Linking dopaminergic physiology to working memory related neural circuitry

Abstract

Working memory is the ability to hold information "online" over a delay in order to perform a task. This kind of memory is thought to be encoded in the brain by persistent neural activity that outlasts the presentation of a stimulus. Interestingly, patients with schizophrenia, a heritable neurological disorder, perform poorly in working memory tasks that require the retention of a target in space, indicating that persistent neural activity related to spatial locations may be impaired in the disease. At the biophysical level, NMDA receptors and dopamine receptors have been continually implicated in supporting persistent activity during spatial working memory. Perhaps relatedly, drugs that target the dopamine system are regularly used in the treatment of schizophrenia, and drugs that target NMDARs induce schizophrenia-like symptoms in healthy individuals. In this thesis, I seek to further examine the possible connection between NMDA receptors, the dopamine system, and schizophrenia-related working memory deficits. We find that homocysteine, a dopamine breakdown product that is upregulated in the blood of schizophrenia patients, strongly impacts NMDAR currents by reducing channel desensitization and altering peak amplitude. Additionally, we find that the dopamine system itself, which is traditionally studied in areas like striatum and prefrontal cortex, is organized in a behaviorally relevant pattern in the superior colliculus (SC), a brain region that shows persistent activity during spatial working memory tasks. The electrophysiological affects of dopamine on the SC suggest that dopamine dysregulation could have previously unexplored effects on spatial attention, sensorimotor integration, and working memory.