Effects of NPY on Hippocampal Circuit Function

NPY 对海马回路功能的影响

• 批准号: 8987815
• 负责人: LYNN E DOBRUNZ
• 金额: $ 36.75万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8987815
• 关键词: Affect; Amygdaloid structure; Animal Model; Anti-Anxiety Agents; Anxiety; Anxiety Disorders; Bathing; Biological Assay; Cells; Clinical; Dense Core Vesicle; Equilibrium; Frequencies; Fright; Functional disorder; Glutamates; Hippocampus (Brain); Human; Injection of therapeutic agent; Interneurons; Lead; Learning; Measures; Modeling; Mus; Neurons; Neuropeptides; Pathway interactions; Patients; Pattern; Physiological; Post-Traumatic Stress Disorders; Property; Pyramidal Cells; Regulation; Rodent; Role; Sensory; Severities; Signal Transduction; Stress; Synapses; Testing; Time; Tissues; anxiety symptoms; base; entorhinal cortex; feeding; gamma-Aminobutyric Acid; mouse model; nervous system disorder; neural circuit; neuropeptide Y; neuropsychiatry; new therapeutic target; novel; novel therapeutics; preclinical study; prevent; public health relevance; research study; response; stress resilience; therapeutic target; transmission process

 DESCRIPTION (provided by applicant): Neuropeptide Y (NPY) is an endogenous neuropeptide with robust anxiolytic properties. NPY has been implicated in a wide variety of anxiety disorders, including posttraumatic stress disorder (PTSD), and enhancement of NPY levels has been proposed as a potential therapy for PTSD and other anxiety disorders. Low levels of (NPY have been measured in patients with PTSD, and in rodents using the Predator Scent Stress model, which is a model of stress-induced anxiety/PTSD. However, the effect of Predator Scent Stress on NPY release in hippocampus has not yet been demonstrated. Anxiety disorders are considered a maladaptive form of learning, and hippocampal dysfunction has been implicated in anxiety disorders and PTSD. Because of its many clinical implications, it is important to understand how the endogenous release of NPY is regulated. In hippocampus, NPY is released from a subset of inhibitory interneurons that also release GABA. Despite the importance of NPY, very little is known about the physiological properties of the interneurons in hippocampus that release NPY. Experiments in this proposal will investigate the synaptically-evoked spiking properties of NPY-containing interneurons in the CA1 region of hippocampus, including the short-term plasticity of their excitatory inputs from Schaffer collateral (SC) synapses from CA3 and temporoammonic (TA) synapses from entorhinal cortex. Exogenous NPY has been shown to modulate glutamate release at SC synapses onto CA1 pyramidal cells and to decrease the strength of feed-forward inhibition from SC stimulation. It is not known if NPY modulates TA synapses or TA-induced feed-forward inhibition onto CA1 pyramidal cells. We will test the effect of exogenous (bath applied) NPY on the excitation/inhibition ratio and circuit function in CA1 in response to SC and TA stimulation. In addition, the effects on CA1 pyramidal cells of endogenously released NPY will be tested. Finally, we will test for alterations in the release of endogenous NPY in CA1 in a mouse model of anxiety, test for mechanisms underlying the changes, and investigate the effects on CA1 circuit function. These studies will lead to a greater understanding of the regulation of NPY cell spiking and the effects of endogenously released NPY, and may lead to potential therapeutic targets to increase NPY cell spiking and thus raise endogenous levels of NPY.

 描述（由申请人提供）：神经肽Y（NPY）是一种具有强大抗焦虑特性的内源性神经肽。 NPY 与多种焦虑症有关，包括创伤后应激障碍 (PTSD)，并且提高 NPY 水平已被提议作为治疗 PTSD 和其他焦虑症的潜在疗法。已经在 PTSD 患者和使用捕食者气味压力模型（压力诱发的焦虑/PTSD 模型）的啮齿动物中测量了低水平的 NPY。然而，捕食者气味压力对海马 NPY 释放的影响尚未得到证实。焦虑症被认为是一种适应不良的学习形式，而海马功能障碍与焦虑症和 PTSD 有关。 NPY 具有许多临床意义，因此了解 NPY 的内源性释放是如何调节的非常重要。在海马体中，NPY 由抑制性中间神经元子集释放，这些中间神经元也释放 GABA。尽管 NPY 很重要，但人们对海马中释放 NPY 的中间神经元的生理特性知之甚少。本提案中的实验将研究含 NPY 的突触诱发尖峰特性 海马 CA1 区域的中间神经元，包括来自 CA3 的谢弗侧支 (SC) 突触和内嗅皮层的颞氨 (TA) 突触的兴奋性输入的短期可塑性。外源 NPY 已被证明可以调节 SC 突触向 CA1 锥体细胞释放谷氨酸，并降低 SC 刺激的前馈抑制强度。它是 不知道 NPY 是否调节 TA 突触或 TA 诱导的对 CA1 锥体细胞的前馈抑制。我们将测试外源性（浸浴）NPY 对 CA1 响应 SC 和 TA 刺激的激发/抑制比和电路功能的影响。此外，还将测试内源释放的 NPY 对 CA1 锥体细胞的影响。最后，我们将测试内源性 NPY 释放的变化 在小鼠焦虑模型的 CA1 中，测试变化背后的机制，并研究对 CA1 回路功能的影响。这些研究将有助于更好地了解 NPY 细胞尖峰的调节和内源性释放 NPY 的影响，并可能导致潜在的治疗靶点增加 NPY 细胞尖峰，从而提高 NPY 的内源水平。