Effects of NPY on Hippocampal Circuit Function

家长资助摘要：NPY对海马区电路功能的影响(5R01MH180342-04；PI：Dobrunz)。 父母赠款的主要目标是调查丰富表达的 神经肽，神经肽Y(NPY)，调节海马体回路功能，影响焦虑行为， 可能导致新的治疗靶点，旨在增加NPY的释放，以治疗或预防焦虑。这个 最重要的假设是，NPY抑制了通向CA1的颞氨(TA)通路中的突触可塑性， 焦虑症中NPY释放的缺失会改变海马神经元的功能，从而导致适应不良 学习。三个相互关联的具体目标集中在NPY细胞的属性及其决定因素的输入上 突触诱发的兴奋性和触发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性焦虑对内源性神经肽Y的影响 在TA-CA1突触释放。到目前为止，我们已经发现NPY细胞属性的异质性 导致突触诱发的棘波和NPY释放的差异，含NPY的神经胶质样 CA1远端的细胞起前馈中间神经元的作用，具有强大的激活和NPY的特性 释放，而NPY释放抑制了TA-CA1突触的突触短期便利化，提供了关键的 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 在应激性焦虑的啮齿动物模型中，NPY的释放受到损害，改变了电路功能。因此，我们有 开发了一种新的实验范式，使研究内源性释放的NPY如何调制 健康和疾病状态下的海马区回路。补充：Not-AG-18-039阿尔茨海默病和 其相关痴呆(AD/ADRD)NPY水平在阿尔茨海默病(AD)患者中降低， 死后AD大鼠海马区NPY+细胞数量减少。NPY具有抗焦虑和抗抑郁作用 抑郁特性，高达50%的AD患者有焦虑和/或抑郁，这表明与 NPY水平降低。同样相关的是，女性患阿尔茨海默病、焦虑和抑郁的风险要大得多， 更重要的是，雌二醇会增加神经肽Y的表达和释放。NPY的释放、焦虑和 女性抑郁、阿尔茨海默病和高风险之间的联系从未被研究过。新的方法可用于 测定内源性释放的神经肽Y对亲本R01发育的海马神经元的影响 使研究NPY对AD海马区的影响成为可能。在两个具体目标中，我们将测试 假设AD大鼠的海马神经肽Y水平降低，而雌激素的丢失会加剧这种情况 在女性中，导致NPY的释放受损，并改变海马回路功能。我们将利用我们的 在内源性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.