Sex Differences in the Neurobiological Significance of Orexin Stress Signaling

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

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.