Department of Pharmacology and Physiology, College of Medicine, Drexel University, 245 S. 15th Street, Philadelphia, PA, 19102, USA.
Department of Anesthesiology and Critical Care Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.
Brain Struct Funct. 2019 May;224(4):1429-1446. doi: 10.1007/s00429-019-01837-5. Epub 2019 Feb 14.
Stress-related psychiatric diseases are nearly twice as prevalent in women compared to men. We recently showed in male rats that the resident-intruder model of social stress differentially engages stress-related circuitry that regulates norepinephrine-containing neurons of the locus coeruleus (LC) depending on coping strategy as determined by the latency to assume a defeat posture. Here, we determined whether this social stress had similar effects in female rats. LC afferents were retrogradely labeled with Fluorogold (FG) and rats had one or five daily exposures to an aggressive resident. Sections through the nucleus paragigantocellularis (PGi), a source of enkephalin (ENK) afferents to the LC, and central nucleus of the amygdala (CeA), a source of corticotropin-releasing factor (CRF) afferents to the LC, were processed for immunocytochemical detection of c-fos, a marker of neuronal activity, FG and ENK or CRF. Like male rats, female rats defeated with a relatively short latency (SL) in response to a single resident-intruder exposure and showed significant c-fos activation of LC neurons, PGi-ENK LC afferents, and CeA-CRF-LC afferents. With repeated exposure, some rats exhibited a long latency to defeat (LL). LC neurons and CeA-CRF-LC afferents were activated in SL rats compared to control and LL, whereas PGi-ENK LC afferents were not. Conversely, in LL rats, PGi-ENK LC and CeA-CRF-LC afferents were activated compared to controls but not LC neurons. CRF type 1 receptor (CRF1) and µ-opioid receptor (MOR) expression levels in LC were decreased in LL rats. Finally, electron microscopy showed a relative increase in MOR on the plasma membrane of LL rats and a relative increase in CRF1 on the plasma membrane of SL rats. Together, these results suggest that as is the case for males, social stress engages divergent circuitry to regulate the LC in female rats depending on coping strategy, with a bias towards CRF influence in more subordinate rats and opioid influence in less subordinate rats.
与男性相比，应激相关的精神疾病在女性中几乎高出两倍。我们最近在雄性大鼠中表明，社交应激的常驻入侵者模型根据潜伏期确定的应对策略，不同地参与调节去甲肾上腺素能神经元的应激相关回路，去甲肾上腺素能神经元位于蓝斑核（LC）。在这里，我们确定这种社交应激是否对雌性大鼠有类似的影响。LC 传入纤维用荧光金（FG）逆行标记，大鼠每天接受一次或五次攻击性常驻入侵者的暴露。穿过弓状旁巨细胞核（PGi）和杏仁中央核（CeA）的切片，是 LC 中脑啡肽（ENK）传入纤维和 LC 中促肾上腺皮质激素释放因子（CRF）传入纤维的来源，进行免疫细胞化学检测 c-fos，神经元活性的标志物，FG 和 ENK 或 CRF。与雄性大鼠一样，在单次常驻入侵者暴露后，潜伏期相对较短（SL）的雌性大鼠被击败，并显示出 LC 神经元、PGi-ENK LC 传入纤维和 CeA-CRF-LC 传入纤维的显著 c-fos 激活。经过重复暴露，一些大鼠表现出较长的潜伏期（LL）。与对照和 LL 相比，SL 大鼠的 LC 神经元和 CeA-CRF-LC 传入纤维被激活，但 PGi-ENK LC 传入纤维没有被激活。相反，在 LL 大鼠中，PGi-ENK LC 和 CeA-CRF-LC 传入纤维的激活与对照相比，但 LC 神经元没有被激活。LC 中的 CRF 型 1 受体（CRF1）和μ-阿片受体（MOR）表达水平在 LL 大鼠中降低。最后，电子显微镜显示，LL 大鼠的 MOR 质膜相对增加，SL 大鼠的 CRF1 质膜相对增加。总之，这些结果表明，与雄性大鼠一样，社交应激通过不同的回路来调节雌性大鼠的 LC，这取决于应对策略，在从属程度较高的大鼠中偏向于 CRF 影响，在从属程度较低的大鼠中偏向于阿片影响。
