Sex Differences in the Neurobiological Significance of Orexin Stress Signaling

最近的元分析表明，男性和女性的神经回路受到压力的影响并不相同 暴露，因此女性心理障碍的发生率明显更高，男性更高， 自杀率。与应激反应相关的遗传标记，在基底外侧核表达 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。的 前边缘（PrL）PFC支配前BLA（aBLA）中表达Rspo 2基因的特定细胞 标记，形成一个前压力电路。还存在连接边缘下（IL）PFC的并联抗应力电路 携带Drd 1遗传标记的神经元，到表达Ppp 1 r1 b的后BLA（pBLA）细胞。这两 微电路产生可变的应激反应，当有利于促应激PrL-aBLA/Rspo 2活性时， 导致过度的压力反应并潜在地导致情感性心理障碍。这些 微电路由食欲素/下丘脑泌素（Orx）通过Orx 1和Orx 2受体亚型调节， 特异性定位于促应激（PrL-aBLA/Rspo 2 Orx 1）和抗应激（IL/Drd 1-pBLA/Ppp 1 r1 b Orx 2） 这些电路的组成部分。BLA Orx 1和Orx 2受体的激活也在功能上相反， 差异触发增强或抑制的应激反应。数据表明， Orx 1和Orx 2刺激电路控制应力响应的输出。女性的体重 Orx 2受体的表达。重点是确定是否激活这些之间的平衡 两个微电路，和压力反应的性别差异，是由Orx 2抗- 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 出现在Orx 2受体激活下游的系统，通过该系统降低了应激反应， 两种稳定的表型：表现出增强的恐惧条件反射的应激反应个体，以及 表现出主动回避压力的人目的1：BLA和PFC Orx 2受体介导PLC向mToR信号转导。 由Orx 2触发的细胞内分子信号传导途径PLC或mToR决定了细胞的功能性。 结果。使用激光显微切割技术测量PLC和mToR转录本和蛋白质， 标记的细胞特异性PrL-aBLA/Rspo 2促应激和IL/Drd 1-pBLA/Ppp 1 r1 b抗应激微电路将 允许表型、性别和回路水平激活的差异。另一种分子变化会产生 应激反应的性别差异是Orx 2活性同源地增加了可用的 Orx 2受体。目的2：BLA Orx 2受体表达的上调降低了应激反应， 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Orx 2受体的作用，这些受体被战略性地置于抑制促应激回路的位置，特别是在那些 表现出增强的恐惧条件反射的个体。可变的分子级联和上调 Orx 2受体可能产生更强的抗应激微电路活性和降低的应激反应性。

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.