Serotonin and the Modulation of Brain Behavior

血清素和大脑行为的调节

• 批准号: 10355521
• 负责人: JAY A GINGRICH
• 金额: $ 54.04万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10355521
• 关键词: Acute; Adult; Affect; Amygdaloid structure; Anatomy; Anxiety; Anxiety Disorders; Behavior; Behavioral; Biological; Brain; Child; Cognitive; Cognitive deficits; Cues; Development; Diagnosis; Environmental Risk Factor; Exhibits; Exposure to; Extinction (Psychology); Fiber; Fluoxetine; Fright; Functional disorder; Genetic; Glutamates; Goals; HTR2A gene; Halorhodopsins; Human; Impaired cognition; Impairment; Injections; Language; Lead; Learned Helplessness; Learning; Measurable; Medial; Mediating; Mental Depression; Methaqualone; Methods; Mus; Neurons; Odors; Pathway interactions; Pattern; Pharmacogenetics; Pharmacology; Phenocopy; Phenotype; Physiological; Physiology; Prefrontal Cortex; Prevention strategy; Psychiatry; Reporting; Research; Rhodopsin; Role; Selective Serotonin Reuptake Inhibitor; Serotonin; Signal Transduction; Slice; Stress; Synapses; Testing; Viral; Wild Type Mouse; anxiety-like behavior; base; behavioral phenotyping; behavioral study; brain behavior; brain circuitry; child depression; cognitive function; conditioned fear; density; design; drug development; emotional behavior; experimental study; extracellular; fetal; gene therapy; hippocampal pyramidal neuron; improved; in utero; in vivo; insight; knowledge of results; molecular drug target; motor disorder; mouse model; mutant; nerve supply; neural circuit; neurophysiology; neuropsychiatric disorder; novel; optogenetics; periadolescent; postnatal; postnatal development; postsynaptic; public health relevance; relating to nervous system; response; serotonin receptor; serotonin transporter; symptomatology; tool; treatment strategy

Project Summary. Most neuropsychiatric disorders have developmental origins. Such vulnerability is often restricted to sensitive periods, but affected behaviors, modulating factors, and underlying mechanisms are scarcely understood. We have identified an early postnatal 5-HT-sensitive period in mice that affects adult anxiety/depression-related behaviors and cognitive function. Altered adult behaviors are associated with reduced anatomical connectivity between the raphe, the basolateral amygdala (BLA) and the medial prefrontal cortex (mPFC) in this mouse model, but it remains unknown what the consequences are on physiological connectivity and how alterations causally impact behavior. In wildtype mice, it is well established that raphe-mPFC-BLA circuitry regulates anxiety and depression-related behaviors and cognitive function. But also here, mechanistic insight especially at the level of 5-HTergic circuitry remains superficial. Hence, in the context of understanding normal brain function as well as developmental vulnerability, we view it as critical to elucidate the role of 5-HT input into postsynaptic circuits and its relationship with behavior. We furthermore believe that such insight into circuit function is needed to improve diagnosis and treatment strategies for neuropsychiatric disorders. Our proposal focuses on studying the raphe-mPFC-BLA circuit because of its central role in mediating and modulating emotional behaviors. Through optogenetics, we will directly investigate reciprocal circuit nodes at the physiological and behavioral level in WT mice and after developmental 5-HT interference. Furthermore, our developmental mouse models demonstrate that pharmacologic and genetic interventions to serotonin transporter or MAOA function produce comparable effects on behavior. Here we investigate the critical question if this vulnerability extends to 5-HTergic neuronal activity, using a pharmacogenetic approach. Our research will impact the understanding of the pathophysiology in depression/anxiety and cognitive impairment. Our research will likewise impact our understanding of how to treat these same conditions. We find that increased 5-HT signaling during development leads to functionally blunted 5-HTergic and mPFC pathways in adulthood, which in turn cause deficits in stress adaptation and fear extinction, and increase amygdala reactivity and fear conditioned learning. Conversely, 5-HT terminal activity in the BLA selectively reduces fear conditioning learning. These findings already indicate that terminal 5-HT activity in the BLA might be a promising biological target for the treatment of fear-related symptomatology. 5-HT receptors within the amygdala that relay the 5-HTergic signal to the postsynaptic circuitry might be interesting molecular targets for drug development. Furthermore, altered activity patterns identified here, might become measurable through non-invasive methods in humans to aid diagnosis. While more research is needed to increase confidence in such ideas, these examples provide strong evidence that the novel insight our studies will provide could in fact lead to improved diagnosis, prevention and treatment strategies in psychiatry.

