Program in Neuroscience, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
Center for Neuroscience and Regenerative Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
BMC Neurosci. 2021 Jan 28;22(1):5. doi: 10.1186/s12868-020-00607-y.
The Period Circadian Regulator 2 (Per2) gene is important for the modulation of circadian rhythms that influence biological processes. Circadian control of the hypothalamus-pituitary-adrenal (HPA) axis is critical for regulation of hormones involved in the stress response. Dysregulation of the HPA axis is associated with neuropsychiatric disorders. Therefore, it is important to understand how disruption of the circadian rhythm alters the HPA axis. One way to address this question is to delete a gene involved in regulating a central circadian gene such as Per2 in an animal model and to determine how this deletion may affect the HPA axis and behaviors that are altered when the HPA axis is dysregulated. To study this, corticosterone (CORT) levels were measured through the transition from light (inactive phase) to dark (active phase). Additionally, CORT levels as well as pituitary and adrenal mRNA expression were measured following a mild restraint stress. Mice were tested for depressive-like behaviors (forced swim test (FST)), acoustic startle response (ASR), and pre-pulse inhibition (PPI).
The present results showed that Per2 knockout impacted CORT levels, mRNA expression, depressive-like behaviors, ASR and PPI. Unlike wild-type (WT) mice, Per2 knockout (Per2) mice showed no diurnal rise in CORT levels at the onset of the dark cycle. Per2-/- mice had enhanced CORT levels and adrenal melanocortin receptor 2 (Mc2R) mRNA expression following restraint. There were no changes in expression of any other pituitary or adrenal gene. In the FST, Per2-/- mice spent more time floating (less time struggling) than WT mice, suggesting increased depressive-like behaviors. Per2-/- mice had deficits in ASR and PPI startle responses compared to WT mice.
In summary, these findings showed that disruption of the circadian system via Per2 gene deletion dysregulated the HPA stress axis and is subsequently correlated with increased depressive-like behaviors and deficits in startle response.
周期节律调节因子 2（Per2）基因对于调节影响生物过程的昼夜节律非常重要。下丘脑-垂体-肾上腺（HPA）轴的昼夜节律控制对于调节应激反应中涉及的激素至关重要。HPA 轴的失调与神经精神疾病有关。因此，了解昼夜节律的破坏如何改变 HPA 轴非常重要。解决这个问题的一种方法是在动物模型中删除参与调节中央生物钟基因（如 Per2）的基因，并确定这种删除如何影响 HPA 轴以及当 HPA 轴失调时会改变哪些行为。为了研究这一点，通过从光照（不活动期）到黑暗（活动期）的转变来测量皮质酮（CORT）水平。此外，还测量了轻度束缚应激后 CORT 水平以及垂体和肾上腺 mRNA 的表达。通过强迫游泳试验（FST）、声发射反应（ASR）和前脉冲抑制（PPI）测试小鼠的抑郁样行为。
本研究结果表明，Per2 基因敲除影响 CORT 水平、mRNA 表达、抑郁样行为、ASR 和 PPI。与野生型（WT）小鼠不同，Per2 基因敲除（Per2）小鼠在暗周期开始时 CORT 水平没有昼夜上升。Per2-/- 小鼠在束缚后 CORT 水平和肾上腺黑素皮质素受体 2（Mc2R）mRNA 表达增强。其他垂体或肾上腺基因的表达没有变化。在 FST 中，Per2-/- 小鼠比 WT 小鼠漂浮（挣扎时间更少）的时间更多，表明抑郁样行为增加。与 WT 小鼠相比，Per2-/- 小鼠的 ASR 和 PPI 起始反应存在缺陷。
总之，这些发现表明，通过 Per2 基因敲除破坏昼夜节律系统会使 HPA 应激轴失调，随后与抑郁样行为增加和起始反应缺陷相关。
