Serotonergic modulation of hippocampal function

海马功能的血清素调节

• 批准号: 10231006
• 负责人: Mark Sascha Ansorge
• 金额: $ 42.75万
• 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/10231006
• 关键词: Acute; Adult; Affect; Agonist; Animals; Anxiety; Anxiety Disorders; Architecture; Axon; Behavior; Behavioral; Behavioral inhibition; Biological; Brain; Calcium; Chemosensitization; Complement; Data; Depressed mood; Development; Diagnosis; Dorsal; Event; Fiber; Fluoxetine; Functional disorder; Grant; Hippocampus (Brain); Human; Impaired cognition; Label; Lead; Learning; Life; Measures; Mediating; Memory; Memory impairment; Mental Depression; Modeling; 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; Wild Type Mouse; anxiety treatment; anxiety-like behavior; anxiety-related behavior; anxious; awake; base; behavioral study; cognitive function; cognitive performance; density; design; drug development; emotional behavior; emotional functioning; experimental study; genetic approach; hippocampal pyramidal neuron; improved; in vivo; in vivo monitoring; 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都有发育起源。这样的发育 脆弱性通常仅限于敏感时期，但受影响的行为、调节因素和潜在的 机制很少被理解。我们在小鼠中发现了出生后早期 5-HT 敏感期 影响成人焦虑/抑郁相关的行为和认知功能。成人行为的改变是 与该小鼠模型中 5-HTergic 活性降低有关，但尚不清楚是否存在因果关系 存在。在野生型小鼠中，已证实 5-HT 信号传导可调节与焦虑和抑郁相关的症状 行为和认知功能。但同样在这里，5-HTergic 电路水平的机制洞察仍然存在 浅。因此，在了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 输入突触后回路的作用及其与突触后回路的关系至关重要 行为。此外，我们相信，需要对电路功能进行深入了解，以改进诊断和 神经精神疾病的治疗策略。我们的建议重点是研究 5-HTergic 输入 海马体。我们研究海马体，因为它接受来自中缝核的密集 5-HTergic 神经支配， 它调解和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-HTergic 神经传递之间的关系 以及空间记忆和焦虑。我们关注CA1，因为它是收敛点和输出区域 海马体内的直接和间接通路。我们分别研究背侧和腹侧 CA1， 因为它们在认知和情感功能中假设的不同作用。 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。重要的是，我们的研究同样会影响我们对如何治疗这些疾病的理解 状况。我们的初步数据表明，在发育过程中增加 5-HTergic 信号传导会导致 成年期 5-HTergic 神经元活动减少，进而导致行为抑制/焦虑和 认知障碍。相反，通过光遗传学手段增加 5-HTergic 活性至少可以逆转 一些认知障碍。这些发现已经表明 5-HTergic 神经元的放电率可能是 治疗焦虑和抑郁相关症状的有希望的生物靶标。我们已经 确定了海马内的 5-HT 受体，该受体将 5-HTergic 信号传递至突触后 改善学习和记忆的电路。该受体可能是药物的一个有趣的分子靶点 发展。显然，需要更多的研究来增强人们对这些想法的信心。然而，我们相信 这些例子提供了强有力的证据，表明我们的研究将提供的新颖见解实际上可能会导致 改进精神病学的诊断、预防和治疗策略。

项目成果

Hippocampal 5-HT Input Regulates Memory Formation and Schaffer Collateral Excitation.

• DOI: 10.1016/j.neuron.2018.04.030
• 发表时间: 2018-06-06
• 期刊: Neuron
• 影响因子: 16.2
• 作者: Teixeira CM;Rosen ZB;Suri D;Sun Q;Hersh M;Sargin D;Dincheva I;Morgan AA;Spivack S;Krok AC;Hirschfeld-Stoler T;Lambe EK;Siegelbaum SA;Ansorge MS
• 通讯作者: Ansorge MS