Department of Psychology, Center for Development and Behavioral Neuroscience, Developmental Exposure Alcohol Research Center, Binghamton University, Binghamton, NY 13902, United States.
Department of Psychology, Center for Development and Behavioral Neuroscience, Developmental Exposure Alcohol Research Center, Binghamton University, Binghamton, NY 13902, United States.
Prog Neuropsychopharmacol Biol Psychiatry. 2020 Mar 2;98:109812. doi: 10.1016/j.pnpbp.2019.109812. Epub 2019 Nov 7.
Adolescence is a developmental period marked by robust neural alterations and heightened vulnerability to stress, a factor that is highly associated with increased risk for emotional processing deficits, such as anxiety. Stress-induced upregulation of the dynorphin/kappa opioid receptor (DYN/KOP) system is thought to, in part, underlie the negative affect associated with stress. The basolateral amygdala (BLA) is a key structure involved in anxiety, and neuromodulatory systems, such as the DYN/KOP system, can 1) regulate BLA neural activity in an age-dependent manner in stress-naïve animals and 2) underlie stress-induced anxiety in adults. However, the role of the DYN/KOP system in modulating stress-induced anxiety in adolescents is unknown. To test this, we examined the impact of an acute, 2-day forced swim stress (FSS - 10 min each day) on adolescent (postnatal day (P) 35) and adult Sprague-Dawley rats (P70), followed by behavioral, molecular and electrophysiological assessment 24 h following FSS. Adolescent males, but not adult males or females of either age, demonstrated social anxiety-like behavioral alterations indexed via significantly reduced social investigation and preference when tested 24 h following FSS. Conversely, adult males exhibited increased social preference. While there were no FSS-induced changes in expression of genes related to the DYN/KOP system in the BLA, these behavioral alterations were associated with alterations in BLA KOP function. Specifically, while GABA transmission in BLA pyramidal neurons from non-stressed adolescent males responded variably (potentiated, suppressed, or was unchanged) to the KOP agonist, U69593, U69593 significantly inhibited BLA GABA transmission in the majority of neurons from stressed adolescent males, consistent with the observed anxiogenic phenotype in stressed adolescent males. This is the first study to demonstrate stress-induced alterations in BLA KOP function that may contribute to stress-induced social anxiety in adolescent males. Importantly, these findings provide evidence for potential KOP-dependent mechanisms that may contribute to pathophysiological interactions with subsequent stress challenges.
青春期是一个发育阶段，以强大的神经改变和对压力的高度脆弱性为特征，这是导致情绪处理缺陷（如焦虑）风险增加的一个重要因素。应激诱导的强啡肽/κ 阿片受体（DYN/KOP）系统的上调被认为部分地导致了与应激相关的负性情绪。外侧杏仁核（BLA）是参与焦虑的关键结构，而神经调节系统，如 DYN/KOP 系统，可以 1）以年龄依赖的方式调节应激-naive 动物的 BLA 神经活动，2）在成年期产生应激诱导的焦虑。然而，DYN/KOP 系统在调节青少年应激诱导的焦虑中的作用尚不清楚。为了检验这一点，我们研究了急性、为期两天的强迫游泳应激（FSS-每天 10 分钟）对青少年（出生后第 35 天）和成年 Sprague-Dawley 大鼠（P70）的影响，然后在 FSS 后 24 小时进行行为、分子和电生理评估。只有青春期雄性大鼠，而不是成年雄性或雌性大鼠，在 FSS 后 24 小时测试时表现出社交焦虑样行为改变，表现为社交探索和偏好明显减少。相反，成年雄性表现出更高的社交偏好。尽管在 BLA 中与 DYN/KOP 系统相关的基因表达没有 FSS 诱导的变化，但这些行为改变与 BLA KOP 功能的改变有关。具体来说，虽然非应激青春期雄性大鼠的 BLA 锥体神经元中的 GABA 传递对 KOP 激动剂 U69593 的反应不同（增强、抑制或不变），但 U69593 显著抑制了应激青春期雄性大鼠中大多数神经元的 BLA GABA 传递，这与应激青春期雄性大鼠中观察到的焦虑表型一致。这是第一项研究表明，BLA KOP 功能的应激诱导改变可能导致青春期雄性大鼠的应激诱导社交焦虑。重要的是，这些发现为潜在的 KOP 依赖性机制提供了证据，这些机制可能与随后的应激挑战中的生理病理相互作用有关。
