Methamphetamine Effects on Prefrontal Cortical PV+ Interneurons and Resulting Cognitive Deficits

项目摘要 神经精神障碍是一个非常严重的医学和社会问题，有许多不同的根源， 然而，在这些疾病中发现的一个常见和普遍的缺陷是额叶下垂。新兴理论假设 额叶下部[兴奋性(E)和抑制性(I)突触传递的比率变化]是基础 精神分裂症、焦虑、成瘾、自闭症谱系障碍和抑郁。 甲基苯丙胺(冰毒)成瘾者经常出现额叶下垂和工作记忆缺陷 (Wm)、注意力和冲动。同样，在啮齿类动物中，重复给予精神刺激剂或自我- 给药会导致额叶下垂、WM缺陷、精神病样行为、对外部环境的兴趣下降 刺激和周围环境，以及社会功能下降，这表明心理刺激药物的使用 代表了一种强有力的、表面上有效的模型，用于研究构成基本大脑机制的 冰毒成瘾中的额叶下垂和认知功能障碍。 拟议研究的总体目标是确定甲基磺酸对大脑皮层活动的影响。 小白蛋白阳性快速放电中间神经元(PV+FSIS)及由此引起的E-I比值的变化。 中心假设--以强有力的初步数据和文献为依据--是冰毒治疗能引起 前额叶皮质GABA能突触传递增加所致的认知障碍 PV+FSIS。这项提议的基本原理是，这些实验将产生与 了解冰毒和Will诱发前额叶低的细胞和突触机制 为控制前额叶皮质E-I平衡的基本机制提供新的见解。我们将测试 通过追求以下具体目标，中心假说：目标1将确定PV+FSIS在冰毒中的作用。 诱导性认知缺陷。AIM 2将确定是否需要PFC PV+FSIS中的D1R信令来满足以下要求 诱导增强GABA能传递。目标3将确定PFC中的D1R信号 PV+FSIS是冰毒SA诱导的认知障碍和冰毒恢复所必需的。 这项拟议的研究意义重大，因为它将填补与以下方面有关的知识的根本空白 冰毒成瘾前额叶低的机制及精神刺激剂在活动中的作用 皮质PV+FSIS。此外，从拟议的实验中获得的知识将有助于开发 有效的治疗方法可以改善药物相关的认知障碍，并可以为基础研究提供新的见解 其他神经精神疾病中额叶下移的潜在机制。

Project Summary Neuropsychiatric disorders are a very serious medical and societal problem with many different origins, however, a common and prevalent deficit found in these disorders is hypofrontality. Emerging theories posit that hypofrontality [alterations in the ratio of excitatory (E) and inhibitory (I) synaptic transmission] underlie schizophrenia, anxiety, addiction, autism spectrum disorders and depression. Methamphetamine (METH) addicts frequently develop hypofrontality and deficits in working memory (WM), attention, and impulsivity. Similarly, in rodents, repeated psychostimulant administration or self- administration elicits hypofrontality, WM deficits, psychosis-like behaviors, decreased interest in external stimuli and surroundings, and decreased social functioning, suggesting that psychostimulant administration in rodents represents a strong, face-valid model for studying the basic brain mechanisms that underlie hypofrontality and cognitive disabilities in METH addiction. The overall objective of the proposed studies is to identify the effects of METH-SA on the activity of cortical parvalbumin positive fast spiking interneurons (PV+FSIs) and the resulting changes in E-I ratio. The central hypothesis- informed by strong preliminary data and literature- is that METH treatment elicits cognitive deficits due to an increase in GABAergic synaptic transmission in the PFC via D1R activation of PV+FSIs. The proposal’s rationale is that the experiments will yield fundamental knowledge pertaining to the understanding of the cellular and synaptic mechanisms underlying hypofrontality induced by METH and will provide new insights into the basic mechanisms governing E-I balance in the prefrontal cortex. We will test the central hypothesis by pursuing the following specific aims: Aim 1 will determine the role of PV+FSIs in METH- induced cognitive deficits. Aim 2 will determine whether D1R signaling in PFC PV+FSIs is required for METH- induced enhancements of GABAergic transmission. Aim 3 will determine whether D1R signaling in PFC PV+FSIs is required for METH SA-induced cognitive deficits and METH reinstatement. The proposed research is significant because it will fill a fundamental gap in knowledge pertaining to the mechanisms underlying hypofrontality in METH-addiction and the effects of the psychostimulant in the activity of cortical PV+FSIs. Furthermore, the knowledge obtained from the proposed experiments will help to develop effective treatments to ameliorate drug-related cognitive deficits and can provide new insights into the basic mechanisms underlying hypofrontality in other neuropsychiatric conditions.