项目摘要。大多数神经精神疾病都有发育起源。此类漏洞往往 仅限于敏感时期，但受影响的行为、调节因素和潜在机制是 几乎不明白。我们在小鼠中发现了产后早期 5-HT 敏感期，该期会影响成年小鼠 焦虑/抑郁相关的行为和认知功能。成人行为的改变与减少 中缝、基底外侧杏仁核 (BLA) 和内侧前额皮质之间的解剖连接 （mPFC）在该小鼠模型中，但仍不清楚其对生理连通性的影响 以及改变如何因果影响行为。在野生型小鼠中，已明确中缝-mPFC-BLA 电路调节焦虑和抑郁相关的行为和认知功能。但同样在这里，机械 特别是在 5-HTergic 电路水平上的见解仍然很肤浅。因此，在理解的背景下 正常的大脑功能以及发育脆弱性，我们认为阐明 5-HT 的作用至关重要 突触后回路的输入及其与行为的关系。我们还相信，这种洞察力 需要回路功能来改善神经精神疾病的诊断和治疗策略。我们的 该提案的重点是研究 raphe-mPFC-BLA 回路，因为它在调解和调节中发挥着核心作用。 调节情绪行为。通过光遗传学，我们将直接研究互易电路节点 WT 小鼠和发育 5-HT 干扰后的生理和行为水平。此外，我们的 发育小鼠模型表明，药理和遗传干预对血清素的影响 转运蛋白或 MAOA 功能对行为产生类似的影响。在这里我们调查关键问题 如果这种脆弱性延伸到 5-HTergic 神经元活动，请使用药物遗传学方法。 我们的研究将影响对抑郁/焦虑和认知病理生理学的理解 损害。我们的研究同样会影响我们对如何治疗这些相同病症的理解。我们发现 发育过程中 5-HT 信号传导增加会导致 5-HTergic 和 mPFC 通路功能减弱 成年后，这反过来会导致压力适应和恐惧消失的缺陷，并增加杏仁核 反应性和恐惧制约了学习。相反，BLA 中的 5-HT 末端活性选择性地减少恐惧 调节学习。这些发现已经表明 BLA 中的末端 5-HT 活性可能是一种有前途的 治疗恐惧相关症状的生物学目标。杏仁核内的 5-HT 受体负责传递 突触后回路的 5-HTergic 信号可能是药物开发中有趣的分子靶标。 此外，此处确定的改变的活动模式可能可以通过非侵入性方法进行测量 在人类中帮助诊断。虽然需要更多的研究来增强人们对这些想法的信心，但这些例子 提供强有力的证据表明我们的研究将提供的新颖见解实际上可以改善诊断， 精神病学的预防和治疗策略。

项目成果

Serotonin transporter deficient mice are vulnerable to escape deficits following inescapable shocks.

• DOI: 10.1111/j.1601-183x.2010.00652.x
• 发表时间: 2011-03
• 期刊: Genes, brain, and behavior
• 作者: Muller JM;Morelli E;Ansorge M;Gingrich JA
• 通讯作者: Gingrich JA

Dopamine and serotonin signaling during two sensitive developmental periods differentially impact adult aggressive and affective behaviors in mice.

在两个敏感发育时期，多巴胺和5-羟色胺信号传导差异影响小鼠的成人侵略性和情感行为。

• DOI: 10.1038/mp.2014.10
• 发表时间: 2014-06
• 期刊: MOLECULAR PSYCHIATRY
• 影响因子: 11
• 作者: Yu, Q.;Teixeira, C. M.;Mahadevia, D.;Huang, Y.;Balsam, D.;Mann, J. J.;Gingrich, J. A.;Ansorge, M. S.
• 通讯作者: Ansorge, M. S.

New Insights into How Serotonin Selective Reuptake Inhibitors Shape the Developing Brain.

• DOI: 10.1002/bdr2.1085
• 发表时间: 2017-07-17
• 期刊: Birth defects research
• 影响因子: 2.1
• 作者: Gingrich JA;Malm H;Ansorge MS;Brown A;Sourander A;Suri D;Teixeira CM;Caffrey Cagliostro MK;Mahadevia D;Weissman MM
• 通讯作者: Weissman MM

Optogenetic stimulation of DAergic VTA neurons increases aggression.

DAergic VTA 神经元的光遗传学刺激会增加攻击性。

• DOI: 10.1038/mp.2014.45
• 发表时间: 2014
• 期刊: Molecular psychiatry
• 影响因子: 11
• 作者: Yu,Q;Teixeira,CM;Mahadevia,D;Huang,Y-Y;Balsam,D;Mann,JJ;Gingrich,JA;Ansorge,MS
• 通讯作者: Ansorge,MS