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。大多数神经精神障碍都有发育性起源。这样的发展 脆弱性通常局限于敏感期，但受影响的行为、调节因素和潜在的 人们对这一机制知之甚少。我们已经在小鼠中发现了一个出生后早期的5-羟色胺敏感期 影响成人焦虑/抑郁相关的行为和认知功能。改变的成人行为是 在这个小鼠模型中与5-羟色胺能活性降低有关，但尚不清楚是否存在因果关系 是存在的。在野生型小鼠中，众所周知，5-羟色胺信号调节焦虑和抑郁相关 行为和认知功能。但在这里，5-H能电路水平上的机械论洞察力仍然存在 肤浅的。因此，在了解正常大脑功能以及发育脆弱性的背景下， 我们认为理解5-羟色胺在突触后回路中的作用及其与突触后回路的关系至关重要 行为。我们还认为，需要对电路功能的这种洞察来提高诊断和 神经精神障碍的治疗策略。我们的建议重点是研究5-HTerable输入到 海马体。我们研究海马体，因为它接受来自中缝核的密集的5-羟色胺能神经支配， 它调节和调节情绪行为和认知功能。通过光遗传学和活体实验 钙光度法，我们将直接研究CA1区5-羟色胺能神经递质之间的关系 以及空间记忆和焦虑。我们将重点放在CA1上，因为它是 海马体内的直接和间接途径。我们分别研究了背侧和腹侧的CA1， 因为它们在认知和情感功能上的假设不同作用。 我们的研究将影响对抑郁/焦虑和认知的病理生理学的理解 减损。重要的是，我们的研究同样会影响我们对如何对待这些问题的理解 条件。我们的初步数据表明，发育期间增加的5-羟色胺能信号会导致 成年期5-羟色胺能神经元活性降低，进而导致行为抑制/焦虑和 认知障碍。相反，通过光遗传手段增加5-羟色胺能活性至少可以逆转 一些认知障碍。这些发现已经表明，5-羟色胺能神经元的放电率可能是 有望成为治疗焦虑和抑郁相关症状的生物靶点。我们已经 确定了海马区内的5-羟色胺受体，它将5-羟色胺能信号传递到突触后 改善学习和记忆的电路。这种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加人们对这些想法的信心。然而，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、预防和治疗策略。