The neurochemistry underlying higher cognitive functions in the primate fronto-striatal network

Abstract

This thesis advances our understanding of the neurochemistry of higher cognitive functions in 5 different projects. In the first project, the utility of a neurochemical sampling tool is demonstrated through novel in vivo measurements of glutamate, dopamine, acetylcholine and choline simultaneously in multiple brain regions. In the second project, it is shown that different doses of the acetylcholinesterase inhibitor donepezil optimally enhance performance in a visual search task and a set shifting task. In the third project, use of a selective M1 positive allosteric modulator suggests that the M1 muscarinic receptor supports cognitive flexibility but not attention processes. In the fourth project, the alpha-2A adrenoceptor agonist guanfacine is shown to improve reversal learning performance by enhancing learning rates in a reinforcement learning model. In the fifth and final project, the findings in the fourth project are expanded upon through neural recordings in the dorsolateral prefrontal cortex, anterior cingulate cortex and the caudate nucleus. Guanfacine resulted in enhanced outcome encodings throughout the fronto-striatal network and enhanced reward prediction error encoding in the anterior cingulate cortex and the caudate, but not the dorsolateral prefrontal cortex, resulting in faster behavioral adjustments after unexpected errors. Overall, this thesis identified behavioral, neural, and neurochemical correlates of flexible cognitive behaviors in primates supported by the fronto-striatal network.