Serotonin and the Modulation of Brain Behavior

血清素和大脑行为的调节

基本信息

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
项目类别：
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

项目摘要

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具有发育起源。这样的脆弱性通常是仅限于敏感时期，但是受影响的行为，调节因素和基本机制是几乎没有理解。我们已经确定了小鼠产后5-HT敏感时期的早期影响，这会影响成人焦虑/抑郁相关的行为和认知功能。成人行为改变与减少有关 Raphe，基底外侧杏仁核（BLA）和内侧前额叶皮层之间的解剖连通性（MPFC）在此鼠标模型中，但尚不清楚生理连通性的后果以及改变如何影响行为。在Wildtype小鼠中，raphe-mpfc-bla已经很好地确定电路调节焦虑和抑郁相关的行为和认知功能。但在这里，机械洞察力，尤其是在5个矫正电路水平上仍然是浅表的。因此，在理解的背景下正常的大脑功能以及发育脆弱性，我们认为这对于阐明5-HT的作用至关重要输入突触后电路及其与行为的关系。我们此外，我们相信这种洞察力需要电路功能来改善神经精神疾病的诊断和治疗策略。我们的提案重点是研究Raphe-MPFC-Bla电路，因为它在中介和中心作用调节情绪行为。通过光遗传学，我们将直接研究互惠电路节点 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，对5-羟色胺的药理和遗传干预措施转运蛋白或MAOA功能对行为产生可比的影响。在这里，我们调查一个关键问题如果这种脆弱性使用药物遗传学方法扩展到5座神经元活性。我们的研究将影响抑郁/焦虑和认知中病理生理学的理解损害。我们的研究同样将影响我们对如何治疗这些相同条件的理解。我们发现在开发过程中增加了5-HT信号传导导致功能上钝化的5次矫正和MPFC途径在成年后，这反过来导致压力适应和恐惧灭绝，并增加杏仁核反应性和恐惧条件学习。相反，BLA中的5-HT终端活动有选择地减少恐惧调理学习。这些发现已经表明BLA中的5-HT活动可能是一个有前途的治疗与恐惧相关症状的生物学靶标。中继的杏仁核内的5-HT受体到突触后回路的5次矫正信号可能是药物发育的有趣分子靶标。此外，这里确定的活动模式可能通过非侵入性方法来衡量在人类中有助于诊断。虽然需要进行更多的研究来增加对这些想法的信心，但这些例子提供有力的证据表明，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

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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
影响因子：
0
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.

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