Neural and psychological mechanisms of trait impulsivity

点击翻译按钮获取中文摘要

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.