Electronic Thesis and Dissertation Repository

Degree

Doctor of Philosophy

Program

Anatomy and Cell Biology

Supervisor

Dr. Raj Rajakuamr

Abstract

In our daily life, we come across situations where we meet unanticipated challenges, we must take certain decisions, pay attention, be flexible and inhibit impulsive actions to achieve goal directed behaviour. During these processes, we unknowingly use sets of interdependent cognitive processes collectively called ‘executive function’. Executive function is mainly regulated by the frontal lobe. Impaired executive function is associated with disorders such as schizophrenia, Alzheimer’s disease, autism and attention deficit hyperactivity disorder (ADHD).

In this thesis, we investigated neurotransmitters and interactions among them regulating executive function. Further, we investigated mechanisms underlying those interactions mediating executive function in rats using an operant conditioning-based set-shifting task, a common and validated test in animals to assess executive function. In our first study, we identified for the first time that systemic injections of dopamine D1 and glutamate N-methyl-D-aspartate (NMDA) receptor antagonists cause impaired set-shifting and increased the occurrence of perseverative errors only after combined administration at doses that failed to affect set-shifting following separate injections. The discovery of this novel synergistic effect of glutamate and dopamine antagonists on set-shifting prompted us to undertake our second study to determine if such synergy occurs within the medial PFC (mPFC)- an important brain area associated with executive function in rodents. Our results confirmed that mPFC is a site where seemingly mild suppression of glutamate and dopamine activities, similar to that has been reported in schizophrenia brains, may act cooperatively to manifest deficits in executive function via increasing perseverative errors. Our third study was to identify molecular mechanisms underlying such synergy. We found that protein kinase A (PKA) and extracellular signal-regulated kinase (ERK1/2) signaling cascades transduce this effect, with ERK1/2 phosphorylation in mPFC neurons as an obligatory step for set-shifting.

The present results have substantially advanced our understanding of the mechanisms underlying executive function. Our results also point to potential novel intracellular targets for therapeutic intervention in cognitive deficits.

Available for download on Thursday, March 01, 2018


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