Serotonergic modulation of hippocampal function

海马功能的血清素调节

• 批准号: 9365602
• 负责人: Mark Sascha Ansorge
• 金额: $ 48.6万
• 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: 2017
• 资助国家: 美国
• 起止时间: 2017-08-08 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9365602
• 关键词: Acute; Adult; Affect; Agonist; Animals; Anxiety; Anxiety Disorders; Architecture; Axon; Behavior; Behavioral; Behavioral inhibition; Biological; Brain; Calcium; Chemosensitization; Cognitive; Complement; Data; Depressed mood; Development; Diagnosis; Dorsal; Emotional; Event; Fiber; Fluoxetine; Functional disorder; Grant; Hippocampus (Brain); Human; Impaired cognition; Label; Lead; Learning; Life; Measures; Mediating; Memory; Memory impairment; Mental Depression; Modeling; Monitor; Mus; Neurons; Output; Pathway interactions; Pharmacology; Photometry; Physiology; Positioning Attribute; Pregnancy; Preparation; Prevention strategy; Protocols documentation; Psychiatry; Research; Risk; Role; Serotonergic System; Serotonin; Serotonin Receptors 5-HT4; Signal Transduction; Slice; Synapses; Testing; Virus; anxiety treatment; anxiety-like behavior; anxiety-related behavior; anxious; awake; base; behavioral study; cognitive function; cognitive performance; density; design; drug development; emotional behavior; experimental study; genetic approach; hippocampal pyramidal neuron; improved; in vivo; insight; maternal depression; molecular drug target; mouse model; nerve supply; neural circuit; neurophysiology; neuropsychiatric disorder; neurotransmission; neurotransmitter release; novel; optogenetics; postnatal; postsynaptic; raphe nuclei; receptor; response; serotonin receptor; spatial memory; symptomatology; tool; treatment strategy

Project Summary. Most neuropsychiatric disorders have developmental origins. Such developmental 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 5-HTergic activity in this mouse model, but it remains unknown if a causal relationship exists. In wildtype mice, it is well established that 5-HT signaling modulates anxiety and depression-related behaviors and cognitive function. But also here, mechanistic insight 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 understand 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 5-HTergic input into the hippocampus. We study the hippocampus, because it receives dense 5-HTergic innervation from raphé nuclei, and it mediates and modulates emotional behaviors and cognitive function. Through optogenetics and in vivo calcium-photometry, we will directly investigate the relationship between 5-HTergic neurotransmission in CA1 and spatial memory and anxiety. We focus on CA1, because it is the converging point and the output region of the direct and indirect pathway within the hippocampus. We study the dorsal and ventral CA1 separately, because of their hypothesized differential role in cognitive and emotional function. Our research will impact the understanding of the pathophysiology in depression/anxiety and cognitive impairment. Importantly our research will likewise impact our understanding of how to treat these same conditions. Our preliminary data suggest that increased 5-HTergic signaling during development leads to reduced 5-HTergic neuronal activity in adulthood, which in turn causes behavioral inhibition/anxiety and cognitive impairment. Conversely, increasing 5-HTergic activity through optogenetic means reverses at least some cognitive impairment. These findings already indicate that the firing rate of 5-HTergic neurons might be a promising biological target for the treatment of anxiety and depression related symptomatology. We already identified the 5-HT receptor within the hippocampus that relays the 5-HTergic signal to the postsynaptic circuitry to improve learning and memory. This receptor might be an interesting molecular target for drug development. Clearly, more research is needed to increase confidence in such ideas. However, we believe 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。这样的发展 脆弱性通常仅限于敏感时期，但受影响的行为，调节因素和基础 机制几乎没有理解。我们已经确定了小鼠的早期早期5-HT敏感时期 影响成人动画/与抑郁症相关的行为和认知功能。成人行为改变是 与该鼠标模型中的5个纤维活性降低相关，但是是否有因果关系仍然未知 存在。在野生型小鼠中，众所周知，5-HT信号传导调节动画和抑郁有关 行为和认知功能。但在这里，在5握电路的水平上的机械洞察力仍然存在 浅。因此，在理解正常大脑功能以及发育脆弱性的背景下， 我们认为了解5-HT输入对突触后电路的作用及其与之的关系至关重要 行为。我们此外认为，需要对电路功能的这种见解来改善诊断和 神经精神疾病的治疗策略。我们的建议重点是研究5个顽固的输入 海马。我们研究海马，因为它从强奸核里获得了密集的5个韧性神经， 它介导并调节情绪行为和认知功能。通过光遗传学和体内 钙光度法，我们将直接研究CA1中5链神经传递之间的关系 以及空间记忆和动画。我们专注于CA1，因为它是融合点和输出区域 海马内的直接和间接途径。我们分别研究背侧和腹侧CA1， 由于它们在认知和情感功能中的假设差异作用。 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。重要的是，我们的研究同样会影响我们对如何对待这些的理解 状况。我们的初步数据表明，开发过程中增加了5个韧性信号传导导致 成年后降低了5个纤维神经元活性，进而导致行为抑制/焦虑和 认知障碍。相反，通过光遗传学手段至少逆转增加了5个韧性活性 一些认知障碍。这些发现已经表明5个髋关节神经元的发射速率可能是 有望治疗动画和抑郁症相关症状的生物学靶标。我们已经 鉴定了海马内的5-HT受体，该受体将5握信号转移到突触后的情况下 改善学习和记忆的电路。该接收器可能是药物的有趣分子靶标 发展。显然，需要更多的研究来增加对此类想法的信心。但是，我们相信 这些例子提供了有力的证据，表明我们的研究将提供的新颖见解实际上可能导致 改进了精神病学的诊断，预防和治疗策略。