Neurotrophins and consolidation of learning-related synaptic plasticity

神经营养素和学习相关突触可塑性的巩固

• 批准号: 10663312
• 负责人: ROBERT D HAWKINS
• 金额: $ 37.39万
• 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: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10663312
• 关键词: Address; Afferent Neurons; Alzheimer' s Disease; Animals; Aplysia; Association Learning; Autocrine Communication; Behavioral; Brain-Derived Neurotrophic Factor; Cell Culture System; Cell Culture Techniques; Cell Separation; Disease; Drug Addiction; Feedback; Functional disorder; Gene Expression Regulation; Growth; Huntington Disease; Learning; Ligands; Mammals; Memory; Mental Depression; Mental disorders; Molecular; Motor Neurons; Nervous System; Neurodevelopmental Disorder; Neurons; Orthologous Gene; Parkinson Disease; Physiological; Play; Preparation; Protein Isoforms; Reflex action; Rett Syndrome; Role; Schizophrenia; Sensory; Signal Transduction; Source; Synapses; Synaptic plasticity; System; Testing; Varicosity; Withdrawal; autocrine; habituation; nervous system disorder; neurotrophic factor; novel; postsynaptic; postsynaptic neurons; presynaptic; receptor; tool

BDNF and other neurotrophins (NTs) have widespread and powerful roles in the mammalian nervous system, and are thought to be involved in synaptic plasticity, learning, and memory, as well as in a number of psychiatric and neurological disorders including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Rett syndrome, drug addiction, schizophrenia, and depression. However, how NTs function at the cellular and synaptic levels is not well understood. For example, it is not clear whether NTs are released from or act on the pre- or postsynaptic neuron, or whether and how multiple mammalian NTs interact at a single synapse. Aplysia sensory-motor neuron cell culture is an ideal system for addressing these types of questions. We had previously identified an Aplysia BDNF ortholog (ApNT) and its Trk receptor (ApTrk) and found that they are important for the induction of long-term facilitation (LTF) and consolidation of short-term (ST) to early intermediate-term (IT) facilitation. Our results do not support the simple linear cascade that we and others had expected, but rather reveal that ApNT plays surprising roles in two synaptic feedback loops: [1] as an autocrine signal in a presynaptic positive feedback loop that amplifies the molecules required, and [2] as both an anterograde and retrograde signal in a transynaptic feedback loop that coordinates mechanisms in the presynaptic and postsynaptic compartments. These loops provide novel mechanisms for consolidation of learning-related plasticity that could well contribute more generally. We now propose to extend those studies in three new directions: 1. The roles of ApNT and ApTrk in consolidation of long-term plasticity. We will investigate the roles of ApNT and ApTrk in consolidation of early IT to late IT and LT plasticity. We will also explore possible functions of the feedback loops, and investigate the roles of ApNT and ApTrk in gene regulation and the assembly of pre- and postsynaptic components in a synaptic growth cascade. 2. The roles of pro and mature isoforms of ApNT. Like other neurotrophins ApNT has pro and mature forms whose relative functions are unclear. Investigating the roles of those isoforms of a NT is much easier in the Aplysia system, which only has a single neurotrophin. Our preliminary results suggest the hypothesis that release of the mature form from sensory neurons may act as an autocrine signal that contributes to induction of facilitation, whereas release of the pro form from motor neurons may act as a retrograde signal that contributes to stabilization, perhaps by interacting with CPEB or PKM. We will test that hypothesis in several ways. 3. The causal roles of ApNT and ApTrk and their integration with other mechanisms during behavioral learning. The exact roles of neurotrophins in behavioral learning and memory are also unclear. To address that question, we have been studying mechanisms of simple forms of learning under physiological conditions in a reduced preparation of the Aplysia siphon withdrawal reflex. We will now use that preparation to explore the causal roles of ApNT and ApTrk and their integration with other cellular and molecular mechanisms during behavioral learning.

BDNF和其他神经营养蛋白（NTS）在哺乳动物神经系统中具有宽度和强大的作用， 并被认为参与突触可塑性，学习和记忆以及许多精神病学 以及包括阿尔茨海默氏病，帕金森氏病，亨廷顿氏病，RETT在内的神经系统疾病 综合征，药物成瘾，精神分裂症和抑郁症。但是，NTS如何在细胞和 突触水平尚不很好。例如，目前尚不清楚nts是释放还是在 突触前神经元或多种哺乳动物NTS在单个突触时是否相互作用。 Aplysia 感觉运动神经元细胞培养是解决这类问题的理想系统。我们以前有 鉴定出Aplysia bdnf直系同源物（APNT）及其TRK受体（APTRK），发现它们对于 长期设施（LTF）的诱导以及短期（ST）与早期中期（IT）的合并 便利。我们的结果不支持我们和其他人期望的简单线性级联反应，而是 揭示apnt在两个突触反馈循环中扮演令人惊讶的角色：[1]作为突触前的自分泌信号 放大分子所需的正反馈回路，[2]作为顺序和逆行 信号中的透射反馈回路，该回路协调突触前和突触后的机制 车厢。这些循环提供了合并与学习相关可塑性的新型机制 贡献更广泛。现在，我们建议将这些研究扩展到三个新的方向： 1。apnt和aptrk在巩固长期可塑性中的作用。我们将调查apnt的角色 和APTRK早期将其固结至较晚和LT可塑性。我们还将探讨 反馈循环，并研究APNT和APTRK在基因调节中的作用以及预 - 和组装 突触生长级联中的突触后成分。 2。apnt的Pro和成熟同工型的作用。像其他神经营养蛋白一样 其相对功能尚不清楚。调查NT的同工型的作用要容易得多 Aplysia系统，仅具有单个神经营养蛋白。我们的初步结果表明了以下假设 从感觉神经元中释放成熟形式可能充当自分泌信号，有助于诱导 促进，而从运动神经元释放Pro形式可能充当逆行信号 稳定，也许是通过与CPEB或PKM相互作用。我们将以几种方式检验该假设。 3。apnt和aptrk的因果关系及其与行为学习过程中其他机制的整合。 神经营养蛋白在行为学习和记忆中的确切作用也不清楚。为了解决这个问题， 我们一直在研究在降低的生理条件下简单学习形式的机制 虹膜撤回反射的准备。现在，我们将利用这种准备来探索 在行为学习过程中，APNT和APTRK及其与其他细胞和分子机制的整合。

项目成果

Distribution, cellular localization, and colocalization of several peptide neurotransmitters in the central nervous system of Aplysia.

• DOI: 10.1101/lm.053758.123
• 发表时间: 2023-05
• 期刊: LEARNING & MEMORY
• 影响因子: 2
• 作者: Hawkins, Robert D.;Brodin, Lennart;Theodorsson, Elvar;Vegvari, Akos;Kandel, Eric R.;Hokfelt, Tomas
• 通讯作者: Hokfelt, Tomas

Possible novel features of synaptic regulation during long-term facilitation in Aplysia.

• DOI: 10.1101/lm.053124.120
• 发表时间: 2021-07
• 期刊: Learning & memory (Cold Spring Harbor, N.Y.)
• 作者: Jin I;Kassabov S;Kandel ER;Hawkins RD
• 通讯作者: Hawkins RD