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.

近期的元素表明，男性和女性的神经环节不受压力的平等影响暴露于暴露，使女性的心理疾病率明显更高，男性较高自杀率。基底外侧表达的与压力反应相关的遗传标记杏仁核（BLA）和前额叶皮层（PFC）可能有助于解释女性和男性的差异。这前BIC（PRL）PFC支配表达RSPO2遗传的前BLA（ABLA）中的特定细胞标记，形成一个支持压力电路。还存在连接输液（IL）PFC的平行抗压力电路携带DRD1遗传标记物的神经元转移到表达PPP1R1B的后BLA（PBLA）细胞。这两个微电路会产生可变的应力响应性，在偏爱pro压力PRL-ABLA/RSPO2活性时，导致夸张的压力反应性，并可能导致情感心理疾病。这些微电路是由Orx1和Orx2受体亚型的Orexins/dypocretins（ORX）调节的特别定位于亲压（PRL-ABLA/RSPO2 ORX1）和抗压力（IL/DRD1-PBLA/PPP1R1B ORX2）该电路的元素。 BLA ORX1和ORX2受体的激活在功能上也相反，并且差异触发了增强或抑制压力反应能力。数据表明相互作用 ORX1-和ORX2刺激的电路控制应力反应性的输出。女性升高了 ORX2受体的表达。重点是确定激活之间的平衡是否两个微电路，以及压力反应性的性差异，受orx2抗的密度约束应力受体以及存在哪些特定分子级联反应。我们建议检查分子出现ORX2受体激活下游的系统，通过这些系统，应降低压力响应性两种稳定的表型：表现出增强恐惧条件的压力反应性个体，个人这种积极避免压力。 AIM 1：BLA和PFC ORX2受体将PLC修改为MTOR信号传导。由ORX2触发的细胞内分子信号通路PLC或MTOR决定了功能结果。使用遗传学的激光微解剖测量PLC和MTOR转录本和蛋白质明显的细胞特异性PRL-ABLA/RSPO2促性压力和IL/DRD1-PBLA/PPP1R1B抗压力微电路将在激活中允许表型，性和电路水平差异。将产生的另一种分子变化压力反应性中的性别差异是ORX2活性同源增加可用的数量 ORX2受体。 AIM 2：BLA ORX2受体表达的上调可降低压力反应性女性与男性相比。我们认为女性和男性之间的差异源于分子策略性地放置ORX2受体以抑制亲应力电路的作用，尤其是在那些情况下表现出增强的恐惧条件的人。可变的分子级联和上调 ORX2受体可能会产生更强的抗压力微电路学活性并降低应激反应性。