Neural and psychological mechanisms of trait impulsivity

冲动的人在延迟满足方面有特别的困难，他们倾向于“过早行动”，在收集到足够的信息之前过早地做出反应。使用一种完善的啮齿动物冲动性测量范式（5选择系列反应时间任务，5CSRTT），我们之前已经表明，成年大鼠的“性状样”冲动性与ncab壳中D2/3受体表达和结合减少有关（Besson等人，2010；Caprioli等人，2015；Jupp等人，2013）。随后的研究表明，该区域D2/3受体可用性的降低可能导致多巴胺释放过多，进而增强了寻求奖励的行为。NAcb的核心区域也与冲动性有关，但通过不同的机制，包括局部减少gaba能神经传递（Caprioli等，2014）。本项目的主要目的是研究nnacb的壳区和核心区在冲动性表达中的精确贡献。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法和化学遗传学来研究nnacb核和壳中的中边缘多巴胺能机制分别如何相互调节5CSRTT的抑制控制。快速扫描循环伏安法将用于检测大鼠参与5CSRTT任务时NAcb核和壳中多巴胺释放的变化。以化学遗传学为基础的干预将用于操纵NAcb中的神经活动，从而推断出因果关系。最后，本项目将利用纵向磁共振成像（MRI）研究大脑发育关键时期nnacb的结构和功能完整性，研究“特质”冲动的起源。这种方法将通过一系列体内和离体技术来增强，以分离主要的神经基质和机制，这些技术可能与多动症和一系列其他冲动强迫性脑部疾病的病因和治疗有关。参考资料besson， M., Belin， D., McNamara， R., Theobald, d.e., Castel， A., Beckett， V., Crittenden， B., Newman， A., Everitt， B., Robbins， T. & Dalley， J.（2010）伏隔核核心和壳亚区多巴胺D2/3受体对大鼠冲动的可解离控制。神经精神药理学35,560-569。Caprioli， D., Sawiak， S., Merlo， E., Theobald， D., Spoelder， M., Jupp， B., Voon， V., Carpenter， T., Everitt， B., Robbins， T.和Dalley， J.（2014）伏隔核核心的γ氨基丁酸能和神经元结构标记是特征样冲动行为的基础。精神病学杂志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.和Dalley， J.W.（2015）口服哌醋甲酯对冲动性和D2/3受体可用性的可解离速率依赖效应。中华神经科学杂志，35(3):347 - 355。Jupp， B., Caprioli， D., Saigal， N., Reverte， I., Shrestha， S., Cumming， P., Everitt， B., Robbins， T. & Dalley， J.（2013）大鼠冲动性的多巴胺能和gaba能标记物：腹侧纹状体和前额皮质解剖定位的证据。中华神经科学杂志，37(2):519- 528。

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.