Role of prefrontal monoamines in a novel translational test of working memory for rodents

Abstract

[eng] In this thesis I have several stepwise and interrelated hypotheses:

Rodent Self-Ordered Working Memory (rSOWM) paradigm

1) Increasing the number of response options in the novel rSOWM task in rats will increase working memory load and render it more sensitive for detecting cognitive impairments or enhancements a. Dentate gyrus lesions will result in deficits in patern separation (inter-stimulus distance) while damage to CA3 will cause impairments under conditions of increasing stimulus number or delay in the rSOWM task. b. Systemic modafinil administration will enhance rSOWM performance particularly under conditions of increasing stimulus number or delay, mirroring the nootropic effects of modafinil in the human CANTAB SWM task. c. Microinfusion of modafinil directly into the medial prefrontal cortex will augment rSOWM performance, mediated at least in part by enhancement of the dopaminergic system. 2) The novel rSOWM task will measure working memory in mice, with task performance sensitive to memory load and delay a. Medial prefrontal dopamine release fluctuations will track key task events (e.g., stimuli, actions, rewards), and be associated with rSOWM performance at higher WM load. b. Medial prefrontal serotonin release fluctuations will track key task events (e.g., stimuli, actions, rewards), and be elevated by waiting during delays prior to stimulus presentation.

Rodent Delay and Reward magnitude Discounting (rDRD) paradigm

3) The novel rDRD task will quatitatively measure individual differences in delay discounting and reward magnitude sensitivity a. Medial prefrontal dopamine release fluctuations will track key task events (e.g., stimuli, actions, rewards), and will not be associated with waiting during delays prior to reward delivery b. Medial prefrontal serotonin release fluctuations will track key task events (e.g., stimuli, actions, rewards), and be elevated by waiting during delays prior to reward presentation.