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Sex Differences in the Neurobiological Significance of Orexin Stress Signaling

食欲素应激信号的神经生物学意义的性别差异

基本信息

批准号：
10291077
负责人：
CLIFF H SUMMERS
金额：
$ 42.73万
依托单位：
UNIVERSITY OF SOUTH DAKOTA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10291077
关键词：
Adult Affect Affective Agonist American Amygdaloid structure Anterior Behavior Brain Cells Conflict (Psychology)Data Development Down-Regulation Elements Emotions Equilibrium Exhibits FRAP1 gene Female Fright Future Gene Expression Gene Expression Regulation Genetic Genetic Markers Goals Hypothalamic structure Individual Lasers Learning Lifestyle-related condition Measures Mediating Mental disorders Microdissection Modeling Modification Molecular Mood Disorders Mus Neurobiology Neuronal Plasticity Neurons Neuropeptides Outcome Output Pathway interactions Patients Peptides Periodicity Phenotype Play Population Prefrontal Cortex Property Proteins Receptor Activation Role Sex Differences Sex Differentiation Signal Pathway Signal Transduction Stress Symptoms System Therapeutic Transcript Up-Regulation avoidance behavior biological adaptation to stress conditioned fear density differential expression emotional behavior experimental study functional outcomes gamma-Aminobutyric Acid hypocretin male neural circuit novel orexin B receptor protein expression receptor receptor expression relating to nervous system response sex social social stress stem stress reactivity stress reduction suicide rate

项目摘要

Recent metanalyses suggest that neurocircuits in males and females are not equally affected by stress exposure, such that females have demonstrably higher rates of psychological disorders, and males, higher rates of suicide. Genetic markers associated with stress responsiveness, expressed in basolateral amygdala (BLA) and prefrontal cortex (PFC), may help explain differences in females and males. The prelimbic (PrL) PFC innervates specific cells in the anterior BLA (aBLA) expressing the Rspo2 genetic marker, forming a pro-stress circuit. A parallel anti-stress circuit also exists connecting infralimbic (IL) PFC neurons carrying the Drd1 genetic marker, to posterior BLA (pBLA) cells that express Ppp1r1b. These two microcircuits produce variable stress responsivity, that when favoring pro-stress PrL-aBLA/Rspo2 activity, results in exaggerated stress reactivity and potentially leads to affective psychological disorders. These microcircuits are modulated by orexins/hypocretins (Orx) by means of Orx1 and Orx2 receptor subtypes, specifically localized to pro-stress (PrL-aBLA/Rspo2 Orx1) and anti-stress (IL/Drd1-pBLA/Ppp1r1b Orx2) elements of this circuitry. Activation of BLA Orx1 and Orx2 receptors are also functionally opposed, and differentially trigger enhanced or inhibited stress responsiveness. The data suggest that interplay between Orx1- and Orx2-stimulated circuits control the output of stress responsivity. Females have elevated expression of Orx2 receptors. The focus is to determine whether the balance between activation of these two microcircuits, and the sexual differences in stress responsivity, is governed by density of Orx2 anti- stress receptors and which specific molecular cascades are present. We propose to examine the molecular systems that appear downstream of Orx2 receptor activation, by which stress responsivity is reduced, in two stable phenotypes: stress-reactive individuals that exhibit enhanced fear conditioning, and individuals that exhibit active avoidance of stress. Aim 1: BLA and PFC Orx2 receptors modify PLC to mToR signaling. The intracellular molecular signaling pathway, PLC or mToR, triggered by Orx2 determines the functional outcome. Measuring PLC and mToR transcripts and proteins using laser microdissection of genetically marked cell-specific PrL-aBLA/Rspo2 pro-stress and IL/Drd1-pBLA/Ppp1r1b anti-stress microcircuits will allow phenotype, sexual, and circuit level disparity in activation. Another molecular change that will produce sexual distinctions in stress responsivity is Orx2 activity homologously increasing the number of available Orx2 receptors. Aim 2: Up-regulation of BLA Orx2 receptor expression reduces stress responsiveness in females compared with males. We posit that differences between females and males stem from molecular actions that increase Orx2 receptors strategically placed to inhibit pro-stress circuitry, especially in those individuals that exhibit enhanced fear conditioning. Changeable molecular cascades and up-regulation of Orx2 receptors are likely to produce stronger anti-stress microcircuitry activity and reduced stress reactivity.

最近的荟萃分析表明，男性和女性的神经回路受到压力的影响并不相同暴露，因此女性患心理障碍的几率明显更高，而男性则更高自杀率。与应激反应相关的遗传标记，在基底外侧表达杏仁核（BLA）和前额皮质（PFC）可能有助于解释女性和男性的差异。这前边缘 (PrL) PFC 神经支配表达 Rspo2 基因的前部 BLA (aBLA) 中的特定细胞标记，形成促应力电路。还存在连接边缘下 (IL) PFC 的并联抗应激电路携带 Drd1 遗传标记的神经元到表达 Ppp1r1b 的后 BLA (pBLA) 细胞。这两个微电路产生可变的应激响应性，当有利于促应激 PrL-aBLA/Rspo2 活性时，导致过度的应激反应并可能导致情感心理障碍。这些微电路由食欲素/下丘脑分泌素 (Orx) 通过 Orx1 和 Orx2 受体亚型进行调节，专门针对促应激 (PrL-aBLA/Rspo2 Orx1) 和抗应激 (IL/Drd1-pBLA/Ppp1r1b Orx2) 该电路的元件。 BLA Orx1 和 Orx2 受体的激活在功能上也是相反的，并且不同地触发增强或抑制的应激反应。数据表明，之间的相互作用 Orx1 和 Orx2 刺激电路控制应力响应性的输出。女性已升高 Orx2 受体的表达。重点是确定这些激活之间是否达到平衡两个微电路，以及应激反应性的性别差异，是由 Orx2 抗-的密度决定的。应激受体以及存在哪些特定的分子级联。我们建议检查分子 Orx2 受体激活下游出现的系统，通过该系统降低应激反应性，两种稳定的表型：表现出增强的恐惧调节的应激反应个体和个体表现出积极回避压力。目标 1：BLA 和 PFC Orx2 受体将 PLC 修改为 mToR 信号传导。 Orx2 触发的细胞内分子信号通路 PLC 或 mToR 决定了功能结果。使用基因激光显微切割测量 PLC 和 mToR 转录本和蛋白质标记的细胞特异性 PrL-aBLA/Rspo2 促应激和 IL/Drd1-pBLA/Ppp1r1b 抗应激微电路将允许表型、性别和回路水平的激活差异。另一种分子变化将产生应激反应性中的性别差异是 Orx2 活性同源地增加了可用的数量 Orx2 受体。目标 2：BLA Orx2 受体表达的上调可降低应激反应女性与男性相比。我们认为女性和男性之间的差异源于分子增加 Orx2 受体的作用，战略性地抑制促应激回路，尤其是在那些表现出增强的恐惧调节的个体。可变的分子级联和上调 Orx2 受体可能产生更强的抗应激微电路活性并降低应激反应性。