Genes; Mediating; Midbrain structure; Mus; Narcolepsy; Neurobiology; Neurons; Nucleus solitarius; Paper; Parkinson Disease; Pathway interactions; Pharmacology; Phenotype; Physiology; Preoptic Areas; Property; Psychoses; Publications; REM Sleep; Rattus; Regulation; Rodent; Schizophrenia; Seizures; Signal Transduction; Sleep; Spinal; System; Technology; Testing; Therapeutic; Ventral Tegmental Area; Wakefulness; Wild Type Mouse; antagonist; awake; base; cell type; dopaminergic neuron; dorsal raphe nucleus; efficacy evaluation; in vitro activity; in vivo; mRNA Expression; microendoscopy; mouse model; neural circuit; neurochemistry; neuromechanism; neuropsychiatry; nonhuman primate; novel; novel therapeutics; overexpression; psychostimulant; receptor

PROJECT SUMMARY Trace amine-associated receptor 1 (TAAR1) is a G protein-coupled receptor involved in the regulation of dopaminergic, serotonergic and glutamatergic activity. TAAR1 agonists have anxiolytic, antidepressant-, and antipsychotic-like properties in both rodent and non-human primates; TAAR1 agonists are in clinical trials for schizophrenia and Parkinson’s disease psychosis. We have previously shown that TAAR1 agonists are wake- promoting in mice, rats and, most recently, non-human primates, characterized the sleep/wake phenotype of Taar1 knockout (KO) and overexpressing (OE) mice, and evaluated the effects of TAAR1 agonists on sleep/wake in wildtype (WT), KO and OE mice. We also showed that two different TAAR1 agonists suppressed REM sleep and reduced cataplexy in mouse models of narcolepsy, precisely the properties desirable in a narcolepsy therapeutic. Having established TAAR1 agonists as potential novel treatments for narcolepsy, we will now investigate the underlying in vivo neurobiology. In Taar1-LacZ mice, we will determine whether TAAR1 is expressed in monoaminergic, glutamatergic or other cell types and use the RNAscope technology to determine endogenous Taar1 mRNA expression in WT and KO mice and rats. Since TAAR1 negatively regulates dopaminergic (DA) neuronal activity in vitro, we will test the hypothesis that TAAR1 partial agonism promotes wakefulness by modulating DA arousal systems. To address this hypothesis, we will assess neuronal activity in the ventral tegmental area and dorsal raphe nuclei of DAT-ires-Cre mice using in vivo Ca2+ microendoscopy, and determine whether pretreatment with DA D1- and D2-receptor antagonists attenuates TAAR1-mediated wake-promotion. Since serotonergic neurons are wake-active and REM-inactive and TAAR1 negatively regulates serotonergic neuronal activity in vitro, we will also test the hypothesis that TAAR1 partial agonism promotes wakefulness by modulating serotonergic arousal systems. We will determine whether TAAR1 partial agonists modulate the activity of DRN serotonergic neurons using in vivo Ca2+ microendoscopy in Fev-Cre mice and assess whether blockade of serotonergic signaling attenuates the wake-promoting effects of TAAR1 partial agonists. We have found that TAAR1 deletion elevates high-frequency gamma EEG activity, suggesting that TAAR1 modulates cortical function. To determine whether TAAR1-mediated elevation of gamma activity is conserved across species and specific to TAAR1, we will investigate basal sleep/wake physiology and conduct quantitative EEG analyses in Taar1 KO and OE rats and Taar2-9 KO mice. Together, these Aims will begin to establish the neural circuitry and mechanisms that underlie the efficacy of TAAR1 agonists.

