Effects of NPY on Hippocampal Circuit Function

家长资助摘要：NPY对海马回路功能的影响（5 R 01 MH 180342 -04; PI：Dobrunz）。 父母补助金的主要目的是调查大量表达的 神经肽Y（NPY）调节海马回路功能，影响焦虑行为， 潜在地导致旨在增加NPY释放以治疗或预防焦虑的新的治疗靶点。的 最重要的假设是NPY抑制了到CA 1的颞氨（TA）通路中的突触可塑性， 焦虑症中神经肽Y释放的缺失改变了海马回路的功能，导致适应不良， 学习三个相互关联的具体目标集中在神经肽Y细胞的特性和它们的输入， 突触诱发的尖峰和触发NPY释放，内源性释放的NPY对兴奋性和 抑制性突触传递和可塑性，以及应激诱导的焦虑对内源性NPY的影响 在TA-CA 1突触处释放。到目前为止，我们已经发现了NPY细胞特性的异质性， 有助于突触诱发的尖峰和NPY释放的差异，含有NPY的神经胶质细胞 远端CA 1中的细胞充当前馈中间神经元，并且具有能够实现稳健激活和NPY的特性。 释放，并且NPY的释放抑制TA-CA 1突触的突触短期易化，提供关键的 在调节记忆巩固和恐惧学习的通路中的电路调制。最后，我们发现 神经肽Y的释放在啮齿类动物的压力诱导焦虑模型中受损，改变了电路功能。因此，我们有 开发了一种新的实验范式，能够研究内源性释放的NPY如何调节 健康和疾病状态下的海马电路。声明：非AG-18-039阿尔茨海默病和 阿尔茨海默病（AD）患者的AD/ADRD相关的NPY水平降低， AD海马组织中NPY+细胞数量减少。NPY具有抗焦虑和抗 AD患者中，高达50%的患者有焦虑和/或抑郁，这表明与AD相关。 降低NPY水平。同样相关的是，女性患AD、焦虑和抑郁的风险要大得多， 重要的是，雌二醇增加了NPY的表达和释放。无论是神经肽Y的释放，焦虑， 抑郁症、AD和女性高风险之间的联系从未被研究过。的新方法 测量内源性释放的NPY对在PANAR 01中发育的海马回路的影响 能够调查AD中NPY对海马回路的影响。在2个具体目标中，我们将测试 假设AD大鼠海马中NPY水平降低，而雌激素的丧失加剧了这种情况 在女性中，导致NPY释放受损和海马回路功能改变。我们将利用我们 在研究内源性NPY释放及其对突触传递的影响方面的专业知识，与我们的专业知识， 在AD、性别差异和基因调控方面的合作者，开始测试这一点。

Parent Grant Summary: Effects of NPY on Hippocampal Circuit Function (5R01MH180342-04; PI:Dobrunz). The main objective of the parent grant is to investigate the mechanisms by which the abundantly expressed neuropeptide, Neuropeptide Y (NPY), modulates hippocampal circuit function to affect anxiety behavior, potentially leading to new therapeutic targets aimed at increasing NPY release to treat or prevent anxiety. The overarching hypothesis is that NPY suppresses synaptic plasticity in the temporammonic (TA) pathway to CA1, and that loss of NPY release in anxiety disorders alters hippocampal circuit function, contributing to maladaptive learning. Three interrelated specific aims focus on the properties of NPY cells and their inputs that determine synaptically-evoked spiking and trigger NPY release, effects of endogenously released NPY on excitatory and inhibitory synaptic transmission and plasticity, and the impact of stress-induced anxiety on endogenous NPY release at TA-CA1 synapses. Thus far, we have discovered heterogeneity in the properties of NPY cells that contribute to differences in synaptically-evoked spiking and NPY release, that NPY-containing neurogliaform cells in distal CA1 act as feed-forward interneurons and have properties that enable robust activation and NPY release, and that release of NPY dampens synaptic short-term facilitation at TA-CA1 synapses, providing critical circuit modulation in a pathway that regulates memory consolidation and fear learning. Finally, we discovered that NPY release is impaired in a rodent model of stress-induced anxiety, altering circuit function. Thus, we have developed a new experimental paradigm enabling the study of how endogenously released NPY modulates hippocampal circuits in health and disease states. SUPPLEMENT:NOT- AG-18-039 Alzheimer’s Disease and its related Dementias (AD/ADRD) NPY levels are reduced in patients with Alzheimer’s Disease (AD), and the number of NPY+ cells is decreased in postmortem AD hippocampal tissue. NPY has anti-anxiety and anti- depressant properties, and up to 50% of AD patients have anxiety and/or depression, suggesting a link to decreased NPY levels. Also relevant is the much greater risk of both AD and anxiety and depression in women, and importantly, estradiol increases NPY expression and release. Whether NPY release, anxiety and depression, AD, and heightened risk in females are connected has never been studied. Novel methods for measuring the effects of endogenously released NPY on hippocampal circuits developed in the PARENT R01 enables an investigation of the effects of NPY on hippocampal circuits in AD. In 2 specific aims, we will test the hypothesis that NPY levels are reduced in hippocampus of AD rats, and that loss of estrogen exacerbates this in females, leading to impaired release of NPY and altered hippocampal circuit function. We will leverage our expertise in studying endogenous NPY release and its effects on synaptic transmission, with the expertise of our collaborators in AD, sex differences, and in gene regulation, to begin to test this.