Neural and psychological mechanisms of trait impulsivity

冲动的人在推迟满足感方面尤其困难，在收集到足够的信息之前，他们倾向于“草率行事”并过早做出反应。使用一个成熟的测量啮齿动物冲动性的范例(5选择系列反应时间任务，5CSRTT)，我们先前已经表明，成年大鼠的“特征样”冲动性与NAcb壳中D2/3受体的表达和结合减少有关(Besson等人。2010年；Caprioli等人。2015年；Jupp等人。2013)。随后的研究表明，D2/3受体在该区域的可获得性减少可能会导致多巴胺的过度释放，进而增强寻求奖赏的行为。NAcb的核心区域也与冲动有关，但通过不同的机制涉及GABA能神经传递的局部减少(Caprioli等人。2014年)。这个项目的主要目的是研究NAcb的外壳和核心区在冲动表达中的准确贡献。为了做到这一点，我们将使用一系列技术，如快速扫描，循环伏安和化学遗传学，分别研究NAcb核心和外壳中的中脑边缘多巴胺能机制，并交互调节5CSRTT中的抑制控制。快速扫描循环伏安法将被用来检测在大鼠进行5CSRTT任务时，NAcb核心和外壳中多巴胺释放的变化。基于化学遗传的DREADDS干预将被用来操纵NAcb中的神经活动，从而能够推断因果关系。最后，这个项目将使用纵向磁共振成像(MRI)来研究“特质”冲动的起源，以调查大脑发育关键时期NAcb的结构和功能的完整性。这一方法将被一系列体内和体外技术扩大，以分离主要的神经底物和机制，这些共同可能与ADHD和一系列其他冲动性强迫症的脑部疾病的病因和治疗相关。参考文献Sesson，M.，Belin，D.，McNamara，R.，Theobald，D.E.，Castel，A.，Beckett，V.，Crittenden，B.，Newman，A.，Everitt，B.，Robbins，T.&Dley，J.(2010)伏隔核核心和外壳亚区的多巴胺D2/3受体对大鼠冲动的分离控制。神经精神药理学35,560-569。Caprioli，D.，Sawiak，S.，Merlo，E.，Theobald，D.，Spoeder，M.，Jupp，B.，Voon，V.，Carpenter，T.，Everitt，B.，Robbins，T.&Dley，J.(2014)伏隔核核心的氨基丁酸能和神经元结构标记是特质样冲动行为的基础。生物精神病学75,115-123。Caprioli，D.，Jupp，B.，Hong，Y.T.，Sawiak，S.J.，Ferrari，V.，Wharton，L.，Williamson，D.J.，McNabb，C.，Berry，D.，AigBirhio，F.I.，Robbins，T.W.，Fryer，T.D.&Dley，J.W.(2015)口服哌醋甲酯对纹状体冲动和D2/3受体可用性的可解离速率依赖效应。J Neurosci 35,3747-3755Jupp，B.，Caprioli，D.，Saigal，N.，Reverte，I.，Shrestha，S.，Cumming，P.，Everitt，B.，Robbins，T.&Dley，J.(2013)大鼠冲动的多巴胺能和GABA能标记物：腹侧纹状体和前额叶皮质解剖定位的证据。EUJ Neurosci 37,1519-1528。

Impulsive individuals have a particular difficulty in deferring gratification and are inclined to 'jump the gun' and respond prematurely before sufficient information has been gathered. Using a well-established paradigm for measuring impulsivity in rodents (the 5-choice serial reaction time task, 5CSRTT), we have previously shown that 'trait-like' impulsivity in adult rats is associated with reduced D2/3 receptor expression and binding in the NAcb shell (Besson et al. 2010; Caprioli et al. 2015; Jupp et al. 2013). Subsequent work suggests that the diminished availability of D2/3 receptors in this region may lead to excessive dopamine release and in turn augmented reward seeking behaviour. The core region of the NAcb has also been implicated in impulsivity but via different mechanisms involving a localized reduction in GABA-ergic neurotransmission (Caprioli et al. 2014). The main aim of this project is to investigate the precise contributions of the shell and core regions of the NAcb in the expression of impulsivity. To do this we will use a range of techniques such as fast-scan cyclic voltammetry and chemogenetics to examine how mesolimbic dopaminergic mechanisms in the NAcb core and shell separately and interactively regulate inhibitory control in the 5CSRTT. Fast-scan cyclic voltammetry will be used to detect changes in dopamine release in the NAcb core and shell while rats engage on the 5CSRTT task. Chemogenetic-based interventions with DREADDs will be used to manipulate neural activity in the NAcb thereby enabling causal relationships to be inferred. Finally, this project will investigate the origin of 'trait' impulsivity using longitudinal magnetic resonance imaging (MRI) to investigate the structural and functional integrity of the NAcb during critical periods of brain development. This approach will be augmented by a range of in-vivo and ex-vivo techniques to isolate primary neural substrates and mechanisms, which collectively may be relevant for the aetiology and treatment of ADHD and a range of other impulsive-compulsive brain disorders. REFERENCESBesson, M., Belin, D., McNamara, R., Theobald, D.E., Castel, A., Beckett, V., Crittenden, B., Newman, A., Everitt, B., Robbins, T. & Dalley, J. (2010) Dissociable control of impulsivity in rats by dopamine D2/3 receptors in the core and shell subregions of the nucleus accumbens. Neuropsychopharmacology 35, 560-569. Caprioli, D., Sawiak, S., Merlo, E., Theobald, D., Spoelder, M., Jupp, B., Voon, V., Carpenter, T., Everitt, B., Robbins, T. & Dalley, J. (2014) Gamma aminobutyric acidergic and neuronal structural markers in the nucleus accumbens core underlie trait-like impulsive behavior. Biol Psychiatry 75, 115-123. Caprioli, D., Jupp, B., Hong, Y.T., Sawiak, S.J., Ferrari, V., Wharton, L., Williamson, D.J., McNabb, C., Berry, D., Aigbirhio, F.I., Robbins, T.W., Fryer, T.D. & Dalley, J.W. (2015) Dissociable rate-dependent effects of oral methylphenidate on impulsivity and D2/3 receptor availability in the striatum. J Neurosci 35, 3747-3755. Jupp, B., Caprioli, D., Saigal, N., Reverte, I., Shrestha, S., Cumming, P., Everitt, B., Robbins, T. & Dalley, J. (2013) Dopaminergic and GABA-ergic markers of impulsivity in rats: evidence for anatomical localisation in ventral striatum and prefrontal cortex. Eur J Neurosci 37, 1519-1528.