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的起源。这种发育 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 机制几乎不被理解。我们已经确定了小鼠出生后早期的5-HT敏感期， 影响成人焦虑/抑郁相关行为和认知功能。成人行为的改变 与该小鼠模型中5-HTergic活性降低相关，但其因果关系是否仍然未知 存在.在野生型小鼠中，已经确定5-HT信号调节焦虑和抑郁相关的 行为和认知功能。但同样在这里，5-HTergic电路水平上的机械洞察力仍然存在， 肤浅因此，在理解正常大脑功能以及发育脆弱性的背景下， 我们认为理解5-HT输入到突触后回路的作用及其与突触后通路的关系是至关重要的。 行为我们还认为，需要对电路功能的这种洞察来改善诊断和治疗。 神经精神疾病的治疗策略。我们的建议侧重于研究5-HTergic输入到 海马体。我们研究海马，因为它接受来自中缝核的密集的5-HT能神经支配， 它调节情绪行为和认知功能。通过光遗传学和体内 本研究将直接探讨5-HT能神经传递在CA 1区的作用， 空间记忆和焦虑我们专注于CA 1，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CA 1， 因为他们在认知和情感功能中的假设差异作用。 我们的研究将影响对抑郁症/焦虑症和认知障碍的病理生理学的理解。 损伤重要的是，我们的研究将同样影响我们对如何治疗这些相同疾病的理解。 条件我们的初步数据表明，在发育过程中增加的5-HTergic信号传导导致 成年期5-HT能神经元活动减少，这反过来又导致行为抑制/焦虑， 认知障碍相反，通过光遗传学手段增加5-HTergic活性至少逆转了 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一个重要的因素。 有望成为治疗焦虑和抑郁症的生物靶点。我们已经 确定了海马内的5-HT受体，该受体将5-HT能信号传递到突触后神经元。 改善学习和记忆的电路。该受体可能是一个有趣的药物分子靶点 发展显然，需要更多的研究来增加对这些想法的信心。但我们认为 这些例子提供了强有力的证据，证明我们的研究将提供的新见解实际上可能导致 改进精神病学的诊断、预防和治疗战略。

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