Pathway specific dopaminergic regulation of excitatory t

前额叶神经元在没有外部刺激的情况下持续的神经活动是大脑工作记忆系统的标志。这一特性被认为源于锥体神经元之间的相互兴奋，从而产生局部反射神经元活动。体内这种与记忆相关的激活的失败或缺陷被认为是I精神分裂症认知障碍的细胞基础。已经确定，这一过程受到多巴胺、5-羟色胺、GABA和谷氨酸反应的特定受体I的不同影响。因此，在项目3中，我们采用L的方法，即单细胞和多个全细胞记录突触刺激、药物干预和钙成像的方法来研究这些调制影响的突触和信号基础，重点是 多巴胺系统。具体目标1旨在研究D1和D2受体对第3层和第5层已识别神经元之间兴奋性传递的差异调制影响，放大不同元素皮质微电路(ECM)选择性的初步证据。特定目的2对突触增强进行了类似的实验，突触增强是一种短期突触可塑性，在特定的ECM中招募神经元团，类似于体内的持续活动。具体目标3的目的是检查d1和d2受体效应是否通过cAMP-PKA途径或PLC-IP3-PKC途径，通过选择性药物抑制特定ECM中的PKA和PKC来介导，如特定目的1和转基因系统中所描述的那样。因此，体外方法在提供通过体内方法难以或不可能获得的特定细胞类型、亚细胞定位和时间分辨信息方面的优势将补充其他子项目的发现，并代表着对多巴胺参与神经功能和潜在神经病理的新的和具有挑战性的分析水平。

Persistent neural activity in the absence of external stimuliin prefrontal neurons is the hallmark of the brain's working memory systems. This property is thought to arise from mutual excitation between and among pyramidal neurons to generate local reverberatory neuronal activity. The failure or deficiency of this Imemory-related activation in vivo is hypothesized to be the cellular basis of cognitive impairment in Ischizophrenia. It has been determined that this process is subject to different influences by specific receptors I responding to dopamine, serotonin, GABA and glutamate. Accordingly, in Project 3, we employ the methods l of single and multiple whole cell recording with synaptic stimulation, pharmacological intervention, and calcium imaging to examine the synaptic and signaling basis of these modulatory influences, focusing on the dopamine system. Specific Aim 1 is directed at examining the differential modulatory influences of D1 and D2 receptors on excitatory transmission between identified neurons in layers 3 and 5, amplifying preliminary evidence of selectivity in different elemental cortical microcircuits (ECMs). Specific Aim 2 carries out similar experiments on synaptic augmentation, a form of short-term synaptic plasticity which recruits neuronal ensembles in specific ECMs and resembles persistent activity in vivo. The objective of Specific Aim 3 is to examine if D1 and D2 receptor effects are mediated by the cAMP-PKA pathway or the PLC-IP3-PKC pathways by selective pharmacological inhibition of PKA and PKC in specific ECMs, as described in Specific Aim 1 and in genetically altered systems as they become available. The advantages of in vitro approaches in providingcell type specific, subcellularly localized, and temporally resolved information which is difficult or impossible to obtain by in vivo methods will therefore complement the findings in other subprojects as well as represent a new and challenging level of analysis of dopamine's involvement in neural function and potential neuropathology.