Chronic Stimulation of Alpha-2A-Adrenoceptors With Guanfacine Protects Rodent Prefrontal Cortex Dendritic Spines and Cognition From the Effects of Chronic Stress.
Chronic Stimulation of Alpha-2A-Adrenoceptors With Guanfacine Protects Rodent Prefrontal Cortex Dendritic Spines and Cognition From the Effects of Chronic Stress.
复制标题
DOI：
10.1016/j.ynstr.2015.01.001
复制
发表时间：
2015
影响因子：
5
通讯作者：
Arnsten, Amy F T
中科院分区：
文献类型：
--
作者：
Hains, Avis Brennan;Yabe, Yoko;Arnsten, Amy F T
前额叶皮质(PFC)对行为、认知和情绪提供自上而下的调节，包括空间工作记忆。然而，暴露在急性或慢性压力下，这些PFC能力会受到极大的损害。慢性应激暴露导致大鼠PFC树突和棘突萎缩，这与工作记忆损伤有关。由于类似的PFC灰质丢失似乎也发生在精神疾病中，因此需要更好地了解这些变化背后的机制。急性应激通过激活前馈cAMP-钙-K+通道信号，削弱突触输入，减少PFC神经元放电，从而损害PFC的认知。已有研究表明，慢性应激引起的脊柱损伤与钙蛋白激酶C信号有关，但目前尚不清楚抑制cAMP信号是否同样能防止反复应激引起的脊椎萎缩。目前的研究考察了慢性应激治疗通过刺激α-2A肾上腺素受体抑制cAMP信号是否会保护PFC脊椎和工作记忆表现。之所以选择金刚烷，是因为1)它对PFC脊髓突触后α-2A受体上的cAMP信号有确定的作用，2)它在治疗儿童应激障碍方面的临床应用越来越多。与赋形剂对照组相比，每日使用愈创新可防止慢性束缚应激大鼠前额叶前核II/III层锥体神经元树突棘的丢失。瓜那法辛还保护了工作记忆能力；认知能力与树突密度相关。这些发现表明，慢性使用鸟嘌呤可能通过保护PFC灰质免受应激的有害影响而具有临床实用价值。
The prefrontal cortex (PFC) provides top-down regulation of behavior, cognition, and emotion, including spatial working memory. However, these PFC abilities are greatly impaired by exposure to acute or chronic stress. Chronic stress exposure in rats induces atrophy of PFC dendrites and spines that correlates with working memory impairment. As similar PFC grey matter loss appears to occur in mental illness, the mechanisms underlying these changes need to be better understood. Acute stress exposure impairs PFC cognition by activating feedforward cAMP-calcium- K+ channel signaling, which weakens synaptic inputs and reduces PFC neuronal firing. Spine loss with chronic stress has been shown to involve calcium-protein kinase C signaling, but it is not known if inhibiting cAMP signaling would similarly prevent the atrophy induced by repeated stress. The current study examined whether inhibiting cAMP signaling through alpha-2A-adrenoceptor stimulation with chronic guanfacine treatment would protect PFC spines and working memory performance during chronic stress exposure. Guanfacine was selected due to 1) its established effects on cAMP signaling at post-synaptic alpha-2A receptors on spines in PFC, and 2) its increasing clinical use for the treatment of pediatric stress disorders. Daily guanfacine treatment compared to vehicle control was found to prevent dendritic spine loss in layer II/III pyramidal neurons of prelimbic PFC in rats exposed to chronic restraint stress. Guanfacine also protected working memory performance; cognitive performance correlated with dendritic spine density. These findings suggest that chronic guanfacine use may have clinical utility by protecting PFC gray matter from the detrimental effects of stress.