项目摘要 痕量胺相关受体1（TAAR1）是与调节的G蛋白偶联受体 多巴胺能，血清素能和谷氨酸能活性。 TAAR1激动剂具有抗焦虑，抗抑郁药和 啮齿动物和非人类隐私的抗精神病药样特性； TAAR1激动剂正在临床试验中 精神分裂症和帕金森氏病精神病。我们以前已经表明taar1激动剂是唤醒的 - 在小鼠，大鼠和最近的非人类隐私中促进，表征了睡眠/唤醒表型 TAAR1敲除（KO）和过表达（OE）小鼠，并评估了TAAR1激动剂对 在Wildtype（WT），KO和OE小鼠中入睡/唤醒。我们还表明，两种不同的TAAR1激动剂抑制了 REM睡眠和降低的发肠内病小鼠模型中的瘫痪，正是在A中所期望的特性 睡病疗法。建立了TAAR1激动剂为潜在的麻醉疗法的新型治疗方法，我们 现在将研究基本的体内神经生物学。在taar1-lacz小鼠中，我们将确定taar1是否 以单胺能，谷氨酸能或其他细胞类型表示，并使用rnascope技术来表达 确定内源性TAAR1 mRNA在WT和KO小鼠和大鼠中的表达。自taar1否定 调节体外多巴胺能（DA）神经元活性，我们将检验以下假设：taar1局部激动 通过调节唤醒系统来促进清醒。为了解决这一假设，我们将评估 使用体内Ca2+的Dat-ires-Cre小鼠的腹侧换段区域和背侧raphe核的神经元活性 微镜检查，并确定使用DA D1-和D2受体拮抗剂的预处理是否减弱 TAAR1介导的唤醒促进。由于血清素能神经元具有唤醒活性和重新活性和TAAR1 在体外调节血清素能神经元活性，我们还将检验以下假设。 激动剂通过调节血清能唤醒系统来促进清醒。我们将确定是否 TAAR1部分激动剂使用体内CA2+微镜检查调节DRN血清素能神经元的活性 在FEV-CRE小鼠和评估中是否阻断了血清能信号传导是否会减轻唤醒效果 taar1部分激动剂。我们发现TAAR1删除会提高高频伽玛脑电图活性， 表明TAAR1调节皮质功能。确定TAAR1介导的升高是 伽马活性在规格之间保存，特定于TAAR1，我们将研究基本的睡眠/唤醒 在TAAR1 KO和OE大鼠和TAAR2-9 KO小鼠中进行生理和进行定量EEG分析。一起， 这些目标将开始建立taar1效率的基础的神经回路和机制 激动剂。

项目成果

Peripheral vs. core body temperature as hypocretin/orexin neurons degenerate: Exercise mitigates increased heat loss.

下丘脑分泌素/食欲素神经元退化时的外周体温与核心体温：运动可减轻热量损失的增加。

• DOI: 10.1016/j.peptides.2023.171002
• 发表时间: 2023
• 期刊: Peptides
• 影响因子: 3
• 作者: Sun,Yu;Tisdale,RyanK;Yamashita,Akira;Kilduff,ThomasS
• 通讯作者: Kilduff,ThomasS

Deficiency of orexin signaling during sleep is involved in abnormal REM sleep architecture in narcolepsy.

• DOI: 10.1073/pnas.2301951120
• 发表时间: 2023-10-10
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Ito, Hiroto;Fukatsu, Noriaki;Rahaman, Sheikh Mizanur;Mukai, Yasutaka;Izawa, Shuntaro;Ono, Daisuke;Kilduff, Thomas S.;Yamanaka, Akihiro
• 通讯作者: Yamanaka, Akihiro

The Development of Sleep/Wake Disruption and Cataplexy as Hypocretin/Orexin Neurons Degenerate in Male vs. Female Orexin/tTA; TetO-DTA Mice.

男性与女性 Orexin/tTA 中下丘脑分泌素/食欲素神经元退化导致睡眠/觉醒中断和猝倒的发展；

• DOI: 10.1093/sleep/zsac039
• 发表时间: 2022
• 期刊: Sleep
• 影响因子: 5.6
• 作者: Sun Y;Tisdale R;Park S;Ma SC;Heu J;Haire M;Allocca G;Yamanaka A;Morairty SR;*Kilduff TS.
• 通讯作者: *Kilduff TS.