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: 10452648
• 负责人: ROBERT D HAWKINS
• 金额: $ 36.92万
• 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/10452648
• 关键词: Address; Afferent Neurons; Alzheimer' s Disease; Animals; Aplysia; Autocrine Communication; Behavioral; Brain-Derived Neurotrophic Factor; Cell Culture System; Cell Culture Techniques; 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 structure; 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; classical conditioning; habituation; nervous system disorder; neurotrophic factor; novel; postsynaptic; postsynaptic neurons; presynaptic; presynaptic neurons; 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 和其他神经营养素 (NT) 在哺乳动物神经系统中具有广泛而强大的作用， 并被认为与突触可塑性、学习和记忆以及许多精神疾病有关 和神经系统疾病，包括阿尔茨海默病、帕金森病、亨廷顿病、雷特病 综合征、毒瘾、精神分裂症和抑郁症。然而，NTs 如何在细胞和 突触水平尚不清楚。例如，尚不清楚 NT 是否是从 突触前或突触后神经元，或者多个哺乳动物 NT 是否以及如何在单个突触处相互作用。海兔 感觉运动神经元细胞培养是解决此类问题的理想系统。我们之前有过 鉴定了海兔 BDNF 直系同源物 (ApNT) 及其 Trk 受体 (ApTrk)，并发现它们对于 长期促进（LTF）的诱导和短期（ST）到早期中期（IT）的巩固 便利化。我们的结果并不支持我们和其他人所期望的简单线性级联，而是支持 揭示 ApNT 在两个突触反馈环路中发挥令人惊讶的作用：[1] 作为突触前的自分泌信号 放大所需分子的正反馈回路，并且 [2] 作为顺行和逆行 跨突触反馈环路中的信号，协调突触前和突触后的机制 隔间。这些循环提供了巩固与学习相关的可塑性的新机制，可以 我们将做出更广泛的贡献。我们现在建议将这些研究扩展到三个新方向： 1. ApNT和ApTrk在巩固长期可塑性中的作用。我们将研究 ApNT 的作用 和 ApTrk 将早期 IT 整合到后期 IT 和 LT 可塑性。我们还将探讨可能的功能 反馈环路，并研究 ApNT 和 ApTrk 在基因调控以及前体和前体组装中的作用 突触生长级联中的突触后成分。 2. ApNT 前亚型和成熟亚型的作用。与其他神经营养素一样，ApNT 也有成熟形式和成熟形式 其相对功能尚不明确。研究 NT 亚型的作用要容易得多 海兔系统只有一种神经营养蛋白。我们的初步结果表明以下假设： 从感觉神经元释放成熟形式可能充当自分泌信号，有助于诱导 促进，而运动神经元释放原形式可能作为逆行信号，有助于 可能通过与 CPEB 或 PKM 相互作用来实现稳定。我们将以多种方式检验该假设。 3. ApNT和ApTrk的因果作用及其在行为学习过程中与其他机制的整合。 神经营养因子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， 我们一直在研究生理条件下简单学习形式的机制 海兔虹吸撤回反射的准备。我们现在将利用这一准备来探索以下因素的因果作用： ApNT 和 ApTrk 及其在行为学习过程中与其他细胞和分子机制的整合。