To identify neural pathways implicated in different forms of attention in rodents and how these may be modulated by the cholinergic (and eventually monoaminergic and glutamatergic) chemical neurotransmitter systems. We have devised two new attentional tasks using computer controlled stimuli and touch-sensitive screens for both rats and mice that measure spatial and non-spatial selective attention and characterised effects of systemically administered cholinergic (nicotinic and muscarinic) agents. To define neural pathways responsible for these effects, central microinfusions of these drugs would first be made into such regions as the medial prefrontal cortex, striatum and hippocampus. A key part of the project is next to develop more refined methods of investigating the pathways in these structures, involving 'designed' receptors that are ligand-dependent (DREADDs). The DREADDs are modified muscarinic receptors that have lost their affinity for acetylcholine while displaying a high affinity for clozapine-N-oxide (CNO). CNO is normally an inert agent but the DREADDS are activated by its administration via the systemic route and can be used to 'turn on' or 'off' any defined neural pathway. The DREADDs can be expressed precisely in the cells by using virally mediated gene transfer. We intend to use this method to activate (and deactivate) the cholinergic pathway from the basal forebrain to the cortex and initially compare effects on the two attentional tasks we have developed for the touch-sensitive screen that we have shown are sensitive to cholinergic pharmacological treatments. PhD project extensions would implement other cognitive tasks or focus on alternative chemical neurotransmitter systems.
- Robbins, T.W. (2002) The 5-choice serial reaction time task: behavioural pharmacology and functional neurochemistry. Psychopharmacology, 163, 362-380.
- Dalley, J.W., Theobald, D.E.H., Bouger, P., Chudasama, Y., Cardinal, R.N. & Robbins, T.W. (2004) Cortical cholinergic function and deficits in visual attentional performance in rats following 192 IgG-saporin-induced lesions of the medial prefrontal cortex. Cerebral Cortex, 14, 922-932
- Romberg, C., Mattson, M.P., Mughal, M.R., Bussey, T.J. & Saksida, L.M. Impaired attention in the 3xTgAD mouse model of Alzheimer′s disease: rescue by donepezil (Aricept). J. Neurosci. 31, 3500–3507 (2011).