Beaudin Stephane A, Strupp Barbara J, Uribe Walter, Ysais Lauren, Strawderman Myla, Smith Donald R
Department of Microbiology and Environmental Toxicology, University of California, Santa Cruz, CA 95064, USA.
Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA; Department of Psychology, Cornell University, Ithaca, NY 14853, USA.
Neurotoxicol Teratol. 2017 May;61:17-28. doi: 10.1016/j.ntt.2017.03.005. Epub 2017 Mar 28.
Recent studies from our lab have demonstrated that postnatal manganese (Mn) exposure in a rodent model can cause lasting impairments in fine motor control and attention, and that oral methylphenidate (MPH) treatment can effectively treat the dysfunction in fine motor control. However, it is unknown whether MPH treatment can alleviate the impairments in attention produced by Mn exposure. Here we used a rodent model of postnatal Mn exposure to determine whether (1) oral MPH alleviates attention and impulse control deficits caused by postnatal Mn exposure, using attention tasks that are variants of the 5-choice serial reaction time task, and (2) whether these treatments affected neuronal dendritic spine density in the medial prefrontal cortex (mPFC) and dorsal striatum. Male Long-Evans rats were exposed orally to 0 or 50Mn/kg/d throughout life starting on PND 1, and tested as young adults (PND 107-115) on an attention task that specifically tapped selective attention and impulse control. Animals were treated with oral MPH (2.5mg/kg/d) throughout testing on the attention task. Our findings show that lifelong postnatal Mn exposure impaired impulse control and selective attention in young adulthood, and that a therapeutically relevant oral MPH regimen alleviated the Mn-induced dysfunction in impulse control, but not selective attention, and actually impaired focused attention in the Mn group. In addition, the effect of MPH was qualitatively different for the Mn-exposed versus control animals across a range of behavioral measures of inhibitory control and attention, as well as dendritic spine density in the mPFC, suggesting that postnatal Mn exposure alters catecholaminergic systems modulating these behaviors. Collectively these findings suggest that MPH may hold promise for treating the behavioral dysfunction caused by developmental Mn exposure, although further research is needed with multiple MPH doses to determine whether a dose can be identified that ameliorates the dysfunction in both impulse control and selective attention, without impairing focused attention.
我们实验室最近的研究表明,在啮齿动物模型中,出生后暴露于锰(Mn)会导致精细运动控制和注意力方面的持久损伤,并且口服哌甲酯(MPH)治疗可以有效治疗精细运动控制功能障碍。然而,尚不清楚MPH治疗是否能减轻锰暴露引起的注意力损伤。在这里,我们使用出生后锰暴露的啮齿动物模型来确定:(1)口服MPH是否能减轻出生后锰暴露引起的注意力和冲动控制缺陷,使用的注意力任务是5选串行反应时任务的变体;(2)这些治疗是否会影响内侧前额叶皮质(mPFC)和背侧纹状体中的神经元树突棘密度。雄性Long-Evans大鼠从出生后第1天开始终生口服0或50mg/kg/d的锰,并在年轻成年期(出生后第107 - 115天)进行一项专门测试选择性注意力和冲动控制的注意力任务。在整个注意力任务测试过程中,动物接受口服MPH(2.5mg/kg/d)治疗。我们的研究结果表明,终生出生后锰暴露会损害年轻成年期的冲动控制和选择性注意力,并且与治疗相关的口服MPH方案减轻了锰诱导的冲动控制功能障碍,但没有减轻选择性注意力,实际上还损害了锰组中的集中注意力。此外,在一系列抑制控制和注意力的行为测量以及mPFC中的树突棘密度方面,MPH对锰暴露动物和对照动物的影响在性质上有所不同,这表明出生后锰暴露改变了调节这些行为的儿茶酚胺能系统。总体而言,这些发现表明MPH可能有望治疗发育性锰暴露引起的行为功能障碍,尽管需要进一步研究多种MPH剂量,以确定是否能找到一种剂量既能改善冲动控制和选择性注意力功能障碍,又不会损害集中注意力。